Alamandine, a protective component of the renin-angiotensin system, reduces cellular proliferation and interleukin-6 secretion in human macrophages through MasR-MrgDR heteromerization.

Alamandine (ALA) exerts protective effects similar to angiotensin (Ang) (1-7) through Mas-related G protein-coupled receptor type D receptor (MrgDR) activation, distinct from Mas receptor (MasR). ALA induces anti-inflammatory effects in mice but its impact in human macrophages remains unclear. We aimed to investigate the anti-inflammatory effects of ALA in human macrophages. Interleukin (IL)-6 and IL-1ß were measured by ELISA in human THP-1 macrophages and human monocyte-derived macrophages exposed to lipopolysaccharide (LPS). Consequences of MasR-MrgDR heteromerization were investigated in transfected HEK293T cells. ALA decreased IL-6 and IL-1ß secretion in LPS-activated THP-1 macrophages. The ALA-induced decrease in IL-6 but not in IL-1ß was prevented by MasR blockade and MasR downregulation, suggesting MasR-MrgDR interaction. In human monocyte-derived M1 macrophages, ALA decreased IL-1ß secretion independently of MasR. MasR-MrgDR interaction was confirmed in THP-1 macrophages, human monocyte-derived macrophages, and transfected HEK293T cells. MasR and MrgDR formed a constitutive heteromer that was not influenced by ALA. ALA promoted Akt and ERK1/2 activation only in cells expressing MasR-MrgDR heteromers, and this effect was prevented by MasR blockade. While Ang-(1-7) reduced cellular proliferation in MasR -but not MrgDR- expressing cells, ALA antiproliferative effect was elicited in cells expressing MasR-MrgDR heteromers. ALA also induced an antiproliferative response in THP-1 cells and this effect was abolished by MasR blockade, reinforcing MasR-MrgDR interaction. MasR-MrgDR heteromerization is crucial for ALA-induced anti-inflammatory and antiproliferative responses in human macrophages. This study broaden our knowledge of the protective axis of the RAS, thus enabling novel therapeutic approaches in inflammatory-associated diseases.

The potential role of renin angiotensin system in acute leukemia: a narrative review.

Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components.

Ionizable Lipid Nanoparticle-Mediated TRAIL mRNA Delivery in the Tumor Microenvironment to Inhibit Colon Cancer Progression.

Introduction: Immunotherapy has revolutionized cancer treatment by harnessing the immune system to enhance antitumor responses while minimizing off-target effects. Among the promising cancer-specific therapies, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted significant attention. Methods: Here, we developed an ionizable lipid nanoparticle (LNP) platform to deliver TRAIL mRNA (LNP-TRAIL) directly to the tumor microenvironment (TME) to induce tumor cell death. Our LNP-TRAIL was formulated via microfluidic mixing and the induction of tumor cell death was assessed in vitro. Next, we investigated the ability of LNP-TRAIL to inhibit colon cancer progression in vivo in combination with a TME normalization approach using Losartan (Los) or angiotensin 1-7 (Ang(1-7)) to reduce vascular compression and deposition of extracellular matrix in mice. Results: Our results demonstrated that LNP-TRAIL induced tumor cell death in vitro and effectively inhibited colon cancer progression in vivo, particularly when combined with TME normalization induced by treatment Los or Ang(1-7). In addition, potent tumor cell death as well as enhanced apoptosis and necrosis was found in the tumor tissue of a group treated with LNP-TRAIL combined with TME normalization. Discussion: Together, our data demonstrate the potential of the LNP to deliver TRAIL mRNA to the TME and to induce tumor cell death, especially when combined with TME normalization. Therefore, these findings provide important insights for the development of novel therapeutic strategies for the immunotherapy of solid tumors.

Novel Insights into the Cardioprotective Effects of the Peptides of the Counter-Regulatory Renin-Angiotensin System.

