Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 28
Filter
Add more filters










Publication year range
1.
Physiol Rep ; 12(12): e16094, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38924381

ABSTRACT

The renin-angiotensin system (RAS)-a classical blood pressure regulator-largely contributes to healthy organ development and function. Besides, RAS activation promotes age-related changes and age-associated diseases, which are attenuated/abolished by RAS-blockade in several mammalian species. RAS-blockers also increase rodent lifespan. In previous work, we discussed how RAS-blockade downregulates mTOR and growth hormone/IGF-1 signaling, and stimulates AMPK activity (together with klotho, sirtuin, and vitamin D-receptor upregulation), and proposed that at least some of RAS-blockade's aging benefits are mediated through regulation of these intermediaries and their signaling to mitochondria. Here, we included RAS-blockade's impact on other aging regulatory pathways, that is, TGF-ß, NF-kB, PI3K, MAPK, PKC, Notch, and Wnt, all of which affect mitochondria. No direct evidence is available on RAS/RAS-blockade-aging regulatory pathway-mitochondria interactions. However, existing results allow to conjecture that RAS-blockers neutralize mitochondrial dysfunction by acting on the discussed pathways. The reviewed evidence led us to propose that the foundation is laid for conducting clinical trials aimed at testing whether angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB)-even at subclinical doses-offer the possibility to live longer and in better health. As ACEi and ARB are low cost and well-tolerated anti-hypertension therapies in use for over 35 years, investigating their administration to attenuate/prevent aging effects seems simple to implement.


Subject(s)
Aging , Angiotensin-Converting Enzyme Inhibitors , Renin-Angiotensin System , Humans , Renin-Angiotensin System/drug effects , Aging/drug effects , Aging/metabolism , Aging/physiology , Animals , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Signal Transduction/drug effects , Mitochondria/metabolism , Mitochondria/drug effects , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use
2.
Am J Physiol Heart Circ Physiol ; 319(4): H744-H752, 2020 10 01.
Article in English | MEDLINE | ID: mdl-32795193

ABSTRACT

Patients presenting with classical cardiovascular risk factors within acceptable or average value ranges often develop cardiovascular disease, suggesting that other risk factors need to be considered. Considering that endothelial progenitor cells (EPCs) contribute to endothelial repair, we investigated whether EPCs might be such a factor. We compared the ability of peripheral blood EPCs to attach to extracellular matrix proteins and to grow and function in culture, between controlled hypertensive patients exhibiting a Framingham score (FS) of <10% while showing severe vascular impairment (intima-media thickness/diameter, carotid-femoral pulse wave velocity, brachial artery flow-mediated dilation, carotid and femoral atherosclerotic plaque presence; vulnerable group, N = 30) and those with an FS of ≥10% and scarce vascular changes (protected group, N = 30). When compared with vulnerable patients, protected patients had significantly higher early and late-EPC and early and late-tunneling nanotube (TNT) numbers. Significant negative associations were found between vascular damage severity and early EPC, late-EPC, or late-TNT numbers, whereas EPC or TNT numbers and patient characteristics or cardiovascular risk factors were not associated. Except for protected patients, in all controlled hypertensive patients, early and late-EPC and early and late-TNT counts were significantly lower than those in the normotensive subjects studied (N = 30). We found that the disparity in vascular status between patients presenting with both an FS of ≥10% and scarce vascular changes and those presenting with both an FS of <10% and severe vascular impairment is related to differences in peripheral blood EPC and TNT numbers. These observations support the role of EPCs as contributors to vascular injury repair and suggest that EPC numbers may be a potential cardiovascular risk factor to be included in the FS calculation.NEW & NOTEWORTHY As individuals who present with risk factors within acceptable or average value ranges often develop cardiovascular (CV) disease, it has been suggested that other CV risk factors need to be considered in addition to those that are commonly combined in the Framingham score (FS) to estimate the risk of general CV disease. We investigated whether peripheral endothelial progenitor cells (EPCs) and tunneling nanotubes (TNTs) deserve to be considered. Here we report that EPCs and TNTs are significantly lower in controlled hypertensive patients versus normotensive subjects and that the disparity in vascular status between patients presenting with an FS of ≥10% with scarce vascular changes and those presenting with an FS of <10% with severe vascular impairment is related to differences in EPC and TNT numbers. These data point to EPC and TNT numbers as potential CV risk factors to be included in the FS calculation.


Subject(s)
Antihypertensive Agents/therapeutic use , Blood Pressure/drug effects , Cell Proliferation , Endothelial Progenitor Cells/pathology , Endothelium, Vascular/pathology , Hypertension/drug therapy , Regeneration , Adult , Aged , Cells, Cultured , Endothelial Progenitor Cells/metabolism , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Female , Humans , Hypertension/metabolism , Hypertension/pathology , Hypertension/physiopathology , Male , Middle Aged , Young Adult
3.
Am J Physiol Heart Circ Physiol ; 309(1): H15-44, 2015 Jul 01.
Article in English | MEDLINE | ID: mdl-25934099

ABSTRACT

Caloric restriction (CR), renin angiotensin system blockade (RAS-bl), and rapamycin-mediated mechanistic target of rapamycin (mTOR) inhibition increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated with their physiological benefits. mTOR inhibition and enhanced sirtuin and KLOTHO signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference. Sirtuins by deacetylating histone and transcription-related proteins modulate signaling and survival pathways and mitochondrial functioning. CR regulates several mammalian sirtuins favoring their role in aging regulation. KLOTHO/fibroblast growth factor 23 (FGF23) contribute to control Ca(2+), phosphate, and vitamin D metabolism, and their dysregulation may participate in age-related disease. Here we review how mTOR inhibition extends lifespan, how KLOTHO functions as an aging suppressor, how sirtuins mediate longevity, how vitamin D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR and upregulates KLOTHO, sirtuin, and vitamin D receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, KLOTHO, and sirtuin expression and vitamin D signaling, paralleling CR actions in age retardation. Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease.


