Increased messenger RNA level of the inhibitory G protein α subunit Giα-2 in human end-stage heart failure

Abstract

In human heart failure the positive inotropic and cAMP-elevating effects of both β-adrenoceptor agonists and phosphodiesterase inhibitors are diminished. This has been explained at least in part by an increase in the inhibitory signal-transducing G protein (Gi) and unchanged stimulatory G protein (Gs). In the present study we determined the mRNA expression pattern of the α subunits of Gi-1 Gi-2, G1-3, and Gs in myocardial tissue samples of patients undergoing heart transplantation. Northern blot analysis of total RNA extracted from left ventricles with 32P-labeled cDNAs demonstrated expression of Giα-2, Giα-3, and Gsα mRNA. In contrast, Giα-1 mRNA was not detectable. To investigate whether the increased ratio of Gi/Gs might be due to altered gene expression, we compared mRNA levels of Giα-2, Giα-3, and Gsα in left ventricular myocardium from failing hearts with idiopathic dilated cardiomyopathy (n=8) and ischemic cardiomyopathy (n=6) and from nonfailing hearts from transplant donors (n=8). Compared with nonfailing control hearts, the Giα-2 mRNA was increased by 75±26% (p<0.05) in idiopathic dilated cardiomyopathy hearts and 90±26% (p<0.05) in ischemic cardiomyopathy hearts. Giα-3 and Gsα mRNA levels were similar in the three groups. The results suggest that as in other mammalian species, Giα-2and Giα-3 mRNA are the predominant Giα mRNA subtypes in human ventricular myocardium. An upregulation of Giα-2 but not of Giα-3 mRNA probably underlies the increase in Giα protein and might thus be involved in the pathophysiological process leading to reduced responsiveness to cAMP-increasing agents in end-stage heart failure.