Currently, cardiovascular diseases are a major contributor to morbidity and mortality worldwide, having a significant negative impact on both the economy and public health. The renin-angiotensin system contributes to a high spectrum of cardiovascular disorders and is essential for maintaining normal cardiovascular homeostasis. Overactivation of the classical renin-angiotensin system is one of the most important pathophysiological mechanisms in the progression of cardiovascular diseases. The counter-regulatory renin-angiotensin system is an alternate pathway which favors the synthesis of different peptides, including Angiotensin-(1-7), Angiotensin-(1-9), and Alamandine. These peptides, via the angiotensin type 2 receptor (AT2R), MasR, and MrgD, initiate multiple downstream signaling pathways that culminate in the activation of various cardioprotective mechanisms, such as decreased cardiac fibrosis, decreased myocardial hypertrophy, vasodilation, decreased blood pressure, natriuresis, and nitric oxide synthesis. These cardioprotective effects position them as therapeutic alternatives for reducing the progression of cardiovascular diseases. This review aims to show the latest findings on the cardioprotective effects of the main peptides of the counter-regulatory renin-angiotensin system.

Antihypertensive treatment of end-stage renal disease patients on hemodialysis does not alter circulating ACE and ACE2 activity and angiotensin peptides.

Cardiovascular diseases (CVD) are the main causes of death in hemodialysis patients, representing a public health challenge. We investigated the effect of different antihypertensive treatments on circulating levels of renin-angiotensin system (RAS) components in end-stage renal disease (ESRD) patients on hemodialysis. ESRD patients were grouped following the prescribed antihypertensive drugs: ß-blocker, ß-blocker+ACEi and ß-blocker+AT1R blocker. ESDR patients under no antihypertensive drug treatment were used as controls. Blood samples were collected before hemodialysis sessions. Enzymatic activities of the angiotensin-converting enzymes ACE and ACE2 were measured through fluorescence assays and plasma concentrations of the peptides Angiotensin II (Ang II) and Angiotensin-(1-7) [Ang-(1-7)] were quantified using mass spectrometry (LC-MS/MS). ACE activity was decreased only in the ß-blocker+ACEi group compared to the ß-blocker+AT1R, while ACE2 activity did not change according to the antihypertensive treatment. Both Ang II and Ang-(1-7) levels also did not change according to the antihypertensive treatment. We concluded that the treatment of ESRD patients on hemodialysis with different antihypertensive drugs do not alter the circulating levels of RAS components.

Effects of oral HPΒCD-angiotensin-(1-7) supplementation on recreational mountain bike athletes: a crossover study.

BACKGROUND: Supplementation with Angiotensin-(1-7) [(Ang-1-7)] has received considerable attention due to its possible ergogenic effects on physical performance. The effects of a single dose of Ang-(1-7) on the performance of mountain bike (MTB) athletes during progressive load tests performed until the onset of voluntary fatigue have previously been demonstrated. This study tested the effects of Ang-(1-7) in two different exercise protocols with different metabolic demands: aerobic (time trial) and anaerobic (repeated sprint). METHODS: Twenty one male recreational athletes were given capsules containing an oral formulation of HPßCD-Ang-(1-7) (0.8 mg) and HPßCD-placebo (only HPßCD) over a 7-day interval; a double-blind randomized crossover design was used. Physical performance was examined using two protocols: a 20-km cycling time trial or 4 × 30-s repeated all-out sprints on a leg cycle ergometer. Data were collected before and after physical tests to assess fatigue parameters, and included lactate levels, and muscle activation during the sprint protocol as evaluated by electromyography (EMG); cardiovascular parameters: diastolic and systolic blood pressure and heart rate; and performance parameters, time to complete (time trial), maximum power and mean power (repeated sprint). RESULTS: Supplementation with an oral formulation of HPßCD-Ang-(1-7) reduced basal plasma lactate levels and promoted the maintenance of plasma glucose levels after repeated sprints. Supplementation with HPßCD-Ang-(1-7) also increased baseline plasma nitrite levels and reduced resting diastolic blood pressure in a time trial protocol. HPßCD-Ang-(1-7) had no effect on the time trial or repeat sprint performance, or on the EMG recordings of the vastus lateralis and vastus medialis. CONCLUSIONS: Supplementation with HPßCD-Ang-(1-7) did not improve physical performance in time trial or in repeated sprints; however, it promoted the maintenance of plasma glucose and lactate levels after the sprint protocol and at rest, respectively. In addition, HPßCD-Ang-(1-7) also increased resting plasma nitrite levels and reduced diastolic blood pressure in the time trial protocol. TRIAL REGISTRATION: RBR-2nbmpbc, registered January 6th, 2023. The study was prospectively registered.

