Cardiac phenylethanolamine N-methyltransferase: localization and regulation of gene expression in the spontaneously hypertensive rat.

Abstract

Phenylethanolamine N-methyltransferase (PNMT) is the terminal enzyme in the catecholamine biosynthetic pathway responsible for adrenaline biosynthesis. Adrenaline is involved in the sympathetic control of blood pressure; it augments cardiac function by increasing stroke volume and cardiac output. Genetic mapping studies have linked the PNMT gene to hypertension. This study examined the expression of cardiac PNMT and changes in its transcriptional regulators in the spontaneously hypertensive (SHR) and wild type Wistar-Kyoto (WKY) rats. SHR exhibit elevated levels of corticosterone, and lower levels of the cytokine IL-1β, revealing systemic differences between SHR and WKY. PNMT mRNA was significantly increased in all chambers of the heart in the SHR, with the greatest increase in the right atrium. Transcriptional regulators of the PNMT promoter show elevated expression of Egr-1, Sp1, AP-2, and GR mRNA in all chambers of the SHR heart, while protein levels of Sp1, Egr-1, and GR were elevated only in the right atrium. Interestingly, only AP-2 protein-DNA binding was increased, suggesting it may be a key regulator of cardiac PNMT in SHR. This study provides the first insights into the molecular mechanisms involved in the dysregulation of cardiac PNMT in a genetic model of hypertension.