Subject(s)
Aging/metabolism , Angiotensin II/metabolism , Caloric Restriction , Longevity , Mitochondria/metabolism , Renin-Angiotensin System , TOR Serine-Threonine Kinases/antagonists & inhibitors , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/metabolism , Glucuronidase/metabolism , Humans , Klotho Proteins , Mechanistic Target of Rapamycin Complex 1 , Multiprotein Complexes/metabolism , Receptors, Calcitriol/metabolism , Signal Transduction , Sirtuins/metabolism , TOR Serine-Threonine Kinases/metabolism , Vitamin D/metabolism
4.
Am J Physiol Heart Circ Physiol ; 307(2): H207-15, 2014 Jul 15.
Article in English | MEDLINE | ID: mdl-24858852

ABSTRACT

Early endothelial progenitor cells (early EPC) and late EPC are involved in endothelial repair and can rescue damaged endothelial cells by transferring organelles through tunneling nanotubes (TNT). In rodents, EPC mobilization from the bone marrow depends on sympathetic nervous system activity. Indirect evidence suggests a relation between autonomic derangements and human EPC mobilization. We aimed at testing whether hypertension-related autonomic imbalances are associated with EPC impairment. Thirty controlled-essential hypertensive patients [systolic blood pressure/diastolic blood pressure = 130(120-137)/85(61-88) mmHg; 81.8% male] and 20 healthy normotensive subjects [114(107-119)/75(64-79) mmHg; 80% male] were studied. Mononuclear cells were cultured on fibronectin- and collagen-coated dishes for early EPC and late EPC, respectively. Low (LF)- and high (HF)-frequency components of short-term heart rate variability were analyzed during a 5-min rest, an expiration/inspiration maneuver, and a Stroop color-word test. Modulations of cardiac sympathetic and parasympathetic activities were evaluated by LF/HF (%) and HF power (ms(2)), respectively. In controlled-hypertensive patients, the numbers of early EPC, early EPC that emitted TNT, late EPC, and late EPC that emitted TNT were 41, 77, 50, and 88% lower than in normotensive subjects (P < 0.008), respectively. In controlled-hypertensive patients, late EPC number was positively associated with cardiac parasympathetic reserve during the expiration/inspiration maneuver (rho = 0.45, P = 0.031) and early EPC with brachial flow-mediated dilation (rho = 0.655; P = 0.049); also, late TNT number was inversely related to cardiac sympathetic response during the stress test (rho = -0.426, P = 0.045). EPC exposure to epinephrine or norepinephrine showed negative dose-response relationships on cell adhesion to fibronectin and collagen; both catecholamines stimulated early EPC growth, but epinephrine inhibited late EPC growth. In controlled-hypertensive patients, sympathetic overactivity/parasympathetic underactivity were negatively associated with EPC, suggesting that reducing sympathetic/increasing parasympathetic activation might favor endothelial repair.


Subject(s)
Antihypertensive Agents/therapeutic use , Blood Pressure/drug effects , Endothelial Cells , Hypertension/drug therapy , Nanotubes , Stem Cells , Sympathetic Nervous System/physiopathology , Adult , Aged , Cell Adhesion , Cell Communication , Cell Proliferation , Cells, Cultured , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelial Cells/pathology , Epinephrine/pharmacology , Female , Heart Rate , Humans , Hypertension/diagnosis , Hypertension/metabolism , Hypertension/pathology , Hypertension/physiopathology , Male , Middle Aged , Norepinephrine/pharmacology , Parasympathetic Nervous System/physiopathology , Stem Cells/drug effects , Stem Cells/metabolism , Stem Cells/pathology , Time Factors , Treatment Outcome , Vasodilation , Young Adult
5.
J Renin Angiotensin Aldosterone Syst ; 15(4): 498-504, 2014 Dec.
Article in English | MEDLINE | ID: mdl-24833624

ABSTRACT

HYPOTHESIS/INTRODUCTION: The relationship between salt intake, blood pressure and RAAS activation is still controversial, being that both high- and low-salt intakes are associated with cardiovascular events in a J-shaped curve pattern. We hypothesized that different patterns of RAAS response to dietary salt intake among hypertensives could be identified, while vascular damage would be related to high-salt intake plus absence of expected RAAS inhibition. OBJECTIVE: We aim to assess the relationship between sodium intake, RAAS and vascular stiffness in hypertension. MATERIALS AND METHODS: We screened 681 hypertensive patients for urinary/plasma electrolytes, renin, aldosterone and pulse wave velocity (PWV) under their usual salt intake level. RESULTS: After applying exclusion criteria, an inverse relation between urinary sodium and RAAS was observed in the 300 remaining subjects. Additionally, four types of response were identified: 1) Low (L) sodium (S)-Low RAAS, 2) LS-High (H) SRAAS, 3) HS-Low RAAS, 4) HS-High RAAS. We found no differences in age/BP among groups, but type 4 response individuals included more females and a higher pulse wave velocity. CONCLUSIONS: We showed a) an inverse salt-RAAS relation, b) an association between HS plus high RAAS with increased PWV that could identify a higher-risk hypertensive condition.


