Diverse Regulation of Cardiac Expression of Relaxin Receptor by α1- and β1-Adrenoceptors

Relaxin, a new drug for heart failure therapy, exerts its cardiac actions through relaxin family peptide receptor 1 (RXFP1). Factors regulating RXFP1 expression remain unknown. We have investigated effects of activation of adrenoceptors (AR), an important modulator in the development and prognosis of heart failure, on expression of RXFP1 in rat cardiomyocytes and mouse left ventricles (LV). Expression of RXFP1 at mRNA (real-time PCR) and protein levels (immunoblotting) was measured in cardiomyocytes treated with alpha- and beta-AR agonists or antagonists. RXFP1 expression was also determined in the LV of transgenic mouse strains with cardiac-restricted overexpression of alpha(1A)-, alpha(1B)- or beta(2)-AR. Specific inhibitors were used to explore signal pathways involved in alpha(1)-AR mediated regulation of RXFP1 in cardiomyocytes. In cultured cardiomyocytes, alpha(1)-AR stimulation resulted in 2-3 fold increase in RXFP1 mRNA (P < 0.001), which was blocked by specific inhibitors for protein kinase C (PKC) or mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK). Activation of beta(1)-, but not beta(2)-AR, significantly inhibited RXFP1 expression (P < 0.001). Relative to respective wild-type controls, RXFP1 mRNA levels in the LV of mice overexpressing alpha(1A)- or alpha(1B)-AR were increased by 3- or 10-fold, respectively, but unchanged in beta(2)-AR transgenic hearts. Upregulation by alpha(1)-AR stimulation RXFP1 expression was confirmed at protein levels both in vitro and in vivo. Expression of RXFP1 was up-regulated by alpha(1)-AR but suppressed by beta-AR, mainly beta(1)-AR subtype, in cardiomyocytes. Future studies are warranted to characterize the functional significance of such regulation, especially in the setting of heart failure.