Abstract 17006: Genistein Rescues Pulmonary Hypertension Induced Right Ventricular Failure by Inhibiting the Proliferation of Pulmonary Artery Smooth Muscle Cells and Reversing Cardiac Hypertrophy
INTRODUCTION Pulmonary Hypertension (PH) induced Right Ventricular Failure (RVF) is a major cause of morbidity and mortality. PH is characterized by thickening of pulmonary vasculature and gradually increasing pulmonary arterial pressure, resulting in RV hypertrophy and failure. We have previously shown that genistein (Gen), a soy isoflavone, is able to rescue PH induced RVF. Here we explore whether inhibition of pulmonary smooth muscle cell proliferation as well as reversal of hypertrophy are the mechanisms involved in the rescue.
METHODS To induce PH, male rats received a single injection of Monocrotaline (60mg/kg, s.c.) or saline as control (CTRL n=7). At day 21, when rats had developed severe PH, Gen therapy was begun (1 mg/kg/day, s.c.) to one group (n=8) until day 30. Some were left untreated to develop severe RVF (n=7). In vitro, proliferation of human pulmonary artery smooth muscle cells (HPASMCs) was measured with or without Gen by MTT assay. Hypertrophy of cardiomyocytes was measured by incubating neonatal rat ventricular myocytes (NRVMs) with pro-hypertrophic phenylephrine (PE, 10uM) with and without Gen. P<0.05 were considered significant. Values are given mean±SE.
RESULTS Gen was able to reverse depressed RV Ejection Fraction (RVEF=65.67±1.08% vs 28.76±0.79% in RVF, p<0.05). The RVF group was characterized by increased pulmonary arteriolar medial thickness (2.55±0.09 vs 1.00±0.05 in CTRL, p<0.05) as well as significant hypertrophy of the RV (RV/(LV+IVS)=0.69±0.08 vs 0.25±0.03 in CTRL, p<0.05). Gen was able to reverse arteriolar thickening and RV hypertrophy (thickening=1.09±0.04; RV/(LV+IVS)=0.35±0.03. all p<0.05 vs RVF). Gen was able to inhibit the proliferation of HPASMCs (0.47±0.07 vs 1.00±0.12 in CTRL, p<0.05). Gen treatment of NRVMs was also able to reverse cardiomyocyte hypertrophy (0.71±0.06 vs 2.45±0.16 in PE alone, normalized to untreated cell size, p<0.05).
CONCLUSION Genistein therapy rescues depressed RV Ejection Fraction and reverses pulmonary arteriolar medial thickness as well as RV hypertrophy in PH-induced RVF rats. Genistein inhibits the proliferation of HPASMCs and reverses the hypertrophy of NRVMs in vitro. These provide a possible physiological mechanism for the rescue of PH induced RVF by Genistein therapy.
- © 2011 by American Heart Association, Inc.