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.

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 Ca(2+)/calmodulin-dependent kinase (CaMK-II) pathways. Myocytes isolated from ISO + VS-1 hearts displayed higher Ca(2+) transients, shorter Ca(2+) decays, higher sarcoplasmic reticulum Ca(2+) levels and higher L-type Ca(2+) current densities than the ISO rat hearts. VS-1 treatment restored the protein expression of sarcoplasmic reticulum Ca(2+) 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, Ca(2+) 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.