G-protein-coupled receptor MAS deletion produces a preeclampsia-like phenotype in FVB/N mice.

BACKGROUND: An unbalance in the renin-angiotensin (Ang) system (RAS) between the Ang II/AT1 and Ang-(1-7)/Mas axis appears to be involved in preeclampsia (PE), in which a reduction in Ang-(1-7) was observed. Here, we tested whether the reduction in the activity of the Ang-(1-7)/Mas axis could be a contributing factor for the development of PE, using Mas-deficient (Mas-/-) mice. METHODS AND RESULTS: Cardiovascular parameters were evaluated by telemetry before, during pregnancy and 4 days postpartum in 20-week-old Mas-/- and wild-type (WT) female mice. Mas-/- mice presented reduced arterial blood pressure (BP) at baseline (91.3 ± 0.8 in Mas-/- vs. 94.0 ± 0.9 mmHg in WT, Diastolic, P<0.05). However, after the 13th day of gestation, BP in Mas-/- mice started to increase, time-dependently, and at day 19 of pregnancy, these animals presented a higher BP in comparison with WT group (90.5 ± 0.7 in Mas-/- vs. 80.3 ± 3.5 mmHg in WT, Diastolic D19, P<0.0001). Moreover, pregnant Mas-/- mice presented fetal growth restriction, increase in urinary protein excretion as compared with nonpregnant Mas-/-, oliguria, increase in cytokines, endothelial dysfunction and reduced ACE, AT1R, ACE2, ET-1A, and eNOS placental mRNA, similar to some of the clinical manifestations found in the development of PE. CONCLUSIONS: These results show that Mas-deletion produces a PE-like state in FVB/N mice.

The Role of Renin-Angiotensin System in Diabetic Cardiomyopathy: A Narrative Review.

Diabetic cardiomyopathy refers to myocardial dysfunction in type 2 diabetes, but without the traditional cardiovascular risk factors or overt clinical atherosclerosis and valvular disease. The activation of the renin-angiotensin system (RAS), oxidative stress, lipotoxicity, maladaptive immune responses, imbalanced mitochondrial dynamics, impaired myocyte autophagy, increased myocyte apoptosis, and fibrosis contribute to diabetic cardiomyopathy. This review summarizes the studies that address the link between cardiomyopathy and the RAS in humans and presents proposed pathophysiological mechanisms underlying this association. The RAS plays an important role in the development and progression of diabetic cardiomyopathy. The over-activation of the classical RAS axis in diabetes leads to the increased production of angiotensin (Ang) II, angiotensin type 1 receptor activation, and aldosterone release, contributing to increased oxidative stress, fibrosis, and cardiac remodeling. In contrast, Ang-(1-7) suppresses oxidative stress, inhibits tissue fibrosis, and prevents extensive cardiac remodeling. Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers improve heart functioning and reduce the occurrence of diabetic cardiomyopathy. Experimental studies also show beneficial effects for Ang-(1-7) and angiotensin-converting enzyme 2 infusion in improving heart functioning and tissue injury. Further research is necessary to fully understand the pathophysiology of diabetic cardiomyopathy and to translate experimental findings into clinical practice.

