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1.
J Am Heart Assoc ; 8(7): e011100, 2019 04 02.
Article in English | MEDLINE | ID: mdl-30929550

ABSTRACT

Background Obesity is a precursor to heart failure with preserved ejection fraction. Biomarkers that identify preclinical metabolic heart disease ( MHD ) in young obese patients would help identify high-risk individuals for heart failure prevention strategies. We assessed the predictive value of GAL3 (galectin-3), FSTL3 (follistatin-like 3 peptide), and NT-proBNP (N-terminal pro-B-type natriuretic peptide) to identify stage B MHD in young obese participants free of clinically evident cardiovascular disease. Methods and Results Asymptomatic obese patients (n=250) and non-obese controls (n=21) underwent echocardiographic cardiac phenotyping. Obese patients were classified as MHD positive ( MHD - POS ; n=94) if they had abnormal diastolic function or left ventricular hypertrophy and had estimated pulmonary artery systolic pressure ≥35 mm Hg. Obese patients without such abnormalities were classified as MHD negative (MHD-NEG; n=52). Serum biomarkers timed with echocardiography. MHD - POS and MHD-NEG individuals were similarly obese, but MHD - POS patients were older, with more diabetes mellitus and metabolic syndrome. Right ventricular coupling was worse in MHD - POS patients ( P<0.001). GAL 3 levels were higher in MHD - POS versus MHD -NEG patients (7.7±2.3 versus 6.3±1.9 ng/mL, respectively; P<0.001). Both GAL 3 and FSTL 3 levels correlated with diastolic dysfunction and increased pulmonary artery systolic pressure but not with left ventricular mass. In multivariate models including all 3 biomarkers, only GAL 3 remained associated with MHD (odds ratio: 1.30; 95% CI , 1.01-1.68; P=0.04). Conclusions In young obese individuals without known cardiovascular disease, GAL 3 is associated with the presence of preclinical MHD . GAL 3 may be useful in screening for preclinical MHD and identifying individuals with increased risk of progression to obesity-related heart failure with preserved ejection fraction.


Subject(s)
Galectin 3/metabolism , Heart Failure/diagnosis , Hypertension, Pulmonary/diagnosis , Metabolic Diseases/diagnosis , Obesity/complications , Adult , Biomarkers/metabolism , Blood Proteins , Case-Control Studies , Echocardiography , Female , Follistatin-Related Proteins/metabolism , Galectins , Heart Failure/physiopathology , Hemodynamics/physiology , Humans , Hypertension, Pulmonary/physiopathology , Hypertrophy, Left Ventricular/diagnosis , Male , Metabolic Diseases/physiopathology , Middle Aged , Natriuretic Peptide, Brain/metabolism , Obesity/physiopathology , Peptide Fragments/metabolism
2.
Circ Heart Fail ; 8(5): 897-904, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26175540

ABSTRACT

BACKGROUND: Despite the substantial overlap of obesity and metabolic disease, there is heterogeneity with respect to cardiovascular risk. We sought to investigate preclinical differences in systolic and diastolic function in obesity, and specifically compare obese individuals with and without metabolic syndrome (MS). METHODS AND RESULTS: Obese individuals without cardiac disease with (OB/MS+, n=124) and without (OB/MS-, n=37) MS were compared with nonobese controls (n=29). Diastolic function was assessed by transmitral and tissue Doppler. Global longitudinal strain (LS) and time-based dyssynchrony were assessed by speckle tracking. Both OB/MS- and OB/MS+ groups had similar ejection fraction but worse systolic mechanics as assessed by LS and dyssynchrony when compared with nonobese controls. Specifically, OB/MS- had 2.5% lower LS (SE, 0.7%; P=0.001 in multivariable-adjusted analyses) and 10.8 ms greater dyssynchrony (SE, 3.3 ms; P=0.002), and OB/MS+ had 1.0% lower LS (SE, 0.3%; P<0.001) and 7.8 ms greater dyssynchrony (SE, 1.5 ms; P<0.001) when compared with controls. Obesity was associated with impaired diastolic function regardless of MS status, as evidenced by greater left atrial diameter and left ventricular mass although diastolic dysfunction was more pronounced in OB/MS+ than in OB/MS- individuals. CONCLUSIONS: Obesity is associated with subclinical differences in both systolic and diastolic function regardless of the presence or absence of MS although MS seems to be associated with worse diastolic dysfunction. When compared with controls, metabolically healthy obese had lower LS, greater dyssynchrony, and early diastolic dysfunction, supporting the notion that obesity per se may have adverse cardiovascular effects regardless of metabolic disease.


Subject(s)
Heart Ventricles/physiopathology , Metabolic Syndrome/physiopathology , Obesity/physiopathology , Stroke Volume , Ventricular Dysfunction, Left/physiopathology , Ventricular Function, Left/physiology , Adult , Diastole , Echocardiography, Doppler , Female , Heart Ventricles/diagnostic imaging , Humans , Male , Metabolic Syndrome/complications , Obesity/complications , Risk Factors , Systole , Ventricular Dysfunction, Left/diagnostic imaging , Ventricular Dysfunction, Left/etiology
3.
J Am Heart Assoc ; 4(3): e001597, 2015 Mar 10.
Article in English | MEDLINE | ID: mdl-25758604