Subject(s)
Hypertension/physiopathology , Renin-Angiotensin System/drug effects , Sodium Chloride, Dietary/adverse effects , Vascular Stiffness/drug effects , Aldosterone/blood , Female , Humans , Hypertension/blood , Hypertension/urine , Male , Middle Aged , Renin/blood , Sodium/urine
6.
Am J Hypertens ; 25(5): 620-4, 2012 May.
Article in English | MEDLINE | ID: mdl-22357414

ABSTRACT

BACKGROUND: Although the impairment of parasympathetic cardiac control was described in hypertensives submitted to a high salt diet, the impact of this autonomic abnormality on metabolic and inflammation markers in patients with mild hypertension has not been explored. METHODS: Four hundred and ninety mild essential hypertensive patients (144 ± 9/94 ± 9 mm Hg, 49.5 ± 13.9 years, 67.9 % male) were studied. Dietary sodium intake was estimated by measuring 24-h urinary sodium excretion (UNa), and the patients were classified according to UNa levels as follows: low (<50 mEq/l), medium (50-99 mEq/l), and high UNa (≥100 mEq/l). Parasympathetic tone was evaluated by assessing heart rate recovery (HRR) after an exercise stress test. HRR, plasma lipids, glucose metabolism, and inflammatory biomarkers were compared across UNa groups. RESULTS: HRR and high-density lipoprotein (HDL)-cholesterol were progressively lower, and insulin (INS), homeostasis model assessment of insulin resistance (HOMAir), ultrasensitive-C-reactive protein (usCRP) were progressively higher across increasing UNa groups. In the low and medium UNa groups, HDL-cholesterol was higher and CRP was lower than that in high UNa (P < 0.01 and P < 0.05, respectively) (Dunnett post-hoc test). In the low UNa group, triglycerides (TGs), INS, and HOMAir were lower than that in high UNa (P < 0.05). Multiple linear regression analysis showed that UNa, HOMAir, and heart rate (HR) were negatively associated with HRR (P < 0.0001, P < 0.0001, and P = 0.001, respectively). CONCLUSIONS: In the essential hypertensive patients studied high sodium intake is associated with parasympathetic inhibition, lipid disturbances, and inflammation. Studies designed to assess causality between sodium intake and metabolic and autonomic status are needed to evaluate the relevance of controlling sodium intake, especially in hypertensive patients.


Subject(s)
Heart Rate/physiology , Hypertension/metabolism , Parasympathetic Nervous System/drug effects , Parasympathetic Nervous System/physiology , Sodium, Dietary/pharmacology , Sodium/urine , Adult , C-Reactive Protein/metabolism , Cholesterol, HDL/blood , Female , Glucose/metabolism , Humans , Insulin/blood , Insulin Resistance/physiology , Lipids/blood , Male , Middle Aged , Regression Analysis
7.
Clin J Am Soc Nephrol ; 7(2): 224-30, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22193234

ABSTRACT

BACKGROUND AND OBJECTIVES: Modern imaging techniques have increased the incidental detection of renal atherosclerotic disease (RAD). Because immune activation may hasten RAD progression, identifying cellular immune markers might provide clues to clinical activity. In this study, cellular immune markers were assessed in early RAD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Immune cell markers in peripheral blood of two groups of hypertensive patients with normal carotid and coronary arteries were evaluated: 28 patients had incidental RAD and 22 patients had normal renal arteries; 21 renal arteries obtained at necropsy from individuals with history of hypertension and tissue evidence of RAD were examined and matched with 21 individuals with normal renal arteries. Cell subpopulations were measured by flow cytometry in peripheral blood and direct cell count, respectively, using T and dendritic cells monoclonal antibodies. RESULTS: Peripheral blood of RAD patients showed increased numbers of cells expressing CD3, CD4, CD83, and CD86. CD4 to CD8 ratio was 8.3 ± 1.4 (RAD) to 3.4 ± 0.9 (normal; P<0.001). No differences were found in CD25, CD8, and S100 among groups. Postmortem samples from RAD showed increased CD3+, CD4+, CD86+, and S100+ cells, whereas CD25+ and CD8+ were unmodified between groups. CD4+ to CD8+ ratio was higher in the RAD(PM) group. CONCLUSIONS: These results are consistent with an increased expression of immune cell markers in early RAD. Additional studies will explore if they may potentially turn into treatment targets to prevent disease progression.


Subject(s)
Atherosclerosis/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Immunity, Cellular , Renal Artery/immunology , Adult , Antigens, CD/blood , Asymptomatic Diseases , Atherosclerosis/blood , Atherosclerosis/pathology , Autopsy , B7-2 Antigen/blood , Biomarkers/blood , CD3 Complex/blood , Case-Control Studies , Female , Flow Cytometry , Humans , Immunoglobulins/blood , Interleukin-2 Receptor alpha Subunit/blood , Male , Membrane Glycoproteins/blood , Middle Aged , Pilot Projects , Prognosis , Prospective Studies , Renal Artery/pathology , S100 Proteins/blood , CD83 Antigen
8.
Cardiovasc Res ; 89(1): 31-40, 2011 Jan 01.
Article in English | MEDLINE | ID: mdl-20819950

