The critical cell signals that trigger cardiac hypertrophy and regulate the transition to heart failure are not known. To determine the role of G␣q-mediated signaling pathways in these events, transgenic mice were constructed that overexpressed wild-type G␣q in the heart using the ␣-myosin heavy chain promoter. Two-fold overexpression of G␣q showed no detectable effects, whereas 4-fold overexpression resulted in increased heart weight and myocyte size along with marked increases in atrial naturietic factor (Ϸ55-fold), ␤-myosin heavy chain (Ϸ8-fold), and ␣-skeletal actin (Ϸ8-fold) expression, and decreased (Ϸ3-fold) ␤-adrenergic receptor-stimulated adenylyl cyclase activity. All of these signals have been considered markers of hypertrophy or failure in other experimental systems or human heart failure. Echocardiography and in vivo cardiac hemodynamic studies indeed revealed impaired intrinsic contractility manifested as decreased fractional shortening (19 ؎ 2% vs. 41 ؎ 3%), dP͞dt max, a negative force-frequency response, an altered Starling relationship, and blunted contractile responses to the ␤-adrenergic agonist dobutamine. At higher levels of G␣q overexpression, frank cardiac decompensation occurred in 3 of 6 animals with development of biventricular failure, pulmonary congestion, and death. The element within the pathway that appeared to be critical for these events was activation of protein kinase C. Interestingly, mitogen-activated protein kinase, which is postulated by some to be important in the hypertrophy program, was not activated. The G␣q overexpressor exhibits a biochemical and physiologic phenotype resembling both the compensated and decompensated phases of human cardiac hypertrophy and suggests a common mechanism for their pathogenesis.

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.

Intrinsic cardiac myocyte G alpha q activation stimulates fetal gene expression and depresses cardiac myocyte contractility. Superimposition of the hemodynamic stress of pressure overload on G alpha q overexpression stimulates a maladaptive form of eccentric hypertrophy that leads to rapid functional decompensation. Therefore G alpha q-stimulated cardiac hypertrophy is functionally deleterious and compromises the ability of the heart to adapt to increased mechanical load. This finding supports a reevaluation of accepted concepts regarding the mechanisms for compensation and decompensation in pressure-overload hypertrophy.

Epidemiological and experimental reports have linked mild-to-moderate wine and/or grape consumption to a lowered incidence of cardiovascular, cerebrovascular, and peripheral vascular risk. This study revealed that resveratrol, an enriched bioactive polyphenol in red wine, selectively induces heme oxygenase 1 (HO1) in a dose-and time-dependent manner in cultured mouse cortical neuronal cells and provides neuroprotection from free-radical or excitotoxicity damage. This protection was lost when cells were treated with a protein synthesis or heme oxygenase inhibitor, suggesting that HO1 induction is at least partially required for resveratrol's prophylactic properties. Furthermore, resveratrol pretreatment dose-dependently protected mice subjected to an optimized ischemicreperfusion stroke model. Mice in which HO1 was selectively deleted lost most, if not all, of the beneficial effects. Together, the data suggest a potential intracellular pathway by which resveratrol can provide cell/organ resistance against neuropathological conditions.