Biomechanical Effects of Angiotensin 1-7 in Diabetes Rats Femur / Efectos Biomecánicos de la Angiotensina 1-7 en el Fémur de Ratas Diabéticas

SUMMARY: It is known that diabetes mellitus has late complications, including microvascular and macrovascular diseases. Diabetes can affect bones through biochemical markers of bone structure, density, and turnover. This study aimed to biomechanically investigate the bone-protective effects of angiotensin 1-7 (Ang 1-7), one of the active peptides in the renin-angiotensin system, in rats with diabetes. Thirty male Wistar albino rats, three months old and weighing 250-300 g, were divided into four groups: diabetes, Ang 1- 7, diabetes plus Ang 1-7, and control. One month later, diabetes developed in rats; the rats were sacrificed, and their right femur was removed. Three-point bending biomechanical tests were performed on the femurs. The diabetic group had significantly higher bone fragility than the other groups (Pr >.05). Bone fragility was lower, and bone flexibility was higher in the Ang 1-7 groups (Pr>F value 0.05). As a result of our study, the effect of Ang 1-7 on the bones of rats with diabetes was investigated biomechanically. Ang 1-7 has a protective impact on the bones of rats with diabetes.

Se sabe que la diabetes mellitus tiene complicaciones tardías, incluyendo enfermedades microvasculares y macrovasculares. La diabetes puede afectar los huesos a través de los marcadores bioquímicos de la estructura, la densidad y el recambio óseo. Este estudio tuvo como objetivo investigar biomecánicamente los efectos protectores en los huesos de la angiotensina 1-7 (Ang 1-7), uno de los péptidos activos en el sistema renina-angiotensina, en ratas con diabetes. Treinta ratas albinas Wistar macho, de tres meses de edad y con un peso de 250-300 g, se dividieron en cuatro grupos: diabetes, Ang 1-7, diabetes más Ang 1-7 y control. Un mes después, se desarrolló diabetes en ratas; se sacrificaron los animales y se extrajo su fémur derecho. Se realizaron pruebas biomecánicas de flexión de tres puntos en los fémures. El grupo diabéticos tenía una fragilidad ósea significativamente mayor que los otros grupos (Pr > 0,05). La fragilidad ósea fue menor y la flexibilidad ósea fue mayor en los grupos Ang 1-7 (valor Pr>F 0,05). Como resultado de nuestro estudio, se determinó biomecánicamente el efecto de Ang 1-7 en los huesos de ratas con diabetes. Se concluye que Ang 1-7 tiene un impacto protector en los huesos de ratas diabéticas.

Central angiotensin 1-7 triggers brown fat thermogenesis.

We tested the hypothesis that third ventricular (3V) injections of angiotensin 1-7 (Ang 1-7) increases thermogenesis in brown adipose tissue (BAT), and whether the Mas receptor mediates this response. First, in male Siberian hamsters (n = 18), we evaluated the effect of Ang 1-7 in the interscapular BAT (IBAT) temperature and, using selective Mas receptor antagonist A-779, the role of Mas receptor in this response. Each animal received 3V injections (200 nL), with 48 h intervals: saline; Ang 1-7 (0.03, 0.3, 3, and 30 nmol); A-779 (3 nmol); and Ang 1-7 (0.3 nmol) + A-779 (3 nmol). IBAT temperature increased after 0.3 nmol Ang 1-7 compared with Ang 1-7 + A-779 at 20, 30, and 60 min. Also, 0.3 nmol Ang 1-7 increased IBAT temperature at 10 and 20 min, and decreased at 60 min compared with pretreatment. IBAT temperature decreased after A-779 at 60 min and after Ang 1-7 + A-779 at 30 and 60 min compared with the respective pretreatment. A-779 and Ang 1-7 + A-779 decreased core temperature at 60 min compared with 10 min. Then, we evaluated blood and tissue Ang 1-7 levels, and the expression of hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) in IBAT. Male Siberian hamsters (n = 36) were killed 10 min after one of the injections. No changes were observed in blood glucose, serum and IBAT Ang 1-7 levels, and ATGL. Ang 1-7 (0.3 nmol) increased p-HSL expression compared with A-779 and increased p-HSL/HSL ration compared with other injections. Ang 1-7 and Mas receptor immunoreactive cells were found in brain regions that coincide with the sympathetic nerves outflow to BAT. In conclusion, 3V injection of Ang 1-7 induced thermogenesis in IBAT in a Mas receptor-dependent manner.

