Regulation of cardiac phenylethanolamine N- methyltransferase in genetic and fetal programming models of hypertension

Cardiac PNMT has been shown to play a role in fetal heart development and has also been implicated in facilitating heart function in adults during the stress response. The purpose of this project was to study the regulation of cardiac PNMT in the genetic rodent model of hypertension. As adverse or sub-optimal fetal environment has been linked to the development of hypertension later in life, the regulation of cardiac PNMT in fetal programming models of hypertension were also examined. Elevated expression of PNMT was observed in all chambers of the heart of the spontaneously hypertensive rat (SHR) compared to the Wistar-Kyoto (WKY). RT-PCR analyses of the key regulators of PNMT, Egr-1, Sp1, AP-2 and GR, show significant increases in all chambers of the SHR heart. The right atrium exhibited the highest elevations in PNMT and associated transcription factor mRNA expression in SHR, and this correlated with protein levels for the transcription factors Egr-1 and GR. The exposure to exogenous glucocorticoids, dexamethasone (Dex) or corticosterone (Cort), during the third trimester revealed the effects of fetal programming on blood pressure physiology, however additional changes in cardiac PNMT expression and regulation in WKY or SHR models as a result of prenatal glucocorticoid exposure were not observed in heart tissues at 17-weeks of age. The results demonstrate that elevated PNMT gene expression associated with hypertension in the SHR is likely mediated by altered transcriptional regulation of cardiac PNMT. Furthermore, findings provide the first evidence of dysregulation of cardiac PNMT which may be contributing to the genetic basis for the pathogenesis of hypertension in SHR, and implicates heart tissues in a potential cardiac adrenergic system for cardiovascular regulation.