Increased messenger RNA level of the inhibitory G protein alpha subunit Gi alpha-2 in human end-stage heart failure.

Abstract

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 (Gi) and unchanged stimulatory G protein (Gs). In the present study we determined the mRNA expression pattern of the alpha subunits of Gi-1, Gi-2, Gi-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 Gi alpha-2, Gi alpha-3, and Gs alpha mRNA. In contrast, Gi alpha-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 Gi alpha-2, Gi alpha-3, and Gs 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 Gi alpha-2 mRNA was increased by 75 +/- 26% (p less than 0.05) in idiopathic dilated cardiomyopathy hearts and 90 +/- 26% (p less than 0.05) in ischemic cardiomyopathy hearts. Gi alpha-3 and Gs alpha mRNA levels were similar in the three groups. The results suggest that as in other mammalian species, Gi alpha-2 and Gi alpha-3 mRNA are the predominant Gi alpha mRNA subtypes in human ventricular myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Muscarinic receptor modulation of basal and beta-adrenergic stimulated function of the failing human left ventricle.

“…Muscarinic stimulation may have activated the inhibitory G protein, G i , leading to reduced adenylate cyclase production of cAMP (25). This may be relevant in the setting of heart failure, where G i activity is increased (5,(15)(16)(17)(18). The effects of acetylcholine may have been secondary to stimulation of inhibitory muscarinic receptors on adrenergic nerve terminals (6,26).…”

“…Alternatively, the negative lusitropic response to acetylcholine may be explained by increased sensitivity to muscarinic stimulation in the setting of heart failure (5). This might occur because of increased muscarinic receptor density (5,12), or because of an increase in G i activity in the setting of heart failure (5,(15)(16)(17)(18). The negative lusitropic effect of acetylcholine may also have resulted from non cAMP-dependent mechanisms including effects on phospholamban phosphorylation (30), and phospholipase C (13), which could stress an already impaired calcium handling system in heart failure (31).…”

“…Muscarinic receptors couple to the inhibitory G protein, G i , which has increased activity in the failing heart (5,(15)(16)(17)(18). Vatner et al (5) have recently confirmed that heart failure, induced by rapid ventricular pacing in dogs, is associated with an increase in muscarinic receptor density and G i in ventricular myocardium.…”

“…Given normal receptor density (13)(14)(15), increased G i activity (5,(15)(16)(17)(18), and the negative inotropic effects of muscarinic stimulation in an animal model of heart failure (5), muscarinic receptor modulation may have important effects on ventricular function in human congestive heart failure. Therefore, this study was performed to determine the effect of myocardial muscarinic receptor modulation on basal and dobutamine stimulated left ventricular systolic and diastolic function in patients with heart failure, and to contrast these effects with observations made in subjects with normal ventricular function.…”

Sarco“MiR” friend or foe: a perspective on the mechanisms of doxorubicin-induced cardiomyopathy

“…This prosurvival phenotype is thought to be at least in part associated with its interaction with G i proteins (43). In human end stage heart failure patients, G i proteins, particularly the α-2 subunit (G 1α-2 ), are up-regulated (44). Down-regulation of G 1α-2 is associated with apoptosis and worsening heart failure (45)(46)(47).…”