ABSTRACT

Protein and lipid oxidation-mainly by mitochondrial reactive oxygen species (mtROS)-was proposed as a crucial determinant of health and lifespan. Angiotensin II (Ang II) enhances ROS production by activating NAD(P)H oxidase and uncoupling endothelial nitric oxide synthase (NOS). Ang II also stimulates mtROS production, which depresses mitochondrial energy metabolism. In rodents, renin-angiotensin system blockade (RAS blockade) increases survival and prevents age-associated changes. RAS blockade reduces mtROS and enhances mitochondrial content and function. This suggests that Ang II contributes to the ageing process by prompting mitochondrial dysfunction. Since Ang II is a pleiotropic peptide, the age-protecting effects of RAS blockade are expected to involve a variety of other mechanisms. Caloric restriction (CR)-an age-retarding intervention in humans and animals-and RAS blockade display a number of converging effects, i.e. they delay the manifestations of hypertension, diabetes, nephropathy, cardiovascular disease, and cancer; increase body temperature; reduce body weight, plasma glucose, insulin, and insulin-like growth factor-1; ameliorate insulin sensitivity; lower protein, lipid, and DNA oxidation, and mitochondrial H(2)O(2) production; and increase uncoupling protein-2 and sirtuin expression. A number of these overlapping effects involve changes in mitochondrial function. In CR, peroxisome proliferator-activated receptors (PPARs) seem to contribute to age-retardation partly by regulating mitochondrial function. RAS inhibition up-regulates PPARs; therefore, it is feasible that PPAR modulation is pivotal for mitochondrial protection by RAS blockade during rodent ageing. Other potential mechanisms that may underlie RAS blockade's mitochondrial benefits are TGF-ß down-regulation and up-regulation of Klotho and sirtuins. In conclusion, the available data suggest that RAS blockade deserves further research efforts to establish its role as a potential tool to mitigate the growing problem of age-associated chronic disease.


Subject(s)
Aging/metabolism , Angiotensin II/antagonists & inhibitors , Mitochondria/metabolism , Aging/drug effects , Aging/genetics , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Caloric Restriction , Gene Expression/drug effects , Glucuronidase/genetics , Humans , Klotho Proteins , Mitochondria/drug effects , Models, Biological , Oxidants/metabolism , Peroxisome Proliferator-Activated Receptors/metabolism , Reactive Oxygen Species/metabolism , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Sirtuins/metabolism
9.
Am J Hypertens ; 23(12): 1318-25, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20706197

ABSTRACT

BACKGROUND: Renin-angiotensin system (RAS) modulation by high dietary sodium may contribute to salt-induced hypertension, oxidative stress, and target organ damage. We investigated whether angiotensin II (Ang-II) type 1 (AT1)-receptor blockade (losartan) could protect the aorta and renal arteries from combined hypertension- and high dietary salt-related oxidative stress. METHODS: Spontaneously hypertensive rats (3-month-old, n = 10/group) received tap water (SHR), water containing 1.5% NaCl (SHR+S), 1.5% NaCl and 30 mg losartan/kg/day (SHR+S+L), or 50 mg atenolol/kg/day (SHR+S+A). Atenolol was used for comparison. Ten Wistar-Kyoto rats (WKY) were controls. Systolic blood pressure (SBP) was determined by tail plethysmography. After 5 months of treatment, vascular remodeling and oxidative stress (superoxide production and NAD(P)H-oxidase activity (chemiluminescence), malondialdehyde (MDA) content (high-performance liquid chromatography), endothelial nitric oxide synthase (eNOS) activity [(14)C-arginine to (14)C citrulline], CuZn-SOD activity (spectrophotometry)) were studied. RESULTS: In SHR, salt-loading significantly aggravated hypertension, urinary protein excretion, intraparenchymal renal artery (IPRArt) perivascular fibrosis, aortic and renal artery oxidative stress, and induced endothelial cell loss in IPRArts. In salt-loaded SHR, 5-month losartan and atenolol treatments similarly reduced SBP, but only losartan significantly prevented (i) urinary protein excretion increase, (ii) or attenuated hypertension-related vascular remodeling, (iii) aortic MDA accumulation, (iv) renal artery eNOS activity lowering, and (v) aortic and renal artery superoxide dismutase (SOD) activity reduction. In SHR+S, the contributions to aortic superoxide production were as follows: uncoupled eNOS > xanthine oxidase (XO) > NAD(P)H oxidase. CONCLUSIONS: In this salt-sensitive genetic hypertension model, losartan protects from hypertension- and high dietary salt-related vascular oxidative stress, exceeding the benefits of BP reduction. Also, during salt overload, BP-independent factors contribute to vascular remodeling, at least part of which derive from AT1-receptor activation.


Subject(s)
Atenolol/pharmacology , Hypertension/physiopathology , Losartan/pharmacology , Oxidative Stress/drug effects , Angiotensin II Type 1 Receptor Blockers/pharmacology , Animals , Aorta/drug effects , Male , Malondialdehyde/metabolism , Nitric Oxide Synthase Type III/metabolism , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Renal Artery/drug effects , Renal Artery/pathology , Renin-Angiotensin System/drug effects , Sodium Chloride, Dietary/administration & dosage , Sodium Chloride, Dietary/pharmacology , Superoxides/metabolism
10.
J Hypertens ; 28(3): 594-601, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20104188

ABSTRACT

OBJECTIVE: To evaluate the serum aldosterone (Ald)/plasmatic renin activity (PRA) ratio as a surrogate marker of renin-angiotensin-aldosterone system status in unilateral (Uni)- and bilateral (Bi)-renal artery stenosis (RAS). METHODS: Seven hundred and eight hypertensive patients (HTP) were studied. Intermediate and high pretest risk of RAS was detected in 66 HTP who subsequently underwent renal gadolinium-enhanced magnetic resonance and arteriography. After application of exclusion criteria 51 HTP remained: 16 with Uni-RAS, 16 with Bi-RAS and 19 essential hypertensives with normal arteries. Nineteen normotensive individuals were also studied. Ald and PRA were determined before and after stenosis resolution by balloon angioplasty and stent implantation. RESULTS: Ald/PRA (ng/dl per (ng/ml per h(-1))) was markedly high in Bi-RAS (5.92 +/- 2.30, P < 0.001), and markedly low in Uni-RAS (0.38 +/- 0.17, P < 0.001) versus essential hypertensives (1.52 +/- 2.02). Multilevel likelihood ratios for Bi-RAS were positive for Ald/PRA higher than 3.6, negative for Ald/PRA lower than 0.2, and neutral for Ald/PRA at least 0.2 and 3.6 or less. ROC analysis identified Ald/PRA lower than 0.5 and Ald/PRA higher than 3.7 to have the best sensitivity and specificity to detect Uni-RAS and Bi-RAS, respectively. In Uni-RAS, but not in Bi-RAS, postinterventional PRA was significantly lower than basal PRA. In Uni-RAS and Bi-RAS, postinterventional Ald was approximately 30% and approximately three times lower than basal Ald, respectively. In essential hypertensives, PRA and Ald showed no changes in the same period. CONCLUSION: In the population studied, Ald, PRA and Ald/PRA were significantly different among essential hypertensives, and HTP with Uni-RAS or Bi-RAS. Studies with a higher number of patients will allow exploration of the usefulness of pharmacologic aldosterone blockade in Bi-RAS, and to assess the relevance of Ald/PRA to differentiate Uni-RAS from Bi-RAS.


