Abstract 16040: Angiogenesis Driven Myocardial Hypertrophy Through a Nitric Oxide-RGS4 Dependent Mechanism
Previously, we reported that an increase of vascular bed in the normal adult heart leads to myocardial hypertrophy in the absence of external stimuli. However the mechanism of angiogenesis-driven myocardial hypertrophy is poorly understood. Our hypothesis is that an increase in vascular endothelium in the heart results in increased nitric oxide (NO) production that in turn controls ubiquitin-dependent degradation of the negative regulator of G protein signaling type 4 (RGS4) in cardiomyocytes (CM) and drives the hypertrophic program via Gα/Gβγ protein signaling.
Methods include cell culture and conditional mouse models. We generated cardiac specific TetOFF inducible transgenic mouse models to selectively (1) stimulate angiogenesis by PlGF (Placental Growth Factor) and (2) stimulate angiogenesis by PlGF while simultaneously inhibiting the hypertrophic response in CM by expression of RGS4.
Results. The treatment of rat neonatal CM with a NO donor results in an increase in cell size associated with reduced RGS4 protein level and Akt-mTORC activation via Gβγ/PI3Kγ pathway. In mice, PLGF induced an increase in capillary/myocyte ratio (1.7 vs 1.0 control, p<0.001) and arteriolar branches up to 96 μm diameters (determined by microCT). The increase in vessel growth after 3 weeks preceded the increase in heart size at 6 weeks post-induction. Myocardial hypertrophy was associated with reduced RGS4 protein levels and increased activation of Akt and p70S6K. Echocardiography showed an increase in LV posterior wall thickness and LV mass/body weight ratio (0.57 vs 0.33 control, p<0.05, n=20); no changes in LVEF or LVFS. No fibrosis or inflammation was associated with hypertrophy. Treatment of PlGF-induced mice with eNOS inhibitor L-NAME, in the last 3 weeks of a 6-week stimulation period resulted in a 54% reduction of the increase in heart size (p<0.01, n=8). Concurrent expression of RGS4 in CM with PlGF expression restored RGS4 protein level and reduced the increase in heart size up to 75% (p<0.001, n=19); PlGF-induced angiogenesis and arteriogenesis were unaffected.
In conclusion, stimulation of vascular growth in heart leads to an increase in cardiac mass via a novel NO-G protein mechanism that involves a reduction of RGS4 and activation of G protein and Akt pathway.
- © 2011 by American Heart Association, Inc.