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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

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Abstract

Purpose

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.

Methods and Result

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.

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Acknowledgments

This work was supported by the Natural Science Foundation of Hubei Province, China (no. 2013CFA117) the Fundamental Research Funds for the Central Universities of China (no. 302274052), and Project of Wuhan Municipal Science and Technology (no.2014060101010033). The authors are grateful to the Wuhan University School of Basic Medical Science Medical Research Center for Structural biology for assisting in the performance of the experiments to test Ca2+ transients.

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Authors and Affiliations

  1. Department of Cardiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuchang District, Wuhan City, Hubei Province, 430060, China

    Dandan Wang, Yingguang Shan, Yan Huang, Yanhong Tang, Yuting Chen, Ran Li, Jing Yang & Congxin Huang

  2. Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China

    Dandan Wang, Yingguang Shan, Yan Huang, Yanhong Tang, Yuting Chen, Ran Li, Jing Yang & Congxin Huang

  3. Hubei Key Laboratory of Cardiology, Wuhan University, Wuhan, 430060, China

    Dandan Wang, Yingguang Shan, Yan Huang, Yanhong Tang, Yuting Chen, Ran Li, Jing Yang & Congxin Huang

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  1. Dandan Wang
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  2. Yingguang Shan
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Correspondence to Congxin Huang.

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Dandan Wang and Yinguang Shan contributed equally to this work.

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Wang, D., Shan, Y., Huang, Y. et al. 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. Cardiovasc Drugs Ther 30, 455–464 (2016). https://doi.org/10.1007/s10557-016-6687-9

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