Vasostatin-1 Stops Structural Remodeling and Improves Calcium Handling via the eNOS-NO-PKG Pathway in Rat Hearts Subjected to Chronic β-Adrenergic Receptor Activation.
OBJECTIVE
Chronically elevated catecholamine levels activate cardiac β-adrenergic receptors, which play a vital role in the pathogenesis of heart failure. Evidence suggests that vasostatin-1 (VS-1) exerts anti-adrenergic effects on isolated and perfused hearts in vitro. Whether VS-1 ameliorates hypertrophy/remodeling by inducing the chronic activation of β-adrenergic receptors is unknown. The present study aims to test the efficacy of using VS-1 to treat the advanced hypertrophy/remodeling that result from chronic β-adrenergic receptor activation and to determine the cellular and molecular mechanisms that underlie this response.


RESULTS
Rats were subjected to infusion with either isoprenaline (ISO, 5 mg/kg/d), ISO plus VS-1 (30 mg/kg/d) or placebo for 2 weeks. VS-1 suppressed chamber dilation, myocyte hypertrophy and fibrosis and improved in vivo heart function in the rats subjected to ISO infusion. VS-1 increased phosphorylated nitric oxide synthase levels and induced the activation of protein kinase G. VS-1 also deactivated multiple hypertrophy signaling pathways that were triggered by the chronic activation of β-adrenergic receptors, such as the phosphoinositide-3 kinase (PI3K)/Akt and Ca2+/calmodulin-dependent kinase (CaMK-II) pathways. Myocytes isolated from ISO + VS-1 hearts displayed higher Ca2+transients, shorter Ca2+decays, higher sarcoplasmic reticulum Ca2+levels and higher L-type Ca2+current densities than the ISO rat hearts. VS-1 treatment restored the protein expression of sarcoplasmic reticulum Ca2+uptake ATPase, phospholamban and Cav1.2, indicating improved calcium handling.


CONCLUSIONS
Chronic VS-1 treatment inhibited the progression of hypertrophy, fibrosis, and chamber remodeling, and improved cardiac function in a rat model of ISO infusion. In addition, Ca2+handling and its molecular modulation were also improved by VS-1. The beneficial effects of VS-1 on cardiac remodeling may be mediated by the enhanced activation of the eNOS-cGMP-PKG pathway.
Department of Cardiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuchang District, Wuhan City, Hubei Province, 430060, China.|Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China.|Hubei Key Laboratory of Cardiology, Wuhan University, Wuhan, 430060, China.
Dandan
D
Wang
Department of Cardiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuchang District, Wuhan City, Hubei Province, 430060, China.|Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China.|Hubei Key Laboratory of Cardiology, Wuhan University, Wuhan, 430060, China.
Yingguang
Y
Shan
Department of Cardiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuchang District, Wuhan City, Hubei Province, 430060, China.|Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China.|Hubei Key Laboratory of Cardiology, Wuhan University, Wuhan, 430060, China.
Yan
Y
Huang
Department of Cardiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuchang District, Wuhan City, Hubei Province, 430060, China.|Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China.|Hubei Key Laboratory of Cardiology, Wuhan University, Wuhan, 430060, China.
Yanhong
Y
Tang
Department of Cardiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuchang District, Wuhan City, Hubei Province, 430060, China.|Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China.|Hubei Key Laboratory of Cardiology, Wuhan University, Wuhan, 430060, China.
Yuting
Y
Chen
Department of Cardiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuchang District, Wuhan City, Hubei Province, 430060, China.|Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China.|Hubei Key Laboratory of Cardiology, Wuhan University, Wuhan, 430060, China.
Ran
R
Li
Department of Cardiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuchang District, Wuhan City, Hubei Province, 430060, China.|Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China.|Hubei Key Laboratory of Cardiology, Wuhan University, Wuhan, 430060, China.
Jing
J
Yang
Department of Cardiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuchang District, Wuhan City, Hubei Province, 430060, China. huangcongxin@vip.163.com.|Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China. huangcongxin@vip.163.com.|Hubei Key Laboratory of Cardiology, Wuhan University, Wuhan, 430060, China. huangcongxin@vip.163.com.
Congxin
C
Huang
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D006332:Cardiomegaly / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D053379:Chromogranin A / Q000494:pharmacology* / Q000627:therapeutic use*; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D005355:Fibrosis; D006321:Heart / Q000187:drug effects / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling / Q000187:drug effects*
D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D053379:Chromogranin A; D010446:Peptide Fragments; C064110:vasostatin I; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D006152:Cyclic GMP; D007545:Isoproterenol; D002118:Calcium
Ca2+ handling; Cardiac remodeling; Isoprenaline; Left ventricular function; Vasostatin-1