Subject(s)
Aldosterone/blood , Hypertension/blood , Renal Artery Obstruction/diagnosis , Renin/blood , Adult , Angioplasty, Balloon , Female , Humans , Hypertension/complications , Male , Middle Aged , Renal Artery Obstruction/complications , Renal Artery Obstruction/surgery , Stents
11.
Free Radic Res ; 43(4): 390-9, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19296328

ABSTRACT

Renal and cardiac benefits of renin-angiotensin system inhibition exceed blood pressure (BP) reduction and seem to involve mitochondrial function. It has been shown that RAS inhibition prevented mitochondrial dysfunction in spontaneously hypertensive rats (SHR) kidneys. Here, it is investigated whether a non-antihypertensive enalapril dose protects cardiac tissue and mitochondria function. Three-month-old SHR received water containing enalapril (10 mg/kg/day, SHR+Enal) or no additions (SHR-C) for 5 months. Wistar-Kyoto rats (WKY) were normotensive controls. At month 5, BP was similar in SHR+Enal and SHR-C. In SHR+Enal and WKY, heart weight and myocardial fibrosis were lower than in SHR-C. Matrix metalloprotease-2 activity was lower in SHR+Enal with respect to SHR-C and WKY. In SHR+Enal and WKY, NADH/cytochrome c oxidoreductase activity, eNOS protein and activity and mtNOS activity were higher and Mn-SOD activity was lower than in SHR-C. In summary, enalapril at a non-antihypertensive dose prevented cardiac hypertrophy and modifies parameters of cardiac mitochondrial dysfunction in SHR.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Enalapril/administration & dosage , Heart/drug effects , Hypertension/drug therapy , Animals , Blood Pressure/drug effects , Cardiomegaly/prevention & control , Hypertension/pathology , Hypertension/physiopathology , Matrix Metalloproteinase 2/metabolism , Membrane Potential, Mitochondrial/drug effects , Mitochondria, Heart/drug effects , Mitochondria, Heart/metabolism , Myocardium/metabolism , Myocardium/pathology , Nitric Oxide Synthase Type III/metabolism , Organ Size/drug effects , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Renin-Angiotensin System/drug effects
12.
Am J Physiol Heart Circ Physiol ; 296(3): H550-8, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19151249

ABSTRACT

Malfunctioning mitochondria strongly participate in the pathogenesis of cardiovascular damage associated with hypertension and other disease conditions. Eukaryotic cells move, assume their shape, resist mechanical stress, accommodate their internal constituents, and transmit signals by relying on the constant remodeling of cytoskeleton filaments. Mitochondrial ATP is needed to support cytoskeletal dynamics. Conversely, mitochondria need to interact with cytoskeletal elements to achieve normal motility, morphology, localization, and function. Extracellular matrix (ECM) quantity and quality influence cellular growth, differentiation, morphology, survival, and mobility. Mitochondria can sense ECM composition changes, and changes in mitochondrial functioning modify the ECM. Maladaptive ECM and cytoskeletal alterations occur in a number of cardiac conditions and in most types of glomerulosclerosis, leading to cardiovascular and renal fibrosis, respectively. Angiotensin II (ANG II), a vasoactive peptide and growth factor, stimulates cytosolic and mitochondrial oxidant production, eventually leading to mitochondrial dysfunction. Also, by inducing integrin/focal adhesion changes, ANG II regulates ECM and cytoskeletal composition and organization and, accordingly, contributes to the pathogenesis of cardiovascular remodeling. ANG II-initiated integrin signaling results in the release of transforming growth factor-beta(1) (TGF-beta(1)), a cytokine that modifies ECM composition and structure, induces reorganization of the cytoskeleton, and modifies mitochondrial function. Therefore, it is possible to hypothesize that the depression of mitochondrial energy metabolism brought about by ANG II is preceded by ANG II-induced integrin signaling and the consequent derangement of the cytoskeletal filament network and/or ECM organization. ANG II-dependent TGF-beta(1) release is a potential link between ANG II, ECM, and cytoskeleton derangements and mitochondrial dysfunction. It is necessary to emphasize that the present hypothesis is among many other plausible explanations for ANG II-mediated mitochondrial dysfunction. A potential limitation of this proposal is that the results compiled here were obtained in different cells, tissues, and/or experimental models.