Mas receptor endocytosis and signaling in health and disease.

The renin angiotensin system (RAS) plays a major role in blood pressure regulation and electrolyte homeostasis and is mainly composed by two axes mediating opposite effects. The pressor axis, constituted by angiotensin (Ang) II and the Ang II type 1 receptor (AT1R), exerts vasoconstrictor, proliferative, hypertensive, oxidative and pro-inflammatory actions, while the depressor/protective axis, represented by Ang-(1-7), its Mas receptor (MasR) and the Ang II type 2 receptor (AT2R), opposes the actions elicited by the pressor arm. The MasR belongs to the G protein-coupled receptor (GPCR) family. To avoid receptor overstimulation, GPCRs undergo internalization and trafficking into the cell after being stimulated. Then, the receptor may induce other signaling cascades or it may even interact with other receptors, generating distinct biological responses. Thus, control of a GPCR regarding space and time affects the specificity of the signals transduced by the receptor and the ultimate cellular response. The present chapter is focused on the signaling and trafficking pathways of MasR under physiological conditions and its participation in the pathogenesis of numerous brain diseases.

The fibrotic niche impairs satellite cell function and muscle regeneration in mouse models of Marfan syndrome.

AIM: It has been suggested that the proliferation and early differentiation of myoblasts are impaired in Marfan syndrome (MFS) mice during muscle regeneration. However, the underlying cellular and molecular mechanisms remain poorly understood. Here, we investigated muscle regeneration in MFS mouse models by analyzing the influence of the fibrotic niche on satellite cell function. METHODS: In vivo, ex vivo, and in vitro experiments were performed. In addition, we evaluated the effect of the pharmacological inhibition of fibrosis using Ang-(1-7) on regenerating skeletal muscles of MFS mice. RESULTS: The skeletal muscle of MFS mice shows an increased accumulation of collagen fibers (81.2%), number of fibroblasts (157.1%), and Smad2/3 signaling (110.5%), as well as an aberrant number of fibro-adipogenic progenitor cells in response to injury compared with wild-type mice. There was an increased number of proinflammatory and anti-inflammatory macrophages (3.6- and 3.1-fold, respectively) in regenerating muscles of wild-type mice, but not in the regenerating muscles of MFS mice. Our data show that proliferation and differentiation of satellite cells are altered (p ≤ 0.05) in MFS mice. Myoblast transplantation assay revealed that the regenerating muscles from MFS mice have reduced satellite cell self-renewal capacity (74.7%). In addition, we found that treatment with Ang-(1-7) reduces fibrosis (71.6%) and ameliorates satellite cell dysfunction (p ≤ 0.05) and muscle contractile function (p ≤ 0.05) in MFS mice. CONCLUSION: The fibrotic niche, caused by Fbn1 mutations, reduces the myogenic potential of satellite cells, affecting structural and functional muscle regeneration. In addition, the fibrosis inhibitor Ang-(1-7) partially counteracts satellite cell abnormalities and restores myofiber size and contractile force in regenerating muscles.

Nephrotic Syndrome and Renin-angiotensin System: Pathophysiological Role and Therapeutic Potential.

