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Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the Zucker obese rat.

ABSTRACT: Insulin resistance is associated with obesity and may be accompanied by left ventricular diastolic dysfunction and myocardial remodeling. Decreased insulin metabolic signaling and increased oxidative stress may promote these maladaptive changes. In this context, the beta-blocker nebivolol has been reported to improve insulin sensitivity, increase endothelial NO synthase activity, and reduce NADPH oxidase-induced superoxide generation. We hypothesized that nebivolol would attenuate diastolic dysfunction and myocardial remodeling by blunting myocardial oxidant stress and promoting insulin metabolic signaling in a rodent model of obesity, insulin resistance, and hypertension. Six-week-old male Zucker obese and age-matched Zucker lean rats were treated with nebivolol (10 mg x kg(-) x day(-1)) for 21 days, and myocardial function was assessed by cine MRI. Compared with untreated Zucker lean rats, untreated Zucker obese rats exhibited prolonged diastolic relaxation time (27.7+/-2.5 versus 40.9+/-2.0 ms; P<0.05) and reduced initial diastolic filling rate (6.2+/-0.5 versus 2.8+/-0.6 microL/ms; P<0.05) in conjunction with increased homeostatic model assessment of insulin resistance (7+/-2 versus 95+/-21; P<0.05), interstitial and pericapillary fibrosis, abnormal cardiomyocyte histoarchitecture, 3-nitrotyrosine, and NADPH oxidase-dependent superoxide. Nebivolol improved diastolic relaxation (32.8+/-0.7 ms; P<0.05 versus untreated Zucker obese), reduced fibrosis, and remodeling in Zucker obese rats, in concert with reductions in nitrotyrosine, NADPH oxidase-dependent superoxide, and improvements in the insulin metabolic signaling, endothelial NO synthase activation, and weight gain (381+/-7 versus 338+/-14 g; P<0.05). Results support the hypothesis that nebivolol reduces myocardial structural maladaptive changes and improves diastolic relaxation in concert with improvements in insulin sensitivity and endothelial NO synthase activation, concomitantly with reductions in oxidative stress.

SUBMITTER: Zhou X

PROVIDER: S-EPMC2841702 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the Zucker obese rat.

Zhou Xinli X Ma Lixin L Habibi Javad J Whaley-Connell Adam A Hayden Melvin R MR Tilmon Roger D RD Brown Ashley N AN Kim Jeong-A JA Demarco Vincent G VG Sowers James R JR

Hypertension (Dallas, Tex. : 1979) 20100222 4

Insulin resistance is associated with obesity and may be accompanied by left ventricular diastolic dysfunction and myocardial remodeling. Decreased insulin metabolic signaling and increased oxidative stress may promote these maladaptive changes. In this context, the beta-blocker nebivolol has been reported to improve insulin sensitivity, increase endothelial NO synthase activity, and reduce NADPH oxidase-induced superoxide generation. We hypothesized that nebivolol would attenuate diastolic dysf ...[more]