Subject(s)
Angiotensin II/metabolism , Cardiovascular Diseases/metabolism , Cytoskeleton/metabolism , Extracellular Matrix/metabolism , Mitochondria/metabolism , Signal Transduction , Animals , Cardiovascular Diseases/pathology , Energy Metabolism , Focal Adhesions/metabolism , Humans , Integrins/metabolism , Mitochondria/pathology , Mitochondrial Size , Receptor, Angiotensin, Type 1/metabolism , Transforming Growth Factor beta1/metabolism
13.
Exp Gerontol ; 43(10): 919-28, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18765277

ABSTRACT

Chronic renin-angiotensin system inhibition protects against liver fibrosis, ameliorates age-associated mitochondrial dysfunction and increases rodent lifespan. We hypothesized that life-long angiotensin-II-mediated stimulation of oxidant generation might participate in mitochondrial DNA "common deletion" formation, and the resulting impairment of bioenergetic capacity. Enalapril (10 mg/kg/d) or losartan (30 mg/kg/d) administered during 16.5 months were unable to prevent the age-dependent accumulation of rat liver mitochondrial DNA "common deletion", but attenuated the decrease of mitochondrial DNA content. This evidence - together with the enhancement of NRF-1 and PGC-1 mRNA contents - seems to explain why enalapril and losartan improved mitochondrial functioning and lowered oxidant production, since both the absolute number of mtDNA molecules and increased NRF-1 and PGC-1 transcription are positively related to mitochondrial respiratory capacity, and PGC-1 protects against increases in ROS production and damage. Oxidative stress evoked by abnormal respiratory function contributes to the pathophysiology of mitochondrial disease and human aging. If the present mitochondrial actions of renin-angiotensin system inhibitors are confirmed in humans they may modify the therapeutic significance of that strategy.


Subject(s)
Aging/physiology , DNA, Mitochondrial/metabolism , Mitochondria/physiology , Mitochondrial Diseases/physiopathology , Oxidative Stress/physiology , Renin-Angiotensin System/physiology , Animals , DNA, Mitochondrial/genetics , Gene Expression , Male , Mitochondria/drug effects , Mitochondrial Diseases/genetics , Oxidative Stress/drug effects , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Renin-Angiotensin System/genetics
14.
Am J Physiol Heart Circ Physiol ; 294(1): H456-65, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18024545

ABSTRACT

To investigate whether ANG II type 1 (AT(1)) receptor blockade could protect kidney mitochondria in streptozotocin-induced Type 1 diabetes, we treated 8-wk-old male Sprague-Dawley rats with a single streptozotocin injection (65 mg/kg ip; STZ group), streptozotocin and drinking water containing either losartan (30 mg.kg(-1).day(-1); STZ+Los group) or amlodipine (3 mg.kg(-1).day(-1); STZ+Amlo group), or saline (intraperitoneally) and pure water (control group). Four-month-long losartan or amlodipine treatments started 30 days before streptozotocin injection to improve the antioxidant defenses. The number of renal lesions, plasma glucose and lipid levels, and proteinuria were higher and creatinine clearance was lower in STZ and STZ+Amlo compared with STZ+Los and control groups. Glycemia was higher in STZ+Los compared with control. Blood pressure, basal mitochondrial membrane potential and mitochondrial pyruvate content, and renal oxidized glutathione levels were higher and NADH/cytochrome c oxidoreductase activity was lower in STZ compared with the other groups. In STZ and STZ+Amlo groups, mitochondrial H(2)O(2) production rate was higher and uncoupling protein-2 content, cytochrome c oxidase activity, and renal glutathione level were lower than in STZ+Los and control groups. Mitochondrial nitric oxide synthase activity was higher in STZ+Amlo compared with the other groups. Mitochondrial pyruvate content and H(2)O(2) production rate negatively contributed to electron transfer capacity and positively contributed to renal lesions. Uncoupling protein-2 content negatively contributed to mitochondrial H(2)O(2) production rate and renal lesions. Renal glutathione reduction potential positively contributed to mitochondria electron transfer capacity. In conclusion, AT(1) blockade protects kidney mitochondria and kidney structure in streptozotocin-induced diabetes independently of blood pressure and glycemia.


Subject(s)
Amlodipine/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Antihypertensive Agents/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 1/drug therapy , Kidney/drug effects , Losartan/pharmacology , Mitochondria/drug effects , Receptor, Angiotensin, Type 1/metabolism , Amlodipine/therapeutic use , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Animals , Antihypertensive Agents/therapeutic use , Antioxidants/metabolism , Blood Glucose/drug effects , Blood Pressure/drug effects , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 1/physiopathology , Electron Transport Complex IV/metabolism , Glutathione/metabolism , Hydrogen Peroxide/metabolism , Ion Channels/metabolism , Kidney/enzymology , Kidney/metabolism , Kidney/pathology , Losartan/therapeutic use , Male , Membrane Potential, Mitochondrial/drug effects , Mitochondria/enzymology , Mitochondria/metabolism , Mitochondria/pathology , Mitochondrial Proteins/metabolism , Nitric Oxide Synthase/metabolism , Pyruvic Acid/metabolism , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Uncoupling Protein 2
15.
Front Biosci ; 12: 1049-62, 2007 Jan 01.
Article in English | MEDLINE | ID: mdl-17127360

ABSTRACT

The objective of improving health is intimately associated with preventing and delaying age-related diseases. Nutritional and pharmacological approaches aimed at retarding aging are uncovering mechanisms, whose definitive roles in cell and tissue physiology need to be defined. In this article we hypothesize that peroxisome proliferator activated receptor (PPAR)-modulation is a pivotal process that underlies the association between mitochondria and the renin-angiotensin system (RAS) in aging. This hypothesis is based on several lines of evidence suggesting that: a) mitochondrial function and oxidant production are active participants in the aging process; b) PPARs, by regulating mitochondrial function and uncoupling proteins (UCP), seem to play a major role in the age-retarding effects of caloric restriction; c) RAS inhibition delays the deleterious effects of aging and also upregulates PPARs; and d) a number of physiological and molecular events that occur in experimental caloric restriction, and experimental and clinical RAS inhibition, involve changes in mitochondrial functions.