Idiopathic Nephrotic Syndrome (INS) is the most frequent etiology of glomerulopathy in pediatric patients and one of the most common causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in this population. In this review, we aimed to summarize evidence on the pathophysiological role and therapeutic potential of the Renin-Angiotensin System (RAS) molecules for the control of proteinuria and for delaying the onset of CKD in patients with INS. This is a narrative review in which the databases PubMed, Web of Science, and Sci- ELO were searched for articles about INS and RAS. We selected articles that evaluated the pathophysiological role of RAS and the effects of the alternative RAS axis as a potential therapy for INS. Several studies using rodent models of nephropathies showed that the treatment with activators of the Angiotensin-Converting Enzyme 2 (ACE2) and with Mas receptor agonists reduces proteinuria and improves kidney tissue damage. Another recent paper showed that the reduction of urinary ACE2 levels in children with INS correlates with proteinuria and higher concentrations of inflammatory cytokines, although data with pediatric patients are still limited. The molecules of the alternative RAS axis comprise a wide spectrum, not yet fully explored, of potential pharmacological targets for kidney diseases. The effects of ACE2 activators and receptor Mas agonists show promising results that can be useful for nephropathies including INS.

Peptide inhibitors of angiotensin-I converting enzyme based on angiotensin (1-7) with selectivity for the C-terminal domain.

The renin-angiotensin system (RAS) is a key regulator of human arterial pressure. Several of its effects are modulated by angiotensin II, an octapeptide originating from the action of angiotensin-I converting enzyme (ACE) on the decapeptide angiotensin-I. ACE possess two active sites (nACE and cACE) that have their own kinetic and substrate specificities. ACE inhibitors are widely used as the first-line treatment for hypertension and other heart-related diseases, but because they inactivate both ACE domains, their use is associated with serious side effects. Thus, the search for domain-specific ACE inhibitors has been the focus of intense research. Angiotensin (1-7), a peptide that also belongs to the RAS, acts as a substrate of nACE and an inhibitor of cACE. We have synthetized 15 derivatives of Ang (1-7), sequentially removing the N-terminal amino acids and modifying peptides extremities, to find molecules with improved selectivity and inhibition properties. Ac-Ang (2-7)-NH2 is a good ACE inhibitor, resistant to cleavage and with improved cACE selectivity. Molecular dynamics simulations provided a model for this peptide's selectivity, due to Val3 and Tyr4 interactions with ACE subsites. Val3 has an important interaction with the S3 subsite, since its removal greatly reduced peptide-enzyme interactions. Taken together, our findings support ongoing studies using insights from the binding of Ac-Ang (2-7)-NH2 to develop effective cACE inhibitors.

The prognostic importance of the angiotensin II/angiotensin-(1-7) ratio in patients with SARS-CoV-2 infection.

BACKGROUND: Information about angiotensin II (Ang II), angiotensin-converting enzyme 2 (ACE2), and Ang-(1-7) levels in patients with COVID-19 is scarce. OBJECTIVE: To characterize the Ang II-ACE2-Ang-(1-7) axis in patients with SARS-CoV-2 infection to understand its role in pathogenesis and prognosis. METHODS: Patients greater than 18 years diagnosed with COVID-19, based on clinical findings and positive RT-PCR test, who required hospitalization and treatment were included. We compared Ang II, aldosterone, Ang-(1-7), and Ang-(1-9) concentrations and ACE2 concentration and activity between COVID-19 patients and historic controls. We compared baseline demographics, laboratory results (enzyme, peptide, and inflammatory marker levels), and outcome (patients who survived versus those who died). RESULTS: Serum from 74 patients [age: 58 (48-67.2) years; 68% men] with moderate (20%) or severe (80%) COVID-19 were analyzed. During 13 (10-21) days of hospitalization, 25 patients died from COVID-19 and 49 patients survived. Compared with controls, Ang II concentration was higher and Ang-(1-7) concentration was lower, despite significantly higher ACE2 activity in patients. Ang II concentration was higher and Ang-(1-7) concentration was lower in patients who died. The Ang II/Ang-(1-7) ratio was significantly higher in patients who died. In multivariate analysis, Ang II/Ang-(1-7) ratio greater than 3.45 (OR = 5.87) and lymphocyte count ⩽0.65 × 103/µl (OR = 8.43) were independent predictors of mortality from COVID-19. CONCLUSION: In patients with severe SARS-CoV-2 infection, imbalance in the Ang II-ACE2-Ang-(1-7) axis may reflect deleterious effects of Ang II and may indicate a worse outcome.

