Abstract
BackgroundNew therapeutic targets for cardiac hypertrophy, an independent risk factor for heart failure and death, are essential. HNO is a novel redox sibling of NO• attracting considerable attention for the treatment of cardiovascular disorders, eliciting cGMP-dependent vasodilatation yet cGMP-independent positive inotropy. The impact of HNO on cardiac hypertrophy (which is negatively regulated by cGMP) however has not been investigated.MethodsNeonatal rat cardiomyocytes were incubated with angiotensin II (Ang II) in the presence and absence of the HNO donor Angeli's salt (sodium trioxodinitrate) or B-type natriuretic peptide, BNP (all 1 µmol/L). Hypertrophic responses and its triggers, as well as cGMP signaling, were determined.ResultsWe now demonstrate that Angeli's salt inhibits Ang II-induced hypertrophic responses in cardiomyocytes, including increases in cardiomyocyte size, de novo protein synthesis and β-myosin heavy chain expression. Angeli's salt also suppresses Ang II induction of key triggers of the cardiomyocyte hypertrophic response, including NADPH oxidase (on both Nox2 expression and superoxide generation), as well as p38 mitogen-activated protein kinase (p38MAPK). The antihypertrophic, superoxide-suppressing and cGMP-elevating effects of Angeli's salt were mimicked by BNP. We also demonstrate that the effects of Angeli's salt are specifically mediated by HNO (with no role for NO• or nitrite), with subsequent activation of cardiomyocyte soluble guanylyl cyclase (sGC) and cGMP signaling (on both cGMP-dependent protein kinase, cGK-I and phosphorylation of vasodilator-stimulated phosphoprotein, VASP).ConclusionsOur results demonstrate that HNO prevents cardiomyocyte hypertrophy, and that cGMP-dependent NADPH oxidase suppression contributes to these antihypertrophic actions. HNO donors may thus represent innovative pharmacotherapy for cardiac hypertrophy.
Highlights
Cardiac hypertrophy is strongly implicated in the development of heart failure of almost all etiologies
Our results provide the first evidence that the HNO donor Angeli’s salt prevents cardiomyocyte hypertrophy, and that cGMP-dependent suppression of cardiomyocyte NADPH oxidase contributes to these antihypertrophic actions
Following 48 h incubation under serum-free conditions, cardiomyocytes were incubated for 48 h in the presence and absence of the hypertrophic stimuli angiotensin II (Ang II, 1 mmol/L, Auspep, Parkville, Australia) or endothelin-1 (ET1, 60 nmol/L) [21,26,30], and/or the HNO donor Angeli’s salt
Summary
Cardiac hypertrophy is strongly implicated in the development of heart failure of almost all etiologies. In addition to heart failure, it remains an independent risk factor for myocardial infarction and sudden death [1,2,3]. Cardiac hypertrophy initially develops in vivo as an adaptive response to maintain myocardial function, for example in hypertension when cardiac workload is chronically elevated [4]. Hypertrophy may progress to a maladaptive state, with progressive decline in ventricular contractility and diastolic function, with adverse outcomes [4,5]. Identification of new therapeutic targets to prevent or reverse cardiac hypertrophy is essential [3]. New therapeutic targets for cardiac hypertrophy, an independent risk factor for heart failure and death, are essential. The impact of HNO on cardiac hypertrophy (which is negatively regulated by cGMP) has not been investigated
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call