Subject(s)
Aging , Mitochondria/metabolism , Peroxisome Proliferator-Activated Receptors/physiology , Renin-Angiotensin System/physiology , Animals , Caloric Restriction , Humans , Models, Biological , Oxidants/metabolism , Oxidative Stress
16.
Am J Physiol Regul Integr Comp Physiol ; 292(4): R1494-501, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17185409

ABSTRACT

The renal and cardiac benefits of renin-angiotensin system (RAS) inhibition in hypertension exceed those attributable to blood pressure reduction, and seem to involve mitochondrial function changes. To investigate whether mitochondrial changes associated with RAS inhibition are related to changes in nitric oxide (NO) metabolism, four groups of male Wistar rats were treated during 2 wk with a RAS inhibitor, enalapril (10 mg x kg(-1) x day(-1); Enal), or a NO synthase (NOS) inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME) (1 mg x kg(-1) x day(-1)), or both (Enal+L-NAME), or were untreated (control). Blood pressure and body weight were lower in Enal than in control. Electron transfer through complexes I to III and cytochrome oxidase activity were significantly lower, and uncoupling protein-2 content was significantly higher in kidney mitochondria isolated from Enal than in those from control. All of these changes were prevented by L-NAME cotreatment and were accompanied by a higher production/bioavailability of kidney NO. L-NAME abolished mitochondrial NOS activity but failed to inhibit extra-mitochondrial kidney NOS, underscoring the relevance of mitochondrial NO in those effects of enalapril that were suppressed by L-NAME cotreatment. In Enal, kidney mitochondria H(2)O(2) production rate and MnSOD activity were significantly lower than in control, and these effects were not prevented by L-NAME cotreatment. These findings may clarify the role of NO in the interactions between RAS and mitochondrial metabolism and can help to unravel the mechanisms involved in renal protection by RAS inhibitors.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Enalapril/pharmacology , Kidney/drug effects , Mitochondria/drug effects , Nitric Oxide/metabolism , Animals , Biological Availability , Blood Pressure/drug effects , Body Weight/drug effects , Drug Interactions , Electron Transport Complex I/metabolism , Electron Transport Complex II/metabolism , Electron Transport Complex III/metabolism , Enzyme Inhibitors/pharmacology , Hydrogen Peroxide/metabolism , Ion Channels/metabolism , Kidney/cytology , Kidney/metabolism , Male , Membrane Potentials/drug effects , Mitochondria/enzymology , Mitochondria/metabolism , Mitochondria/physiology , Mitochondrial Proteins/metabolism , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/pharmacokinetics , Nitric Oxide Synthase Type I/metabolism , Organ Size/drug effects , Random Allocation , Rats , Rats, Wistar , Superoxide Dismutase/metabolism , Uncoupling Protein 2
17.
Am J Physiol Regul Integr Comp Physiol ; 290(6): R1616-25, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16410402

ABSTRACT

Mitochondrial dysfunction is associated with cardiovascular damage; however, data on a possible association with kidney damage are scarce. Here, we aimed at investigating whether 1) kidney impairment is related to mitochondrial dysfunction; and 2) ANG II blockade, compared with Ca2+ channel blockade, can reverse potential mitochondrial changes in hypertension. Eight-week-old male spontaneously hypertensive rats (SHR) received water containing losartan (40 mg.kg-1.day-1, SHR+Los), amlodipine (3 mg.kg-1.day-1, SHR+Amlo), or no additions (SHR) for 6 mo. Wistar-Kyoto rats (WKY) were normotensive controls. Glomerular and tubulointerstitial damage, systolic blood pressure, and proteinuria were higher, and creatinine clearance was lower in SHR vs. SHR+Los and WKY. In SHR+Amlo, blood pressure was similar to WKY, kidney function was similar to SHR, and renal lesions were lower than in SHR, but higher than in SHR+Los. In kidney mitochondria from SHR and SHR+Amlo, membrane potential, nitric oxide synthase, manganese-superoxide dismutase and cytochrome oxidase activities, and uncoupling protein-2 content were lower than in SHR+Los and WKY. In SHR and SHR+Amlo, mitochondrial H2O2 production was higher than in SHR+Los and WKY. Renal glutathione content was lower in SHR+Amlo relative to SHR, SHR+Los, and WKY. In SHR and SHR+Amlo, glutathione was relatively more oxidized than in SHR+Los and WKY. Tubulointerstitial alpha-smooth muscle actin labeling was inversely related to manganese-superoxide dismutase activity and uncoupling protein-2 content. These findings suggest that oxidant stress is associated with renal mitochondrial dysfunction in SHR. The mitochondrial-antioxidant actions of losartan may be an additional or alternative way to explain some of the beneficial effects of AT1-receptor antagonists.


Subject(s)
Amlodipine/pharmacology , Hypertension/drug therapy , Kidney/drug effects , Losartan/pharmacology , Mitochondria/drug effects , Actins/analysis , Amlodipine/therapeutic use , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Animals , Blood Pressure/drug effects , Calcium Channel Blockers/pharmacology , Calcium Channel Blockers/therapeutic use , Electron Transport Complex IV/metabolism , Glomerular Mesangium/chemistry , Glomerular Mesangium/pathology , Glutathione/metabolism , Hydrogen Peroxide/metabolism , Hypertension/complications , Hypertension/physiopathology , Ion Channels , Kidney/pathology , Kidney/physiopathology , Losartan/therapeutic use , Male , Membrane Potentials/drug effects , Membrane Transport Proteins/metabolism , Mitochondria/metabolism , Mitochondria/physiology , Mitochondrial Proteins/metabolism , NADH Dehydrogenase/metabolism , Nitric Oxide Synthase/metabolism , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Superoxide Dismutase/metabolism , Uncoupling Protein 2
18.
Regul Pept ; 128(3): 247-52, 2005 Jun 30.
Article in English | MEDLINE | ID: mdl-15837534