Correlation between Angiotensin Serum Levels and Very-Low-Frequency Spectral Power of Heart Rate Variability during Hemodialysis.

Cardiovascular regulatory mechanisms that fail to compensate for ultrafiltration and cause hypovolemia during hemodialysis (HD) are not completely understood. This includes the interaction between the autonomic nervous system and the biochemistry that regulates blood pressure and modulates cardiac activity and vascular tone in response to hypovolemia in patients treated with HD. The objective was to evaluate the association of spectral indices of heart rate variability (HRV) with serum levels of angiotensin II, angiotensin 1-7, nitric oxide and total antioxidant capacity during HD. Electrocardiographic records were obtained from 20 patients during HD (3 h), from which HRV data and spectral power data in the very-low-frequency (VLF), low-frequency (LF) and high-frequency (HF) bands were generated. Three blood samples per patient were collected during HD (0.0, 1.5, 3.0 h) to determine the levels of biomarkers involved in the pressor response during HD. Angiotensin II had a positive correlation with VLF (r = 0.390) and with LF/HF (r = 0.359) and a negative correlation with LF (r = -0.262) and HF (r = -0.383). There were no significant correlations between HRV and the other biomarkers. These results suggest that during HD, VLF could reflect the serum levels of angiotensin II, which may be associated with the autonomic response to HD.

The potential role of renin-angiotensin system in mild traumatic brain injury.

Traumatic brain injury (TBI) is a serious public health problem, affecting 69 million people worldwide annually. Mild TBI (mTBI) comprises the majority of the cases and remains the most neglected TBI severity. Its intricate pathophysiology involves complex cellular and molecular processes that remain uncomprehended. Although the renin-angiotensin system (RAS) has its well-known roles in blood pressure regulation and fluid balance, accumulating evidence demonstrates its active expression and signaling in the central nervous system. Over the past years, pre-clinical studies have been supporting the role of RAS in mTBI. However, particularly for human TBI, evidence is still missing. Herein, we investigated peripheral levels of angiotensin II (Ang II) and angiotensin-converting enzyme (ACE), components of RAS classical axis, as well as angiotensin-(1-7) [Ang-(1-7)] and ACE2, components of RAS counter-regulatory axis, in 28 mTBI patients and 24 healthy controls. In the first 24 h, mTBI patients displayed lower ACE (p = 0.0004) and ACE2 (p = 0.0047) concentrations and an increase in Ang II (p = 0.0234) and Ang-(1-7) (p = 0.0225) levels compared to controls. Interestingly, at 30 days follow-up, mTBI patients increased the levels of ACE (p = 0.0415) and ACE2 (p = 0.0416) along with a decrease in Ang II (p = 0.0039) and Ang-(1-7) (p = 0.0015) concentrations compared with their measures at 24 h after TBI. Also, our receiver operating curve (ROC) analysis demonstrated that ACE concentration was a good predictor of mTBI diagnosis (AUC = 0.798, p < 0.0001). The current study provides the first clinical evidence of RAS molecule's involvement in mTBI and their possible role as discriminating biomarkers.

Combined Administration of Andrographolide and Angiotensin- (1-7) Synergically Increases the Muscle Function and Strength in Aged Mice.