ABSTRACT

BACKGROUND: Metabolic disease can lead to intrinsic pulmonary hypertension in experimental models. The contributions of metabolic syndrome (MetS) and obesity to pulmonary hypertension and right ventricular dysfunction in humans remain unclear. We investigated the association of MetS and obesity with right ventricular structure and function in patients without cardiovascular disease. METHODS AND RESULTS: A total of 156 patients with MetS (mean age 44 years, 71% women, mean body mass index 40 kg/m(2)), 45 similarly obese persons without MetS, and 45 nonobese controls underwent echocardiography, including pulsed wave Doppler measurement of pulmonary artery acceleration time (PAAT) and ejection time. Pulmonary artery systolic pressure was estimated from PAAT using validated equations. MetS was associated with lower tricuspid valve e' (right ventricular diastolic function parameter), shorter PAAT, shorter ejection time, and larger pulmonary artery diameter compared with controls (P<0.05 for all). Estimated pulmonary artery systolic pressure based on PAAT was 42±12 mm Hg in participants with MetS compared with 32±9 and 32±10 mm Hg in obese and nonobese controls (P for ANOVA <0.0001). After adjustment for age, sex, hypertension, diabetes, body mass index, and triglycerides, MetS remained associated with a 20-ms-shorter PAAT (ß=-20.4, SE=6.5, P=0.002 versus obese). This association persisted after accounting for left ventricular structure and function and after exclusion of participants with obstructive sleep apnea. CONCLUSIONS: MetS is associated with abnormal right ventricular and pulmonary artery hemodynamics, as shown by shorter PAAT and subclinical right ventricular diastolic dysfunction. Estimated pulmonary artery systolic pressures are higher in MetS and preclinical metabolic heart disease and raise the possibility that pulmonary hypertension contributes to the pathophysiology of metabolic heart disease.


Subject(s)
Hemodynamics , Hypertension, Pulmonary/etiology , Metabolic Syndrome/complications , Ventricular Dysfunction, Right/etiology , Ventricular Function, Right , Adult , Arterial Pressure , Case-Control Studies , Diastole , Echocardiography, Doppler, Pulsed , Female , Humans , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/physiopathology , Male , Metabolic Syndrome/diagnosis , Metabolic Syndrome/physiopathology , Middle Aged , Obesity/complications , Obesity/physiopathology , Predictive Value of Tests , Pulmonary Artery/diagnostic imaging , Pulmonary Artery/physiopathology , Risk Factors , Ventricular Dysfunction, Right/diagnosis , Ventricular Dysfunction, Right/physiopathology , Ventricular Function, Left
4.
Am J Cardiol ; 114(6): 838-42, 2014 Sep 15.
Article in English | MEDLINE | ID: mdl-25084691

ABSTRACT

Metabolic syndrome (MS) is commonly associated with left ventricular (LV) diastolic dysfunction and LV hypertrophy. We sought to examine whether preclinical LV diastolic dysfunction can occur independent of LV hypertrophy in MS. We recruited 90 consecutive participants with MS and without cardiovascular disease (mean age 46 years, 78% women) and 26 controls (no risk factors for MS; mean age 43 years, 65% women). Participants underwent echocardiography with tissue Doppler imaging. In age- and gender-adjusted analyses, MS was associated with higher left atrial (LA) diameter, higher LV mass, lower E/A ratio, and lower mean e' (p <0.001 for all). These associations remained significant after further adjusting for blood pressure, antihypertensive medication use, and body mass index. After adjusting for LV mass, MS remained independently associated with higher LA diameter, lower E/A ratio, and lower mean e' (p ≤0.01 for all). Specifically, subjects with MS had a 1.8 cm/s lower mean e' compared with controls (p = 0.01). Notably, differences in mean e' between those with and without MS were more pronounced at younger ages (p for interaction = 0.003). In conclusion, MS was associated with preclinical LV diastolic dysfunction independent of LV mass, as reflected by higher LA diameter, lower E/A ratio, and lower mean e'. This suggests that MS can lead to the development of diastolic dysfunction through mechanisms independent of hypertrophy. Differences in diastolic function were more pronounced at younger ages, highlighting the potential importance of early risk factor modification and preventive strategies in MS.


Subject(s)
Heart Ventricles/diagnostic imaging , Metabolic Syndrome/complications , Ventricular Dysfunction, Left/etiology , Adult , Cross-Sectional Studies , Diastole , Echocardiography, Doppler, Pulsed , Female , Follow-Up Studies , Heart Ventricles/physiopathology , Humans , Incidence , Male , Massachusetts/epidemiology , Metabolic Syndrome/physiopathology , Middle Aged , Prevalence , Ventricular Dysfunction, Left/epidemiology , Ventricular Dysfunction, Left/physiopathology
5.
Am J Cardiol ; 113(4): 691-6, 2014 Feb 15.
Article in English | MEDLINE | ID: mdl-24484862

ABSTRACT

Despite significant advances in therapies for patients with heart failure with reduced ejection fraction (HFrEF), there are no evidence-based therapies for heart failure with preserved ejection fraction (HFpEF), also known as diastolic heart failure (HF). Differences in pathophysiologic mechanisms are touted as to why patients with HFpEF purportedly do not derive similar therapeutic benefits compared with HFrEF. Similarly, the relative frequencies of HFpEF and HFrEF may differ between hospitalized and ambulatory settings. There are limited data on the prevalence, characteristics, treatment, and short-term outcomes of patients hospitalized with HFpEF. We sought to investigate these in patients hospitalized with HFpEF in an urban, hospitalized setting using the Get With The Guidelines registry. We retrospectively reviewed all consecutive discharges (n = 1,701) with a diagnosis of acute decompensated HF from December 1, 2006 to September 30, 2008. Patients with HFpEF (n = 499) were older, overweight, predominantly women, and had underlying hypertension and dyslipidemia. Presenting blood pressure and levels of creatinine were higher, with lower brain natriuretic peptide levels compared with patients with HFrEF (n = 598). Length of stay and 30-day mortality were comparable between patients with HFpEF and HFrEF. Thirty-day readmission was initially lower in patients with HFpEF. However 30-day mortality from any cause after the index HF hospitalization and survival curve at 1-year was no different between patients with HFpEF and HFrEF. In conclusion, lower 30-day readmissions do not translate into improved long-term outcome in patients with HFpEF.


