Abstract 17696: Protection from Myocyte Apoptosis is a Less Likely Mechanism for Rescue of β1-Adrenergic Cardiomyopathy by DN-Mammalian Sterile 20-Like Kinase 1 than Protection from Necrosis and Fibrosis
It is widely held that increased myocyte apoptosis is an important mechanism mediating cardiomyopathy. Our hypothesis is that the overwhelming majority of apoptosis in the heart involves non-myocytes, making the concept, that myocyte apoptosis is the mechanism, less tenable. Furthermore, fibrosis, not likely due to apoptosis but rather necrosis, is increased in cardiomyopathic hearts, and contributes to the left ventricular (LV) dysfunction. A dominant negative (DN) mammalian sterile 20-like kinase 1 (Mst1) mouse was selected to rescue β1-adrenergic receptor (β1-AR) cardiomyopathy, since DN-Mst1 is thought to protect the heart specifically by inhibiting myocyte apoptosis. Mice with transgenic (Tg) cardiac overexpression of the β1-AR have higher heart rates and myocardial contractility, which increase myocardial metabolic demands, which with age cause necrosis resulting in cardiac fibrosis and dilated cardiomyopathy, heart failure and premature mortality. We mated the β1-AR Tg mice with DN-Mst1 mice and followed them for 20 months as they aged. The DN-Mst1 gene rescued the β1-AR cardiomyopathy: As compared with older β1-AR mice, in the older bigenics mortality fell from 50% to 14%; LV ejection fraction rose from 43±5 to 67±12 %; and cardiac fibrosis fell from 19.5±2.7% vs 8.8±1.5%; all changes significant, p<0.05. Apoptosis was measured with TUNEL, and specific myocyte apoptosis was measured using double staining with TUNEL and wheat germ agglutinin or cardiac troponin I. Surprisingly, myocyte apoptosis (0.06±0.01%) was only a quarter of total apoptosis in the β1-AR Tg heart, and was not reduced significantly further in the bigenic mouse heart, despite significant reductions, p<0.05, in apoptosis in cells other than myocytes in the bigenic mouse heart (0.08±0.01%) compared to β1-AR Tg (0.16±0.02%). Thus, inhibiting Mst1 protects the heart and rescues the cardiomyopathy in β1-AR Tg mice. However, in contrast to the widely held concept that this would occur through a mechanism involving protection of myocyte apoptosis, this was not observed. More likely, the DN-Mst1 protected against the necrosis and fibrosis that develops with chronically increased β1-AR signaling, with potentially an additional role for protection of non-myocyte apoptosis.
- © 2012 by American Heart Association, Inc.