BACKGROUND: Sarcopenia is a progressive and generalized skeletal muscle disorder characterized by muscle weakness, loss of muscle mass, and decline in the capacity of force generation. Aging can cause sarcopenia. Several therapeutic strategies have been evaluated to prevent or alleviate this disorder. One of them is angiotensin 1-7 [Ang-(1-7)], an anti-atrophic peptide for skeletal muscles that regulates decreased muscle mass for several causes, including aging. Another regulator of muscle mass and function is andrographolide, a bicyclic diterpenoid lactone that decreases the nuclear factor kappa B (NF-κB) signaling and attenuates the severity of some muscle diseases. OBJECTIVE: Evaluate the effect of combined administration of Ang-(1-7) with andrographolide on the physical performance, muscle strength, and fiber´s diameter in a murine model of sarcopenia by aging. METHODS: Aged male mice of the C57BL/6J strain were treated with Andrographolide, Ang-(1-7), or combined for three months. The physical performance, muscle strength, and fiber´s diameter were measured. RESULTS: The results showed that aged mice (24 months old) treated with Ang-(1-7) or Andrographolide improved their performance on a treadmill test, muscle strength, and their fiber´s diameter compared to aged mice without treatment. The combined administration of Ang-(1-7) with andrographolide to aged mice has an enhanced synergically effect on physical performance, muscle strength, and fiber´s diameter. CONCLUSION: Our results indicated that in aged mice, the effects of andrographolide and Ang-(1-7) on muscle function, strength, and fiber´s diameter are potentiated.

Renin-angiotensin system: Basic and clinical aspects-A general perspective.

The renin-angiotensin system (RAS) is one of the most complex hormonal regulatory systems, involving several organs that interact to regulate multiple body functions. The study of this system initially focused on investigating its role in the regulation of both cardiovascular function and related pathologies. From this approach, pharmacological strategies were developed for the treatment of cardiovascular diseases. However, new findings in recent decades have suggested that the RAS is much more complex and comprises two subsystems, the classic RAS and an alternative RAS, with antagonistic effects that are usually in equilibrium. The classic system is involved in pathologies where inflammatory, hypertrophic and fibrotic phenomena are common and is related to the development of chronic diseases that affect various body systems. This understanding has been reinforced by the evidence that local renin-angiotensin systems exist in many tissue types and by the role of the RAS in the spread and severity of COVID-19 infection, where it was discovered that viral entry into cells of the respiratory system is accomplished through binding to angiotensin-converting enzyme 2, which is present in the alveolar epithelium and is overexpressed in patients with chronic cardiometabolic diseases. In this narrative review, preclinical and clinical aspects of the RAS are presented and topics for future research are discussed some aspects are raised that should be clarified in the future and that call for further investigation of this system.

El sistema renina angiotensina es uno de los sistemas de regulación hormonal más complejos, pues participan varios órganos qué interactúan entre sí para regular múltiples funciones corporales. En un inicio el estudio de este sistema se enfocó en investigar su papel en la regulación, tanto de la función cardiovascular como de las enfermedades relacionadas. A partir de este enfoque se desarrollaron estrategias farmacológicas para el tratamiento de enfermedades cardiovasculares. Sin embargo, en las últimas décadas y con nuevos hallazgos se ha planteado que el sistema renina angiotensina es un sistema mucho más complejo constituido por 2 subsistemas, uno clásico y otro alternativo que tienen efectos antagónicos, normalmente en equilibrio. El predominio del sistema clásico está involucrado en enfermedades donde los fenómenos inflamatorios, hipertróficos y fibróticos son comunes y se relacionan con el desarrollo de enfermedades crónicas que afectan diversos sistemas. Esto se ha reforzado por la evidencia de que existen sistemas renina angiotensina locales en muchos tejidos, y por el papel del sistema renina angiotensina en la propagación y severidad de la infección por la COVID-19, en donde se descubrió que el ingreso del virus en el sistema respiratorio se realiza a través de la enzima convertidora de angiotensina 2, presente en el epitelio alveolar y que se sobreexpresa en pacientes con enfermedades cardiometabólicas crónicas. En la presente revisión narrativa se presentan aspectos preclínicos y clínicos de ese sistema y se plantean algunos aspectos que se deben aclarar en el futuro y que demandarán más investigación de este sistema.