INCREASED MESSENGER-RNA LEVEL OF THE INHIBITORY-G PROTEIN ALPHA-SUBUNIT GI-ALPHA-2 IN HUMAN END-STAGE HEART-FAILURE

In human heart failure the positive inotropic and cAMP-elevating effects of both beta-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 (G(i)) and unchanged stimulatory G protein (G(s)). In the present study we determined the mRNA expression pattern of the alpha-subunits of G(i-1), G(i-2), G(i-3), and G(s) in myocardial tissue samples of patients undergoing heart transplantation. Northern blot analysis of total RNA extracted from left ventricles with P-32-labeled cDNAs demonstrated expression of G(i-alpha-2), G(i-alpha-3), and G(s-alpha) mRNA. In contrast, G(i-alpha-1) mRNA was not detectable. To investigate whether the increased ratio of G(i)/G(s) might be due to altered gene expression, we compared mRNA levels of G(i-alpha-2), G(i-alpha-3), and G(s-alpha) 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 G(i-alpha-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. G(i-alpha-3) and G(s-alpha) mRNA levels were similar in the three groups. The results suggest that as in other mammalian species, G(i-alpha-2) and G(i-alpha-3) mRNA are the predominant G(i-alpha) mRNA subtypes in human ventricular myocardium. An upregulation of G(i-alpha-2) but not of G(i-alpha-3) mRNA probably underlies the increase in G(i-alpha) protein and might thus be involved in the pathophysiological process leading to reduced responsiveness to cAMP-increasing agents in end-stage heart failure.