Enhanced Gαq signaling: A common pathway mediates cardiac hypertrophy and apoptotic heart failure

Abstract

Receptor-mediated Gq signaling promotes hypertrophic growth of cultured neonatal rat cardiac myocytes and is postulated to transduce in vivo cardiac pressure overload hypertrophy. Although initially compensatory, hypertrophy can proceed by unknown mechanisms to cardiac failure. We used adenoviral infection and transgenic overexpression of the alpha subunit of Gq to autonomously activate Gq signaling in cardiomyocytes. In cultured cardiac myocytes, overexpression of wild-type G␣q resulted in hypertrophic growth. Strikingly, expression of a constitutively activated mutant of G␣q, which further increased Gq signaling, produced initial hypertrophy, which rapidly progressed to apoptotic cardiomyocyte death. This paradigm was recapitulated during pregnancy in G␣q overexpressing mice and in transgenic mice expressing high levels of wild-type G␣q. The consequence of cardiomyocyte apoptosis was a transition from compensated hypertrophy to a rapidly progressive and lethal cardiomyopathy. Progression from hypertrophy to apoptosis in vitro and in vivo was coincident with activation of p38 and Jun kinases. These data suggest a mechanism in which moderate levels of Gq signaling stimulate cardiac hypertrophy whereas high level Gq activation results in cardiomyocyte apoptosis. The identification of a single biochemical stimulus regulating cardiomyocyte growth and death suggests a plausible mechanism for the progression of compensated hypertrophy to decompensated heart failure.

Is overall blockade superior to selective blockade of adrenergic receptor subtypes in suppressing left ventricular remodeling in spontaneously hypertensive rats?

“…evidence of cardiocyte apoptosis by activation of the AR-b 1 signaling pathway was derived from isoproterenol-treated rat hearts 46 and transgenic mice overexpressing Gsa 47 or Gqa. 48 In this study, we found that the intracellular free Ca 2+ concentration and the expression levels of PKA, PKC-a, PKC-d and p38-MAPK were substantially decreased after administration of AR antagonists, particularly in the carvedilol-treated group, which may have contributed to the antiapoptotic effects of these medications.…”

G-proteins in growth and apoptosis: lessons from the heart

“…Direct evidence for the activation of apoptotic pathways by Gq signaling derives from in vitro studies using recombinant adenovirus to express a constitutively activated mutant form of the alpha subunit of Gq (GaqQ209L). These studies showed that sustained activation of Gaq and concomitant stimulation of PLC induced marked apoptosis of cultured neonatal rat ventricular myocytes (Adams et al, 1998b). More recently we demonstrated that addition of Gq-coupled receptor agonists (PGF2a or PE) to hypertrophied cardiomyocytes overexpressing wild type Gaq caused robust PLC activation, comparable to that seen with expression of GaqQ209L, and likewise induced apoptosis (Adams et al, 2000).…”

“…(McWhinney et al, 1999). Finally recent experiments in our laboratory have demonstrated that overexpression of the alpha subunit of Gq by adenoviral infection of NRVMs results in increased PLC activity and development of a hypertrophic phenotype similar to that caused by activation of Gq-coupled receptors (Adams et al, 1998b(Adams et al, , 2000. The hypertrophic phenotype, induced by agonist or Gaq expression are evident in Figure 1, where actin ®laments are stained with¯uorescently-tagged phalloidin in ®xed cells.…”

“…Initial studies with these transgenic mice showed that a modest (four-fold) overexpression of Gaq in the myocardium lead to development of a stable form of cardiac hypertrophy (D'Angelo et al, 1997). However, when these mice were subjected to the neurohumoral or hemodynamic stresses associated with parturition (Adams et al, 1998b) or to chronic pressure overload Adams et al, manuscript in preparation) cardiac failure rapidly developed in association with increased cardiomyocyte apoptosis. Another line of transgenic mice expressing an activated rather than wild type form of Gaq in the myocardium rapidly developed marked hypertrophy and a dilated cardiomyopathy (Mende et al, 1998).…”

“…While the initial hypertrophic response to Gqcoupled receptor stimulation in the stressed heart is adaptive, we have demonstrated that prolonged activation of these pathways may become maladaptive as a result of cumulative loss of myocytes through apoptosis (Adams et al, 1998b;Dorn and Brown, 1999). Direct evidence for the activation of apoptotic pathways by Gq signaling derives from in vitro studies using recombinant adenovirus to express a constitutively activated mutant form of the alpha subunit of Gq (GaqQ209L).…”