Regulation of Cardiac Gene Expression by B-adrenergic Signaling and Heart Failure
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Cardiac diseases such as coronary artery disease are the major causes of death around the world. Regulation of -adrenergic receptors by catecholamines is an important facet of understanding cardiac function in health and disease. Acute sympathetic activation of ARs results in an increase in cardiac output; however, sustained stimulation of the ARs is cytotoxic, leading to myocyte death and cardiac remodeling. -adrenergic blockers are a seminal class of drugs that play an important role in improving mortality and symptom control in various cardiac diseases. An important transcriptional regulatory protein target of -adrenergic signaling is MEF2, which plays a crucial role in cardiac gene expression during pathologic and physiological adaptation of the heart. In our experiments, we have observed a robust effect of -blockers on MEF2 transcriptional activity. Myocardial MEF2 responses to -blocker treatment indicates an important physiological linkage between -adrenergic signaling and MEF2 activity in the heart, which underpins changes in cardiac gene expression in response to -adrenergic blockade. In the first set of experiments, the link between MEF2 and cardiac survival pathways in the heart was examined. Collectively, data indicate a mechanism of the beneficial effects of acute 1AR blocker treatment through up-regulation of MEF2 activity, leading to cardiomyocyte survival. In the second set of experiments, changes in MEF2 activity and global gene transcription networks during heart failure and in response to chronic 1-blockade was studied. Together, data demonstrate that chronic 1-blockade inhibits myocardial MEF2 activity while also minimizing dynamic changes in heart failure associated transcriptome dynamics. Communally, both studies indicate molecular events resulting from 1-adrenergic blockade that result in positive effects on heart pathology. These studies define novel molecules and pathways involved in heart pathology that may represent new genetic or pharmacologic targets for heart failure therapies.