Subject(s)
Heart Failure/physiopathology , Hospitalization/statistics & numerical data , Length of Stay/statistics & numerical data , Stroke Volume/physiology , Ventricular Dysfunction, Left/physiopathology , Ventricular Function, Left/physiology , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Retrospective Studies , Survival Rate , Urban Population
6.
J Am Heart Assoc ; 1(5): e000760, 2012 Oct.
Article in English | MEDLINE | ID: mdl-23316284

ABSTRACT

BACKGROUND: Galectin-3 (GAL-3), a ß-galactoside-binding protein, is a new clinical biomarker believed to reflect cardiac remodeling/fibrosis in patients with heart failure (HF). Plasma GAL-3 is inversely related to renal function. It is not known whether the relationship between renal function and GAL-3 is influenced by clinical decompensation, type of HF, or the presence or absence of clinical HF. METHODS AND RESULTS: Patients were prospectively categorized as having acute decompensated HF or stable HF on the basis of clinical status and as having HF with reduced left ventricular ejection fraction or HF with preserved left ventricular ejection fraction. Plasma GAL-3 was measured by enzyme-linked immunosorbent assay in patients with HF (n=75), control patients without HF (n=32), and control patients without HF with moderate renal insufficiency (n=12). Compared to controls without HF (14±4 ng/mL), GAL-3 was higher in patients with both acute decompensated HF (23±11 ng/mL) and stable HF (22±10 ng/mL) (P<0.001 versus controls for both) but did not differ between acute decompensated HF and stable HF (P=0.75). Likewise, GAL-3 was elevated in both HF with preserved left ventricular ejection fraction (23±9 ng/mL) and HF with reduced left ventricular ejection fraction (22±11 ng/mL) (P<0.001 versus controls for both) but did not differ between HF with preserved ejection fraction and HF with reduced ejection fraction (P=0.37). GAL-3 correlated strongly with estimated glomerular filtration rate, both in patients with HF (r=-0.75, P<0.001) and in patients without HF (r=-0.82, P<0.001), and this relationship was unaffected by the presence or absence of clinical HF. CONCLUSIONS: Plasma GAL-3 is inversely related to renal function in patients with and without clinical HF. Concentrations of plasma GAL-3 do not seem to depend on the level of compensation or type of HF. Furthermore, the relationship between GAL-3 and renal function seems to be affected little or not at all by the presence or absence of clinical HF.


Subject(s)
Galectin 3/blood , Heart Failure/blood , Heart/physiopathology , Renal Insufficiency/blood , Aged , Biomarkers/blood , Female , Heart Failure/physiopathology , Humans , Kidney/physiopathology , Kidney Function Tests , Male , Middle Aged , Prospective Studies , Renal Insufficiency/physiopathology , Stroke Volume
8.
Am J Physiol Heart Circ Physiol ; 295(5): H1956-65, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18775851

ABSTRACT

The cardiotoxic effects of doxorubicin, a potent chemotherapeutic agent, have been linked to DNA damage, oxidative mitochondrial damage, and nuclear translocation of p53, but the exact molecular mechanisms causing p53 transactivation and doxorubicin-induced cardiomyopathy are not clear. The present study was carried out to determine whether extracellular signal-regulated kinases (ERKs), which are known to be activated by DNA damaging agents, are responsible for doxorubicin-induced p53 activation and oxidative mitochondrial damage in H9c2 cells. Cell death was measured by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling, annexin V-fluorescein isothiocyanate, activation of caspase-9 and -3, and cleavage of poly(ADP-ribose) polymerase (PARP). We found that doxorubicin produced cell death in H9c2 cells in a time-dependent manner, beginning at 6 h, and these changes are associated decreased expression of Bcl-2, increases in Bax and p53 upregulated modulator of apoptosis-alpha expression, and collapse of mitochondria membrane potential. The changes in cell death and Bcl-2 family proteins, however, were preceded by earlier activation and nuclear translocation of ERKs, followed by increased phosphorylation at Ser15 and nuclear translocation of the phosphorylated p53. The functional importance of ERK1/2 and p53 in doxorubicin-induced toxicity was further demonstrated by the specific ERK inhibitor U-0126 and p53 inhibitor pifithrin (PFT)-alpha, which abrogated the changes in Bcl-2 family proteins and cell death produced by doxorubicin. U-0126 blocked the phosphorylation and nuclear translocation of both ERK1/2 and p53, whereas PFT-alpha blocked only the changes in p53. Doxorubicin and ERK inhibitors produced similar changes in ERK1/2-p53, PARP, and caspase-3 in neonatal rat cultured cardiomyocytes. Thus we conclude that ERK1/2 are functionally linked to p53 and that the ERK1/2-p53 cascade is the upstream signaling pathway responsible for doxorubicin-induced cardiac cell apoptosis. ERKs and p53 may be considered as novel therapeutic targets for the treatment of doxorubicin-induced cardiotoxicity.


Subject(s)
Antibiotics, Antineoplastic/toxicity , Apoptosis/drug effects , Doxorubicin/toxicity , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Myocytes, Cardiac/drug effects , Signal Transduction/drug effects , Tumor Suppressor Protein p53/metabolism , Active Transport, Cell Nucleus , Animals , Animals, Newborn , Benzothiazoles/pharmacology , Butadienes/pharmacology , Caspases/metabolism , Cells, Cultured , Membrane Potential, Mitochondrial/drug effects , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Myocytes, Cardiac/enzymology , Myocytes, Cardiac/pathology , Nitriles/pharmacology , Phosphorylation , Poly(ADP-ribose) Polymerases/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Rats, Sprague-Dawley , Time Factors , Toluene/analogs & derivatives , Toluene/pharmacology , Tumor Suppressor Protein p53/antagonists & inhibitors , bcl-2-Associated X Protein/metabolism
9.
Autoimmunity ; 41(6): 434-41, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18781469

