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NO triggers RGS4 degradation to coordinate angiogenesis and cardiomyocyte growth
Irina M. Jaba, … , Lawrence H. Young, Daniela Tirziu
Irina M. Jaba, … , Lawrence H. Young, Daniela Tirziu
Published March 1, 2013
Citation Information: J Clin Invest. 2013;123(4):1718-1731. https://doi.org/10.1172/JCI65112.
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Research Article Cardiology

NO triggers RGS4 degradation to coordinate angiogenesis and cardiomyocyte growth

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Abstract

Myocardial hypertrophy is an adaptation to increased hemodynamic demands. An increase in heart tissue must be matched by a corresponding expansion of the coronary vasculature to maintain and adequate supply of oxygen and nutrients for the heart. The physiological mechanisms that underlie the coordination of angiogenesis and cardiomyocyte growth are unknown. We report that induction of myocardial angiogenesis promotes cardiomyocyte growth and cardiac hypertrophy through a novel NO-dependent mechanism. We used transgenic, conditional overexpression of placental growth factor (PlGF) in murine cardiac tissues to stimulate myocardial angiogenesis and increase endothelial-derived NO release. NO production, in turn, induced myocardial hypertrophy by promoting proteasomal degradation of regulator of G protein signaling type 4 (RGS4), thus relieving the repression of the Gβγ/PI3Kγ/AKT/mTORC1 pathway that stimulates cardiomyocyte growth. This hypertrophic response was prevented by concomitant transgenic expression of RGS4 in cardiomyocytes. NOS inhibitor L-NAME also significantly attenuated RGS4 degradation, and reduced activation of AKT/mTORC1 signaling and induction of myocardial hypertrophy in PlGF transgenic mice, while conditional cardiac-specific PlGF expression in eNOS knockout mice did not induce myocardial hypertrophy. These findings describe a novel NO/RGS4/Gβγ/PI3Kγ/AKT mechanism that couples cardiac vessel growth with myocyte growth and heart size.

Authors

Irina M. Jaba, Zhen W. Zhuang, Na Li, Yifeng Jiang, Kathleen A. Martin, Albert J. Sinusas, Xenophon Papademetris, Michael Simons, William C. Sessa, Lawrence H. Young, Daniela Tirziu

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