Repression of alpha myosin heavy chain gene expression and promoter activity by the b-agonist isoproterenol – role for Ca2+/calmodulin protein kinase and ERK1/2 pathway

Abstract

Dilated cardiomyopathy (DCM) from either primary or secondary causes is a major cause of chronic heart failure, and is a result of a prolonged condition of compensatory cardiac hypertrophy. The DCM phenotype consists of two pathophysiological components, contractile dysfunction and pathological hypertrophy/remodeling. b-adrenergic activation plays an important role in the natural history of DCM and its activation during periods of decreased myocardial performance or increased hemodynamic load results in increases in heart rate and contractility, effectively improving cardiac output. Heart failure is also characterized by changes in the expression levels of many of the components of the contractile apparatus. Of the changes that are observed in failing hearts, increases in b-MyHC, skeletal a-actin, and ANF, with coordinate decreases in a-MyHC and SRCA2a, are perhaps the most well-known and are generally referred to as fetal gene induction. We have recently shown that patients that respond to b1or b1, b2, a1adrenergic receptor blockade, also have a partial reversal of the fetal gene program with up-regulation of a-MyHC and Serca2A and down-regulation of b-MyHC and ANP. We have also shown that the transcription factor YY1 is upregulated in Human Heart Failure and represses the activity of the aMyHC promoter. In the work presented here, we show that stimulation of b-ARs with isoproterenol does cause a “fetal” response in the relative activities of the human cardiac MyHC promoter that includes the repression of the human a-MyHC promoter with simultaneous activation of the ANF promoter. Furthermore, we show that this “fetal” response of the MyHC promoters to isoproterenol treatment is specifically mediated by the b1-AR, 154