ABSTRACT

An anti-beta(1)-adrenergic receptor antibody against the second extracellular receptor loop (beta(1)-EC(II)) has been shown to cause myocyte apoptosis and dilated cardiomyopathy in animals. We report in this review that the anti-beta(1)-EC(II) antibody increases intracellular Ca(++) transients and exerts a direct apoptotic effect in cultured neonatal rat cardiomyocytes. Both Fab and Fc fragments are required for the full expression of the apoptotic effects of the anti-beta(1)-EC(II) antibody. Our studies further suggest that the anti-beta(1)-EC(II)-antibody acts primarily on the cardiac beta(1)-adrenergic receptor and its post-receptor activation of Ca(++)/Calmodulin dependent protein kinase II (CaMKII) and p-38 mitogen-activated protein kinase (MAPK), leading to endoplasmic reticulum stress as evidenced by the increased expressions of GRP78 and CHOP, as well as the increased processing of the initiator procaspase-12. Also, observed with the apoptotic effect of anti-beta(1)-EC(II) antibody is reduced activity of the phosphatidylinositol (PI) 3-kinase/Akt/STAT3 signaling pathway. Our results suggest that agents that block the activation of p38-MAPK/endoplasmic reticulum stress or reverse the suppression of the prosurvival PI3K/Akt/STAT3 pathway may be explored as potential novel therapeutic modalities in the treatment of dilated cardiomyopathy.


Subject(s)
Antibodies/pharmacology , Apoptosis , Endoplasmic Reticulum/metabolism , Immunoglobulin G/pharmacology , Myocytes, Cardiac/metabolism , Phosphatidylinositol 3-Kinases/physiology , Proto-Oncogene Proteins c-akt/physiology , Receptors, Adrenergic, beta-1/immunology , Animals , Antibodies/immunology , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , Cardiomyopathies/immunology , Cardiomyopathies/metabolism , Caspase 12/metabolism , Cells, Cultured , Endoplasmic Reticulum/drug effects , Enzyme Activation , Immunoglobulin G/immunology , Myocytes, Cardiac/cytology , Myocytes, Cardiac/drug effects , Rats , Signal Transduction
10.
J Mol Cell Cardiol ; 45(2): 250-60, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18586265

ABSTRACT

Dilated human cardiomyopathy is associated with suppression of the prosurvival phosphatidylinositol-3-kinase (PI3K)/Akt and STAT3 pathways. The present study was carried out to determine if restoration of the PI3K/Akt and STAT3 activity by darbepoetin alfa improved cardiac function or reduced cardiomyocyte apoptosis in rabbit autoimmune cardiomyopathy induced by a peptide corresponding to the second extracellular loop of the ss(1)-adrenergic receptor (ss(1)-EC(II)). We found that ss(1)-EC(II) immunization produced progressive LV dilation, systolic dysfunction and myocyte apoptosis as measured by TUNEL, single-stranded DNA antibody, and active caspase-3. These changes were associated with activation of p38 mitogen-activated protein kinase (MAPK), endoplasmic reticulum stress markers (GRP78 and CHOP), and increased cleavage of procaspase-12, as well as decreased phosphorylation of Akt and STAT3, and decreased Bcl2/Bax ratio. As expected, darbepoetin alfa treatment increased phosphorylation of Akt and STAT3. It also increased the myocardial expression of erythropoietin receptor which was reduced in the failing myocardium, and improved cardiac function in the ss(1)-EC(II)-immunized animals. The latter was associated with reductions of myocyte apoptosis and cleaved caspase-3, as well as reversal of increased phosphorylation of p38-MAPK, increased ER stress, and decline in Bcl2/Bax ratio. The anti-apoptotic effects of darbepoetin alfa via Akt and STAT activation were also demonstrated in cultured cardiomyocytes treated with the anti-ss(1)-EC(II) antibody. These effects of darbepoetin alfa in vitro were prevented by LY294002 and STAT3 peptide inhibitor. Thus, we conclude that darbepoetin alfa improves cardiac function and prevents progression of dilated cardiomyopathy probably by activating the PI3K/Akt and STAT3 pathways and reducing ER stress.


Subject(s)
Cardiomyopathy, Dilated/drug therapy , Endoplasmic Reticulum/drug effects , Erythropoietin/analogs & derivatives , Oxidative Stress/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Animals , Animals, Newborn , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , Cardiomyopathy, Dilated/immunology , Cardiomyopathy, Dilated/pathology , Cardiotonic Agents/therapeutic use , Cells, Cultured , Darbepoetin alfa , Endoplasmic Reticulum Chaperone BiP , Erythropoietin/therapeutic use , Humans , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/immunology , Rabbits , Rats , Rats, Sprague-Dawley , Signal Transduction/physiology
11.
J Mol Cell Cardiol ; 44(2): 304-14, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18155231

ABSTRACT

Auto-antibodies against the beta(1)-adrenoceptors are present in 30-40% of patients with dilated cardiomyopathy. Recently, a synthetic peptide corresponding to a sequence of the second extracellular loop of the human beta(1)-adrenoceptor (beta(1)-EC(II)) has been shown to produce endoplasmic reticulum (ER) stress, myocyte apoptosis and cardiomyopathy in immunized rabbits. To study the direct cardiac effects of anti-beta(1)-EC(II) antibody in intact animals and if they are mediated via beta(1)-adrenoceptor stimulation, we administered IgG purified from beta(1)-EC(II)-immunized rabbits to recombination activating gene 2 knock-out (Rag2(-/-)) mice every 2 weeks with and without metoprolol treatment. Serial echocardiography and cardiac catheterization showed that beta(1)-EC(II) IgG reduced cardiac systolic function after 3 months. This was associated with increase in heart weight, myocyte apoptosis, activation of caspase-3, -9 and -12, and increased ER stress as evidenced by upregulation of GRP78 and CHOP and cleavage of ATF6. The Rag2(-/-) mice also exhibited increased phosphorylation of CaMKII and p38 MAPK. Metoprolol administration, which attenuated the phosphorylation of CaMKII and p38 MAPK, reduced the ER stress, caspase activation and cell death. Finally, we employed the small-interfering RNA technology to reduce caspase-12 in cultured rat cardiomyocytes. This reduced not only the increase of cleaved caspase-12 but also of the number of myocyte apoptosis produced by beta(1)-EC(II) IgG. Thus, we conclude that ER stress plays an important role in cell death and cardiac dysfunction in beta(1)-EC(II) IgG cardiomyopathy, and the effects of beta(1)-EC(II) IgG are mediated via the beta(1)-adrenergic receptor.