PMID: 20176997

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Project description:BackgroundAbout half of heart failure (HF) patients, while having preserved left ventricular function, suffer from diastolic dysfunction (so-called HFpEF). No specific therapeutics are available for HFpEF in contrast to HF where reduced ejection fractions (HFrEF) can be treated pharmacologically. Myocardial titin filament stiffening, endothelial dysfunction, and skeletal muscle (SKM) myopathy are suspected to contribute to HFpEF genesis. We previously described small molecules interfering with MuRF1 target recognition thereby attenuating SKM myopathy and dysfunction in HFrEF animal models. The aim of the present study was to test the efficacy of one small molecule (MyoMed-205) in HFpEF and to describe molecular changes elicited by MyoMed-205.MethodsTwenty-week-old female obese ZSF1 rats received the MuRF1 inhibitor MyoMed-205 for 12 weeks; a comparison was made to age-matched untreated ZSF1-lean (healthy) and obese rats as controls. LV (left ventricle) function was assessed by echocardiography and by invasive haemodynamic measurements until week 32. At week 32, SKM and endothelial functions were measured and tissues collected for molecular analyses. Proteome-wide analysis followed by WBs and RT-PCR was applied to identify specific genes and affected molecular pathways. MuRF1 knockout mice (MuRF1-KO) SKM tissues were included to validate MuRF1-specificity.ResultsBy week 32, untreated obese rats had normal LV ejection fraction but augmented E/e' ratios and increased end diastolic pressure and myocardial fibrosis, all typical features of HFpEF. Furthermore, SKM myopathy (both atrophy and force loss) and endothelial dysfunction were detected. In contrast, MyoMed-205 treated rats had markedly improved diastolic function, less myocardial fibrosis, reduced SKM myopathy, and increased SKM function. SKM extracts from MyoMed-205 treated rats had reduced MuRF1 content and lowered total muscle protein ubiquitination. In addition, proteomic profiling identified eight proteins to respond specifically to MyoMed-205 treatment. Five out of these eight proteins are involved in mitochondrial metabolism, dynamics, or autophagy. Consistent with the mitochondria being a MyoMed-205 target, the synthesis of mitochondrial respiratory chain complexes I + II was increased in treated rats. MuRF1-KO SKM controls also had elevated mitochondrial complex I and II activities, also suggesting mitochondrial activity regulation by MuRF1.ConclusionsMyoMed-205 improved myocardial diastolic function and prevented SKM atrophy/function in the ZSF1 animal model of HFpEF. Mechanistically, SKM benefited from an attenuated ubiquitin proteasome system and augmented synthesis/activity of proteins of the mitochondrial respiratory chain while the myocardium seemed to benefit from reduced titin modifications and fibrosis.

Project description:Despite the increasing prevalence of heart failure with preserved left ventricular function, there are no specific treatments, partially because the mechanism of impaired relaxation is incompletely understood. Evidence indicates that cardiac relaxation may depend on nitric oxide (NO), generated by NO synthase (NOS) requiring the co-factor tetrahydrobiopterin (BH(4)). Recently, we reported that hypertension-induced diastolic dysfunction was accompanied by cardiac BH(4) depletion, NOS uncoupling, a depression in myofilament cross-bridge kinetics, and S-glutathionylation of myosin binding protein C (MyBP-C). We hypothesized that the mechanism by which BH(4) ameliorates diastolic dysfunction is by preventing glutathionylation of MyBP-C and thus reversing changes of myofilament properties that occur during diastolic dysfunction. We used the deoxycorticosterone acetate (DOCA)-salt mouse model, which demonstrates mild hypertension, myocardial oxidative stress, and diastolic dysfunction. Mice were divided into two groups that received control diet and two groups that received BH(4) supplement for 7days after developing diastolic dysfunction at post-operative day 11. Mice were assessed by echocardiography. Left ventricular papillary detergent-extracted fiber bundles were isolated for simultaneous determination of force and ATPase activity. Sarcomeric protein glutathionylation was assessed by immunoblotting. DOCA-salt mice exhibited diastolic dysfunction that was reversed after BH(4) treatment. Diastolic sarcomere length (DOCA-salt 1.70±0.01 vs. DOCA-salt+BH(4) 1.77±0.01μm, P<0.001) and relengthening (relaxation constant, τ, DOCA-salt 0.28±0.02 vs. DOCA-salt+BH(4) 0.08±0.01, P<0.001) were also restored to control by BH(4) treatment. pCa(50) for tension increased in DOCA-salt compared to sham but reverted to sham levels after BH(4) treatment. Maximum ATPase rate and tension cost (ΔATPase/ΔTension) decreased in DOCA-salt compared to sham, but increased after BH(4) treatment. Cardiac MyBP-C glutathionylation increased in DOCA-salt compared to sham, but decreased with BH(4) treatment. MyBP-C glutathionylation correlated with the presence of diastolic dysfunction. Our results suggest that by depressing S-glutathionylation of MyBP-C, BH(4) ameliorates diastolic dysfunction by reversing a decrease in cross-bridge turnover kinetics. These data provide evidence for modulation of cardiac relaxation by post-translational modification of myofilament proteins.

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Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the Zucker obese rat.

Publications

Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the Zucker obese rat.

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