Nitroxyl (HNO) stimulates soluble guanylyl cyclase to suppress cardiomyocyte hypertrophy and superoxide generation

Eliane Lin, Jennifer Claire Irvine, Anh H Cao, Amy E Alexander, Jane E Love, Ruchi Patel, Julie R McMullen, David M Kaye, Barbara Kathryn Kemp-Harper, Rebecca H Ritchie

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BACKGROUND: New 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. METHODS: Neonatal 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 micromol/L). Hypertrophic responses and its triggers, as well as cGMP signaling, were determined. RESULTS: We now demonstrate that Angeli s salt inhibits Ang II-induced hypertrophic responses in cardiomyocytes, including increases in cardiomyocyte size, de novo protein synthesis and beta-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). CONCLUSIONS: Our 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.
Original languageEnglish
Article numbere34892
Number of pages11
JournalPLoS ONE
Issue number4
Publication statusPublished - 2012

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