Subject(s)
Adoptive Transfer , Cardiomyopathies/immunology , DNA-Binding Proteins/deficiency , Endoplasmic Reticulum/pathology , Peptides/immunology , Receptors, Adrenergic, beta-1/immunology , Animals , Apoptosis/drug effects , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Cardiomyopathies/diagnostic imaging , Cardiomyopathies/enzymology , Caspase 12/metabolism , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum Chaperone BiP , Enzyme Activation/drug effects , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Hemodynamics/drug effects , Immunoglobulin G/immunology , Metoprolol/pharmacology , Mice , Mitogen-Activated Protein Kinases/metabolism , Myocytes, Cardiac/cytology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/enzymology , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , RNA, Small Interfering/metabolism , Rabbits , Rats , Ultrasonography
12.
Am J Physiol Heart Circ Physiol ; 293(3): H1636-45, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17545481

ABSTRACT

Evidence suggests that the autoimmune cardiomyopathy produced by a peptide corresponding to the sequence of the second extracellular loop of the beta(1)-adrenergic receptor (beta(1)-EC(II)) is mediated via a biologically active anti-beta(1)-EC(II) antibody, but the mechanism linking the antibody to myocyte apoptosis and cardiac dysfunction has not been well elucidated. Since the beta(1)-EC(II) autoantibody is a partial beta(1)-agonist, we speculate that the cardiomyopathy is produced by the beta(1)-receptor-mediated stimulation of the CaMKII-p38 MAPK-ATF6 signaling pathway and endoplasmic reticulum (ER) stress, and that excess norepinephrine (NE) exaggerates the cardiomyopathy. Rabbits were randomized to receive beta(1)-EC(II) immunization, sham immunization, NE pellet, or beta(1)-EC(II) immunization plus NE pellet for 6 mo. Heart function was measured by echocardiography and catheterization. Myocyte apoptosis was determined by terminal deoxytransferase-mediated dUTP nick-end labeling and caspase-3 activity, whereas CaMKII, MAPK family (JNK, p38, ERK), and ER stress signals (ATF6, GRP78, CHOP, caspase-12) were measured by Western blot, immunohistochemistry, and kinase activity assay. beta(1)-EC(II) immunization produced progressive LV dilation, systolic dysfunction, and myocyte apoptosis. These changes were associated with activation of GRP78 and CHOP and increased cleavage of caspase-12, as well as increased CaMKII activity, increased phosphorylation of p38 MAPK, and nucleus translocation of cleaved ATF6. NE pellet produced additive effects. In addition, KN-93 and SB 203580 abolished the induction of ER stress and cell apoptosis produced by the beta(1)-EC(II) antibody in cultured neonatal cardiomyocytes. Thus ER stress occurs in autoimmune cardiomyopathy induced by beta(1)-EC(II) peptide, and this is enhanced by increased NE and caused by activation of the beta(1)-adrenergic receptor-coupled CaMKII, p38 MAPK, and ATF6 pathway.


Subject(s)
Apoptosis/physiology , Autoimmune Diseases/pathology , Cardiomyopathies/pathology , Endoplasmic Reticulum/physiology , Myocytes, Cardiac/pathology , Norepinephrine/physiology , Activating Transcription Factor 6/physiology , Adrenergic alpha-Agonists/pharmacology , Animals , Autoimmune Diseases/metabolism , Autoimmune Diseases/physiopathology , Blood Pressure/drug effects , Blood Pressure/physiology , Calcium-Calmodulin-Dependent Protein Kinase Type 2 , Calcium-Calmodulin-Dependent Protein Kinases/physiology , Cardiomyopathies/metabolism , Cardiomyopathies/physiopathology , Caspase 3/metabolism , Cells, Cultured , Heart Rate/drug effects , Heart Rate/physiology , Immunoglobulin G/pharmacology , Myocytes, Cardiac/metabolism , Norepinephrine/pharmacology , Rabbits , Random Allocation , Receptors, Adrenergic, beta-1/physiology , Signal Transduction/drug effects , Signal Transduction/physiology , p38 Mitogen-Activated Protein Kinases/physiology
13.
Acta Pharmacol Sin ; 28(7): 921-7, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17588326

ABSTRACT

Increased cardiac release of norepinephrine (NE) and depleted cardiac stores of NE are two salient features of the human failing heart. Researches from my laboratory have shown that these changes are accompanied by a functional defect of NE uptake in the cardiac sympathetic nerve terminals. Our studies have shown that the decrease of NE uptake is caused by reduction of NE transporter density in the sympathetic nerve endings, and this change is responsible, at least in part, for the increased myocardial interstitial NE, decreased myocardial adrenoceptor density, and increased myocyte apoptosis in experimental cardiomyopathies. We have also provided evidence in both intact animals and cultured PC12 cells that the decrease of NE transporter is induced by the actions of oxidative metabolites of exogenous NE, involving endoplasmic reticulum stress and impaired N-glycosylation of the NE transporter. This change in the cardiac sympathetic NE uptake function, as demonstrated by [123I] metaiodobenzylguanidine in human studies, may not only serve as an important prognostic variable in patients with congestive heart failure, but also be used as a surrogate for the efficacies of various therapeutic interventions for heart failure. Finally, increasing evidence suggests and further studies are needed to show that the cardiac sympathetic nerve terminal function may be a direct target for pharmacologic treatment of congestive heart failure.


