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Neuronal nitric oxide synthase is up-regulated by angiotensin II and attenuates NADPH oxidase activity and facilitates relaxation in murine left ventricular myocytes
- Source :
-
Journal of Molecular & Cellular Cardiology . Jun2012, Vol. 52 Issue 6, p1274-1281. 8p. - Publication Year :
- 2012
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Abstract
- Abstract: Angiotensin II (Ang II) is critical in myocardial pathogenesis, mostly via stimulating NADPH oxidase. Neuronal nitric oxide synthase (nNOS) has recently been shown to play important roles in modulating myocardial oxidative stress and contractility. Here, we examine whether nNOS is regulated by Ang II and affects NADPH oxidase production of intracellular reactive oxygen species (ROSi) and contractile function in left ventricular (LV) myocytes. Our results showed that Ang II induced biphasic effects on ROSi and LV myocyte relaxation (TR50) without affecting the amplitude of sarcomere shortening and L-type Ca2+ current density: TR50 was prolonged at 30min but was shortened after 3h (or after Ang II treatment in vivo). Correspondingly, ROSi was increased, followed by a reduction to control level. Quantitative RT-PCR and immunoblotting experiments showed that Ang II (3h) increased the mRNA and protein expression of nNOS and increased NO production (nitrite assay) in LV myocyte homogenates, suggesting that nNOS activity may be enhanced and involved in mediating the effects of Ang II. Indeed, n(omega)-nitro-l-arginine methyl ester (l-NAME) or a selective nNOS inhibitor, S-methyl-l-thiocitrulline (SMTC) increased NADPH oxidase production of superoxide/ROSi and abolished faster myocyte relaxation induced by Ang II. The positive lusitropic effect of Ang II was not mediated by PKA-, CaMKII-dependent signaling or peroxynitrite. Conversely, inhibition of cGMP/PKG pathway abolished the Ang II-induced faster relaxation by reducing phospholamban (PLN) Ser16 phosphorylation. Taken together, these results clearly demonstrate that myocardial nNOS is up-regulated by Ang II and functions as an early adaptive mechanism to attenuate NADPH oxidase activity and facilitate myocardial relaxation. [Copyright &y& Elsevier]
Details
- Language :
- English
- ISSN :
- 00222828
- Volume :
- 52
- Issue :
- 6
- Database :
- Academic Search Index
- Journal :
- Journal of Molecular & Cellular Cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 74986486
- Full Text :
- https://doi.org/10.1016/j.yjmcc.2012.03.013