doi: 10.1161/hy1201.097292
(Hypertension. 2002;39:87.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Gene Transfer of cGMP-Dependent Protein Kinase I Enhances the Antihypertrophic Effects of Nitric Oxide in Cardiomyocytes
From the Department of Cardiology and Angiology (K.C.W., B.F., J.H., H.D.) and the Department of Gastroenterology and Hepatology (C.T.), Medizinische Hochschule Hannover, Hannover, Germany; and the Institute for Clinical Biochemistry and Pathobiochemistry, Universität Würzburg (S.G., A.S., E.B., S.M.L.), Würzburg, Germany.
Correspondence to Kai C. Wollert, MD, Department of Cardiology and Angiology, Medizinische Hochschule Hannover, Carl-Neuberg Str 1, 30625 Hannover, Germany. E-mail wollert.kai{at}mh-hannover.de
NO acting through soluble guanylyl cyclase and cGMP formation is a negative regulator of cardiomyocyte hypertrophy. Downstream targets mediating the inhibitory effects of NO/cGMP on cardiomyocyte hypertrophy have not been elucidated. In addition to its antihypertrophic effects, NO promotes apoptosis in cardiomyocytes, presumably through cGMP-independent pathways. We investigated the role of cGMP-dependent protein kinase (PKG) in the antihypertrophic and proapoptotic effects of NO. Incubation of neonatal rat cardiomyocytes with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) (250 µmol/L) or the PKG-selective cGMP analog 8-pCPT–cGMP (500 µmol/L) activated endogenous PKG type I, as shown by the site-specific phosphorylation of vasodilator-stimulated phosphoprotein, a well-characterized PKG substrate. SNAP (250 µmol/L) and 8-pCPT–cGMP (500 µmol/L) modestly attenuated the hypertrophic response to 
1-adrenergic stimulation with phenylephrine. Although a high concentration of SNAP (1000 µmol/L) promoted apoptosis in cardiomyocytes, as evidenced by the formation of histone-associated DNA fragments, antihypertrophic concentrations of SNAP (250 µmol/L) and 8-pCPT–cGMP (500 µmol/L) did not promote cell death. Because chronic activation downregulated endogenous PKG I, we explored whether gene transfer of PKG I would enhance the sensitivity of cardiomyocytes to the antihypertrophic effects of NO/cGMP. Indeed, after adenoviral overexpression of PKG Iß, SNAP (250 µmol/L) and 8-pCPT–cGMP (500 µmol/L) completely suppressed the hypertrophic response to 1-adrenergic stimulation. As observed in noninfected cells, SNAP (250 µmol/L) and 8-pCPT–cGMP (500 µmol/L) did not promote apoptosis in cardiomyocytes overexpressing PKG Iß. Moreover, overexpression of PKG Iß did not enhance the proapoptotic effects of 1000 µmol/L SNAP, implying PKG-independent effects of NO on apoptosis. Endogenous PKG I mediates antihypertrophic but not proapoptotic effects of NO in a cell culture model of cardiomyocyte hypertrophy. Adenoviral gene transfer of PKG I selectively enhances the antihypertrophic effects of NO without increasing the susceptibility to apoptosis.
Key Words: nitric oxide • cyclic GMP • protein kinases • hypertrophy • apoptosis
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