Subject(s)
Heart Failure/physiopathology , Heart/innervation , Norepinephrine/metabolism , Sympathetic Nervous System/physiology , 3-Iodobenzylguanidine , Heart/physiology , Heart Failure/diagnosis , Humans , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Radiopharmaceuticals
14.
Am J Physiol Heart Circ Physiol ; 290(3): H995-1003, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16214845

ABSTRACT

Cardiac sympathetic transmitter stores are reduced in the failing heart. In this study, we proposed to investigate whether the reduction of cardiac sympathetic neurotransmitters was associated with increased interstitial norepinephrine (NE) and reactive oxygen species in congestive heart failure (CHF), using a microdialysis technique and salicylate to detect .OH generation. Rabbits with and without rapid ventricular pacing (340 beats/min) were randomized to receive desipramine (10 mg/day) or placebo for 8 wk. Rapid pacing produced left ventricular dilation and systolic dysfunction. The failing myocardium also showed reduced tissue contents of NE and tyrosine hydroxylase protein and activity. In contrast, myocardial interstitial NE was increased in CHF (0.89 +/- 0.11 ng/ml) compared with the sham-operated animals (0.26 +/- 0.03 ng/ml). In addition, cardiac oxidative stress was increased in CHF animals as measured by myocardial interstitial .OH radical, tissue oxidized glutathione, and oxidized mitochondrial DNA. Desipramine treatment produced significant NE uptake inhibition as evidence by an exaggerated pressor response and a greater increase of myocardial interstitial NE in response to intravenous NE infusion but no significant effects on cardiac function or hemodynamics in sham-operated or CHF animals. However, desipramine treatment attenuated the reductions of tissue NE and tyrosine hydroxylase protein and activity in CHF. Desipramine also prevented the reduction of tyrosine hydroxylase produced by NE in PC12 cells. Thus the reduction of cardiac sympathetic neurotransmitters is related to the increased interstitial NE and tissue oxidative stress in CHF. Also, normal neuronal uptake of NE is required for NE or its oxidized metabolites to exert their neurotoxic effects.


Subject(s)
Cardiomyopathies/drug therapy , Cardiomyopathies/metabolism , Desipramine/administration & dosage , Norepinephrine/metabolism , Reactive Oxygen Species/metabolism , Sympathetic Nervous System/metabolism , Tachycardia/metabolism , Animals , Cardiac Pacing, Artificial/adverse effects , Cardiomyopathies/etiology , Heart/drug effects , Heart/innervation , Neuroprotective Agents/administration & dosage , Rabbits , Sympathetic Nervous System/drug effects , Tachycardia/complications , Tachycardia/drug therapy , Treatment Outcome
15.
Am J Physiol Cell Physiol ; 290(5): C1373-84, 2006 May.
Article in English | MEDLINE | ID: mdl-16338971

ABSTRACT

Norepinephrine (NE) induces endoplasmic reticulum (ER) unfolded protein response and reduces maturation and translocation of NE transporter to cell membrane via enhanced formation of reactive oxygen species in PC-12 cells. In the present study, we investigated whether ER stress is also implicated in the proapoptotic effect of NE. We found that the apoptotic effect of NE was associated with increased processing of ER-resident pro-caspase-12, cleavage of caspase-9 and -3, and mitochondrial release of cytochrome c. ER stress was evidenced by upregulation of ER chaperone GRP78 and transcription factor CHOP and the translocation of XBP-1 from the ER to the nucleus by NE. NE also reduced phospho-Akt (Ser473), indicating suppression of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt survival pathway. Similar results were produced by thapsigargin. NGF, which promotes the PI3-kinase/Akt activity, reduced the effects of NE and thapsigargin on apoptosis and activation of caspase-12 and -3. However, the effects of NE, but not of thapsigargin, were abolished by pretreatment with SOD and catalase. In contrast, the PI3-kinase inhibitors LY-294002 and wortmannin abolished the protective effects of both SOD/catalase and NGF on NE-induced apoptosis. The functional importance of caspase-12 activation was supported by the use of Z-ATAD-FMK, which reduced the NE-induced processing of caspase-12 and cell apoptosis, but the caspase-12, -9, and -3 inhibitors had no effects on the increase in cytosolic cytochrome c produced by NE. In contrast, the release of mitochondrial cytochrome c was abolished by SOD/catalase and NGF. These results indicate that NE induced cell apoptosis by both ER stress and a mitochondrial death pathway and that the effects of NE were mediated via oxidative stress and inhibition of the PI3-kinase/Akt survival pathway.


Subject(s)
Apoptosis/drug effects , Endoplasmic Reticulum/metabolism , Mitochondria/metabolism , Oxidative Stress/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Signal Transduction/physiology , Animals , Cell Survival/drug effects , Dose-Response Relationship, Drug , Endoplasmic Reticulum/drug effects , Mitochondria/drug effects , PC12 Cells , Rats , Signal Transduction/drug effects
16.
J Am Coll Cardiol ; 46(12): 2298-304, 2005 Dec 20.
Article in English | MEDLINE | ID: mdl-16360062