ABSTRACT

Experimental studies indicate that chronic long-term inhibition of the renin-angiotensin system (RAS) can prevent most of the deleterious effects due to aging in the cardiovascular system and in the kidney of the normal mouse and rat. In this review, all the information available on this subject provided by several studies performed by our research group during the last years is been described. Treatment was initiated either after weaning or at 12 months of age that is about half the normal life span of the rat. A converting enzyme inhibitor: enalapril or an angiotensin II type 1 (AT1) receptor blocker: losartan were used to inhibit the RAS. Cognitive behaviour, emotionality, and locomotor activity were also determined at 10 and 18 months of age in treated since weaning and untreated control rats to elucidate the participation of angiotensin II in memory disfunction. A similar observation was obtained in animals treated from 12 to 18 months of age. Results have demonstrated a significant protective effect on the function and the structure of the cardiovascular system, the kidney and the brain in all the treated animals. Damage observed at 12 months of age was not very significant, but treatment stop further deterioration that was evident in untreated animals. The similarity of the results detected with either enalapril or losartan treatment, clearly indicates that most of the effects are exerted through AT1 receptors. Analysis of the nitric oxide and antioxidant enzymes systems suggest that the protective effect is related to an antioxidant action of the RAS inhibitors and a reduced formation of reactive oxygen species. AngII inhibition might produce changes in the mechanisms of oxidative stress specially at the mitochondrial level. Prevention of mitochondrial decrease and/or damage would be related with the delay of the normal aging process.


Subject(s)
Aging/physiology , Renin-Angiotensin System/physiology , Angiotensin II/physiology , Animals , Behavior , Behavior, Animal , Cardiovascular Physiological Phenomena , Humans , Learning
19.
Eur J Biochem ; 271(13): 2607-14, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15206926

ABSTRACT

Monolayer primary cultures of thyroid cells produce, in the presence of insulin, a cytosolic inhibitor of thyroid peroxidase (TPO), lacto peroxidase (LPO), horseradish peroxidase (HRPO) and glutathione peroxidase (GPX). The inhibitor, localized in the cytosol, is thermostable and hydrophylic. Its molecular mass is less than 2 kDa. The inhibitory activity, resistant to proteolytic and nucleolytic enzymes, disappears with sodium metaperiodate treatment, as an oxidant of carbohydrates, supporting its oligosaccharide structure. The presence of inositol, mannose, glucose, the specific inhibition of cyclic AMP-dependent protein kinase and the disappearance of peroxidase inhibition by alkaline phosphatase and alpha-mannosidase in purified samples confirms its chemical structure as inositol phosphoglycan-like. Purification by anionic interchange shows that the peroxidase inhibitor elutes like the two subtypes of inositol phosphoglycans (IPG)P and A, characterized as signal transducers of insulin action. Insulin significantly increases the concentration of the peroxidase inhibitor in a thyroid cell culture at 48 h. The addition of both isolated substances to a primary thyroid culture produces, after 30 min, a significant increase in hydrogen peroxide (H2O2) concentration in the medium, concomitantly with the disappearance of the GPX activity in the same conditions. The presence of insulin or anyone of both products, during 48 h, induces cell proliferation of the thyroid cell culture. In conclusion, insulin stimulates thyroid cell division through the effect of a peroxidase inhibitor, as its second messenger. The inhibition of GPX by its action positively modulates the H2O2 level, which would produce, as was demonstrated by other authors, the signal for cell proliferation.


Subject(s)
Cell Division , Insulin/pharmacology , Peroxidases/antagonists & inhibitors , Thyroid Gland/drug effects , Animals , Cattle , Cells, Cultured , Thyroid Gland/cytology , Thyroid Gland/enzymology
20.
Mol Aspects Med ; 25(1-2): 27-36, 2004.
Article in English | MEDLINE | ID: mdl-15051314

ABSTRACT

Angiotensin-converting enzyme inhibitors (ACEi) and AT-1 receptor blockers (ARB) are two types of drugs that inhibit the renin-angiotensin system (RAS), and can attenuate the progression to cardiac and/or renal functional impairment, secondary to diverse pathologies. Some of the beneficial effects of ACEi and ARB occur independently of the ability of these drugs to reduce arterial blood pressure. Both, in animals, and in humans, we observed an enhancement of antioxidant defenses that occurred after treatment with ACEi. Based on these results, we postulate that some of the beneficial health effects associated to RAS inhibition can be ascribed to the prevention of oxidant-mediated damage. Furthermore, considering that: (i). RAS inhibition attenuates certain age-associated degenerative changes; (ii). aging was postulated to result from the accumulation of oxidant-mediated damage; and (iii). mitochondria are a major source of oxidants, we studied potential associations among RAS inhibition, mitochondrial function and production of oxidants and nitric oxide, and aging. The results obtained suggest, that RAS inhibitors, i.e. enalapril and losartan, can protect against the effects of aging by attenuating oxidant damage to mitochondria, and in consequence, they preserve mitochondrial function. The mechanism(s) explaining such attenuation of oxidant damage can relay on a reduction of the ANG-II-dependent generation of superoxide and/or an increased detoxification of reactive nitrogen and oxygen species by recomposition of antioxidant defense levels.


Subject(s)
Aging/physiology , Antioxidants/physiology , Mitochondria/physiology , Renin-Angiotensin System/physiology , Animals , Humans , Oxidative Stress/physiology , Reactive Oxygen Species/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...