Gαq Signaling in the Regulation of Autophagy and Heart Failure

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The adult heart undergoes distinct remodeling processes in response to either acute or chronic insults, which can lead to myocyte hypertrophy and ventricular wall thickening or myocyte elongation, death, and ventricular dilatation.1–3 Although an increase in cardiac tissue mass diminishes systolic wall stress to improve contractile performance in the short term, prolonged hypertrophy in response to pathological signaling is associated with a progression toward decompensated heart failure (HF).1–3 Accumulating evidence from studies in human patients and animal models suggests that in most instances hypertrophy is not a compensatory response to the change in mechanical load but rather is a maladaptive process.1,2,4 On the other hand, physiological hypertrophy, as occurs during normal postnatal development or in highly trained athletes, represents a beneficial form of cardiac growth.5
Numerous neuroendocrine and autocrine factors such as phenylephrine, angiotensin II, and endothelin-1 are well-known inducers of cardiomyocyte hypertrophy, and inhibition of their actions can be beneficial for the treatment of chronic HF after cardiac hypertrophy.2,3 Many such agonists act through G protein–coupled receptors that couple with Gαq (GqPCRs), which canonically activate phospholipase Cβ (PLCβ), generating the second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol , which then act to mobilize intracellular calcium and activate numerous downstream kinases, respectively. Chronic GqPCR activation results in cardiac hypertrophy and subsequently leads to cardiomyopathy with depressed contractile function.2,3 Although a low level of Gαq overexpression in mice does not significantly affect the heart, mild Gαq overexpression results in increased hypertrophic markers with minimal cardiac dysfunction6,7 and high Gαq overexpression results in marked hypertrophy, HF, and increased mortality.6 Further, Gαq-overexpressing hearts that are exposed to pressure overload show increased apoptosis,8 whereas overexpression of an inhibitory peptide that interferes with Gαq coupling prevents the development of cardiac hypertrophy and dysfunction in pressure-overloaded mice.9,10 Altogether, these data have highlighted the critical role of Gαq-signaling pathways in mediating the hypertrophic signaling and the transition to HF.
Several studies have investigated the potential contributions of cardiomyocyte autophagy on protein turnover and cardiac hypertrophy. Autophagy is an evolutionally conserved mechanism for the degradation of cellular components and organelles by lysosomes. Autophagy also plays an important role in the maintenance of cellular energetics by recycling amino acids and fatty acids for ATP production.11 In eukaryotic cells, autophagy occurs constitutively at low levels to facilitate homeostatic functions such as protein and organelle turnover. However, autophagy is rapidly upregulated in conditions requiring the generation of high intracellular nutrients and energy, such as during starvation, growth factor withdrawal, or removal of damaging cytoplasmic components.11,12 Consistent with these functions, autophagy appears to play a protective role during normal conditions and in response to mild stress.13,14 However, excessive autophagy has been associated to cardiomyocyte death and the development of HF.13,14 Autophagy was observed in failing human hearts caused by dilated cardiomyopathy,15 by valvular disease,16 and by ischemic heart disease.17 Moreover, analysis of hearts from patients with end-stage HF indicated that cardiomyocytes died by a variety of mechanisms including necrosis, apoptosis, and autophagy.18 However, despite considerable evidence linking autophagic activity to HF progression, it is still debated whether autophagy is an adaptive response to protect cardiomyocyte from stress conditions or a maladaptive response that causes HF.
In the current issue of the journal, Liu et al19 provide the first analysis of the role of Gαq activation on autophagy in the heart. Using a cardiomyocyte-specific transgenic mouse model of inducible GαqQ209L, a constitutive Gαq mutant deficient in GTP hydrolysis,7,20 the authors demonstrate that autophagic vacuoles, levels of proteins involved in autophagy, and autophagic activity were enhanced in GαqQ209L hearts at 7 days after transgene induction by tamoxifen treatment.

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