ABSTRACT

OBJECTIVES: The InSync III study evaluated sequential cardiac resynchronization therapy (CRT) in patients with moderate-to-severe heart failure and prolonged QRS. BACKGROUND: Simultaneous CRT improves hemodynamic and clinical performance in patients with moderate-to-severe heart failure (HF) and a wide QRS. Recent evidence suggests that sequentially stimulating the ventricles might provide additional benefit. METHODS: This multicenter, prospective, nonrandomized, six-month trial enrolled a total of 422 patients to determine the effectiveness of sequential CRT in patients with New York Heart Association (NYHA) functional class III or IV HF and a prolonged QRS. The study evaluated: whether patients receiving sequential CRT for six months experienced improvement in 6-min hall walk (6MHW) distance, NYHA functional class, and quality of life (QoL) over control group patients from the reported Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial; whether sequential CRT increased stroke volume compared to simultaneous CRT; and whether an increase in stroke volume translated into greater clinical improvements compared to patients receiving simultaneous CRT. RESULTS: InSync III patients experienced greater improvement in 6MHW, NYHA functional class, and QoL at six months compared to control (all p < 0.0001). Optimization of the sequential pacing increased (median 7.3%) stroke volume in 77% of patients. No additional improvement in NYHA functional class or QoL was seen compared to the simultaneous CRT group; however, InSync III patients demonstrated greater exercise capacity. CONCLUSIONS: Sequential CRT provided most patients with a modest increase in stroke volume above that achieved during simultaneous CRT. Patients receiving sequential CRT had improved exercise capacity, but no change in functional status or QoL.


Subject(s)
Cardiac Output, Low/physiopathology , Cardiac Output, Low/therapy , Cardiac Pacing, Artificial/methods , Aged , Cardiac Output, Low/diagnosis , Electrocardiography , Female , Hemodynamics , Humans , Male , Middle Aged , Quality of Life , Severity of Illness Index , Time Factors , Treatment Outcome , Walking
17.
Biochim Biophys Acta ; 1740(3): 499-513, 2005 Jun 10.
Article in English | MEDLINE | ID: mdl-15949720

ABSTRACT

To determine the temporal changes in oxidative stress, mitogen-activated protein (MAP) kinases and mitochondrial apoptotic proteins, and their relationship to myocyte apoptosis in the remote noninfarcted myocardium after myocardial infarction (MI), rabbits were randomly assigned to either coronary artery ligation to produce MI or sham operation. The animals were sacrificed at 1, 4, 8, or 12 weeks after coronary artery occlusion. Sham rabbits were sacrificed at 12 weeks after surgery. MI rabbits exhibited progressive increases of left ventricular (LV) end-diastolic pressure and end-diastolic dimension, and progressive decreases of LV fractional shortening and dP/dt over 12 weeks. The LV remodeling with LV chamber dilation and LV systolic dysfunction was temporally associated with progressive increases of cardiac oxidative stress as evidenced by decreased myocardial reduced-to-oxidized-glutathione ratio and increased myocardial 8-hydroxydeoxyguanosine and myocyte apoptosis. The ERK and JNK activities were decreased while p38 MAP kinase activity was increased with age of MI. The extent of p38 MAP kinase activation correlated with Bcl-2 phosphorylation. Bcl-2 protein was decreased in both mitochondrial and cytosolic fractions with age of MI. Bax protein was increased in both mitochondrial and cytosolic fractions. Cytochrome c was reduced in mitochondrial fraction and increased in cytosolic fraction in a time-dependent manner after MI. Cleaved caspase 9 and caspase 3 proteins were time-dependently increased after MI. These data suggest that p38 MAP kinase activation is not only time-dependent after MI, but also correlates with oxidative stress, Bcl-2 phosphorylation, and myocyte apoptosis. These changes in the remote noninfarcted myocardium may contribute to LV remodeling and dysfunction after MI.


Subject(s)
Apoptosis/physiology , Myocardial Infarction/metabolism , Myocardial Infarction/physiopathology , Myocytes, Cardiac/physiology , Signal Transduction/physiology , Ventricular Remodeling/physiology , Animals , Blotting, Western , Cytoplasm/metabolism , Echocardiography , Glutathione/metabolism , Immunohistochemistry , In Situ Nick-End Labeling , Ligation , Male , Mitochondria/metabolism , Mitogen-Activated Protein Kinases/metabolism , Oxidative Stress/physiology , Phosphorylation , Proto-Oncogene Proteins c-bcl-2/metabolism , Rabbits
18.
Am J Physiol Heart Circ Physiol ; 288(5): H2381-9, 2005 May.
Article in English | MEDLINE | ID: mdl-15626688

ABSTRACT

Cardiac norepinephrine (NE) uptake is reduced in cardiomyopathy. This change is associated with a decrease of NE transporter (NET) receptor and can be reproduced in PC12 cells by extracellular NE. To study whether this effect of NE is mediated via impaired glycosylation and trafficking of NET in the endoplasmic reticulum (ER), we measured the distribution of glycosylated 80-kDa NET and unglycosylated 46-kDa NET in the membrane and cytosolic fractions of PC12 cells. We found that NE decreased glycosylated NET in both membrane and cytosolic fractions and increased cytosolic unglycosylated NET protein. Similar results were produced by tunicamycin and thapsigargin, two agents that induce ER stress by inhibiting N-glycosylation of membrane proteins and disrupting calcium homeostasis, respectively. Also, like the ER stressors, NE not only increased phosphorylation of both the alpha-subunit of eukaryotic initiation factor-2 and its upstream RNA-dependent protein kinase-like ER kinase over 12 h of treatment but also increased ER chaperone molecule glucose-regulated protein 78 and the nuclear transcription factor C/EBP homologous protein. Antioxidants superoxide dismutase and catalase prevented the downregulation of NET proteins and induction of ER stress signals produced by NE but not by tunicamycin or thapsigargin. The results indicate that the downregulation of membrane NET by NE is mediated by decreased N-glycosylation of NET proteins secondary to induction of ER stress pathways by NE-derived oxidative metabolites. Interventions involving the ER stress pathways may provide novel therapeutic strategies for the treatment of sympathetic dysfunction in heart failure.


Subject(s)
Endoplasmic Reticulum/metabolism , Norepinephrine/pharmacokinetics , Oxidative Stress/drug effects , Sympathomimetics/pharmacokinetics , Symporters/metabolism , Animals , CCAAT-Enhancer-Binding Proteins/genetics , Catalase/metabolism , Down-Regulation/drug effects , Endoplasmic Reticulum/drug effects , Glycosylation , Heat-Shock Proteins/genetics , Heat-Shock Proteins/metabolism , Ligands , Molecular Chaperones/genetics , Molecular Chaperones/metabolism , Neurons/drug effects , Neurons/metabolism , Norepinephrine Plasma Membrane Transport Proteins , PC12 Cells , Protein Folding , RNA, Messenger/analysis , Rats , Superoxide Dismutase/metabolism , Transcription Factor CHOP , Transcription Factors/genetics , Tritium , Up-Regulation/drug effects
19.
Am J Physiol Heart Circ Physiol ; 287(3): H1003-12, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15105169

ABSTRACT

The present study was carried out to determine whether beneficial effects of carvedilol in congestive heart failure (CHF) are mediated via its beta-adrenergic blocking, antioxidant, and/or alpha-adrenergic blocking action. Rabbits with heart failure induced by rapid cardiac pacing were randomized to receive subcutaneous carvedilol, metoprolol, propranolol plus doxazosin, or placebo pellets for 8 wk and compared with sham-operated rabbits without pacing. We found rapid cardiac pacing produced clinical heart failure, left ventricular dilation, and decline of left ventricular fractional shortening. This was associated with an increase in left ventricular end-diastolic pressure, decrease in left ventricular first derivative of left ventricular pressure, and myocyte hypertrophy. Tissue oxidative stress measured by GSH/GSSG was increased in the heart with increased oxidation product of mitochondrial DNA, 8-oxo-7,8-dihydro-2'-deoxyguanosine, increase of Bax, decrease of Bcl-2, and increase of apoptotic myocytes as measured by anti-single-stranded DNA monoclonal antibody. Administration of carvedilol and metoprolol, which had no effect in sham animals, attenuated cardiac ventricular remodeling, cardiac hypertrophy, oxidative stress, and myocyte apoptosis in CHF. In contrast, propranolol plus doxazosin, which has less antioxidant effects, produced smaller effects on left ventricular function and myocyte apoptosis. In all animals, GSH/GSSG correlated significantly with changes of left ventricular end-diastolic dimension (r = -0.678, P < 0.0001), fractional shortening (r = 0.706, P < 0.0001), and apoptotic myocytes (r = -0.473, P = 0.0001). Thus our findings suggest antioxidant and antiapoptotic actions of carvedilol and metoprolol are important determinants of clinical beneficial effects of beta-receptors in the treatment of CHF.


Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Antioxidants/therapeutic use , Apoptosis/drug effects , Deoxyguanosine/analogs & derivatives , Heart Failure/drug therapy , 8-Hydroxy-2'-Deoxyguanosine , Animals , Cell Size , DNA, Mitochondrial/metabolism , Deoxyguanosine/metabolism , Echocardiography , Glutathione/metabolism , Glutathione Disulfide/metabolism , Heart Failure/diagnostic imaging , Heart Failure/etiology , Heart Failure/physiopathology , Hemodynamics , Myocardium/metabolism , Myocytes, Cardiac/pathology , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Rabbits , Rest , bcl-2-Associated X Protein
20.
Am J Physiol Heart Circ Physiol ; 287(1): H29-39, 2004 Jul.
Article in English | MEDLINE | ID: mdl-14962827

ABSTRACT

Cardiac norepinephrine (NE) uptake activity is reduced in congestive heart failure. Our studies in intact animals suggest that this effect on the cardiac sympathetic nerve endings is caused by oxidative stress and/or NE toxic metabolites derived from NE. In this study, we investigated the direct effects of NE on neuronal NE uptake activity and NE transporter (NET), using undifferentiated PC12 cells. Cells were incubated with NE (1-500 microM) either alone or in combination of Cu(2+) sulfate (1 microM), which promotes free radical formation by Fenton reaction for 24 h. NE uptake activity was measured using [(3)H]NE. Cell viability was determined with the use of Trypan blue exclusion and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay, and cellular oxidative stress by dichlorodihydrofluorescein fluorescence and the GSH/GSSG ratio. Cell viability was reduced by NE >100 microM. At lower doses, NE produced oxidative stress and a dose-dependent reduction of NE uptake activity without affecting cell viability significantly. Cu(2+), which has no direct effect on NE uptake activity, potentiated oxidative stress and reduction of NE uptake activity produced by NE. This decrease of NE uptake activity was associated with reductions of NE uptake binding sites and NET protein expression by using the radioligand assay and Western blot analysis, but no changes in NET gene expression. In addition, the free-radical scavenger mannitol, and antioxidant enzymes superoxide dismutase and catalase, reduced oxidative stress and attenuated the reductions of NE uptake activity and NET protein produced by NE/Cu. Thus our results support a functional role of oxidative stress in mediating the neuronal NE uptake reducing effect of NE and that this effect of NE on NET is a posttranscriptional event.


Subject(s)
Extracellular Space/metabolism , Neurons/metabolism , Norepinephrine/metabolism , Oxidative Stress/physiology , Animals , Antioxidants/pharmacology , Binding Sites/drug effects , Cell Membrane/metabolism , Cell Survival/drug effects , Copper Sulfate/pharmacology , Dose-Response Relationship, Drug , Drug Combinations , Neurons/physiology , Norepinephrine/administration & dosage , Norepinephrine/pharmacokinetics , Norepinephrine/poisoning , Norepinephrine Plasma Membrane Transport Proteins , Oxidative Stress/drug effects , PC12 Cells , RNA, Messenger/metabolism , Rats , Symporters/genetics , Symporters/metabolism
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