G Proteins and Heart Failure
Is Gαq a Novel Target for Heart Failure?
Gproteins (GTP-binding proteins) are heterodimeric protein complexes consisting of α, β, and γ subunits. G proteins transduce signals from 7-transmembrane receptors (also known as G protein–coupled receptors [GPCRs]) to effector molecules. There are 20 distinct Gα subunits (≈40 000 molecular weight), 6 distinct β subunits (≈35 000 molecular weight), and 12 γ subunits (≈8 000 molecular weight). The Gα is the major determinant of signaling selectivity, which is largely executed via one of the four major subfamilies: (1) Gα s: activation of adenylate cyclase; (2) Gα i/o: inhibition of adenylate cyclase; (3) Gαq (Gαq, Gα11, Gα14, Gα15/16): activation of phospholipase C; and (4) Gα12/13: function yet unclear.1
Why is it important to research cardiac G proteins? The answer to this question is straightforward. First, GPCRs are present in the heart, and they transduce the major (if not the most important) signaling pathways associated with cardiac remodeling, as evidenced by the action of angiotensin II, endothelin-1, and the sympathetic neurohormonal systems on cardiac remodeling. Second, substantial alteration in the expression and function of Gα proteins occurs in heart failure, eg, increase in Gαi.2 Third, there are proven benefits of specific antagonists of GPCRs, eg, angiotensin II AT1 receptors and β-adrenergic receptor blockers, to induce beneficial reversal of cardiac remodeling in heart failure patients.3
In the past few years, attention has focused on the particular role of the Gαq subtype of the G proteins in cardiac pathology, because Gαq has been recognized as an important component of the signaling induced by agonists of the α1-adrenergic receptor (hypertrophy and Na+-H+ exchange transporter regulation), angiotensin II AT1 receptor (Ca2+ signaling, myocyte hypertrophy, and collagen synthesis/release from cardiac fibroblasts), endothelin-1 (ETa receptor mediating hypertrophy, rhythm, and collagen), prostaglandin F2α, and thromboxane A2 (coronary smooth muscle constriction). Reports from different laboratories and models have demonstrated cardiac hypertrophy associated with Gαq signaling along with reactivation of embryonic genes, such as atrial natriuretic factor, skeletal α-actin, and β-myosin heavy chain. Furthermore, transient expression of a constitutively active mutant of Gαq in transgenic mice consistently resulted in cardiac hypertrophy and dilatation with ultimate cardiac failure and death.4 Furthermore, superimposition of hemodynamic stress (eg, aortic banding that results in pressure overload) stimulates a maladaptive form of eccentric hypertrophy that leads to rapid decompensation.5 Of interest were observations regarding the apoptotic mode of cardiac cell death induced by Gαq overexpression6 ; in fact, the impression from work reported today is that progression of compensated hypertrophy to decompensated hypertrophy, dilation, and, ultimately, apoptosis are the sequelae of Gαq overexpression in these transgenic models.
Most intriguing in this respect are observations that even transient overexpression of a constitutively active Gαq in a cardiac-specific manner results in long-lasting phenotypic changes (hypertrophy and dilatation) via multiple signaling pathways that are chamber-specific.7 This observation is of particular importance, because increases in Gαq expression and signaling were reported in the surviving cardiac tissue undergoing remodeling consequent to the ischemic infarct.8
The precise factors that underlie the activation of Gαq signaling leading to cardiac hypertrophy, dilatation, failure, and apoptosis are poorly understood. The Gαq-signaling pathway leading to hypertrophy has been linked to phospholipase C, A2, and D as well as protein kinase C (isoforms α/δ/ε), the ras/mitogen-activated protein kinase, various tyrosine kinases (including p38 and stress-activated protein kinase), and reduced sarcoplasmic reticulum function.9
In this issue of Circulation Research, Adams et al10 provide new data that significantly advance our knowledge regarding the mechanism associated with cardiac cell apoptosis secondary to Gαq-signaling activation. Using genetic and molecular biology techniques, the authors show for the first time substantial aberrations in mitochondrial function and caspase activation in response to Gαq signaling.10 The authors clearly demonstrate mitochondrial membrane damage (membrane potential loss) resulting in cytochrome c (Cyt c) release, Bcl-2 family protein changes, and caspase 3 activation.10 Using pharmacological tools (caspase inhibitors), the authors show that although caspase 9/3 activation is likely to be the final execution arm of Gαq signaling in this model, these proteases are downstream of the mitochondrial malfunction, because caspase inhibitors did not abolish Cyt c release.10 Thus, a novel link is made between Gαq signaling and mitochondrial integrity; the discrete molecular mechanisms that link Gαq activation to mitochondrial membrane damage remain to be investigated.
Enhancing the knowledge of the Gαq signaling pathway leading to cardiac cell remodeling, hypertrophy, apoptosis, and heart failure has particular importance in view of possible new strategies to intervene pharmacologically in cardiac remodeling and heart failure. Thus, class-specific inhibition of Gαq-mediated signaling generated in the heart by transgenic techniques (by overexpressing the carboxyl-terminal peptide of the Gαq subunit, thereby inducing a dominant-negative effect) resulted in significant abolition of cardiac hypertrophy in response to pressure overload.11 These data show that Gαq interaction with discrete sites of the GPCRs might be blocked pharmacologically to prevent cardiac remodeling. This possibility is additionally supported by reports of possible multiple intracellular GPCR-receptor domains that form binding pockets with Gαq.12 Elucidation of specific sequences in these domains that interact with specific Gαq domain may lead to novel therapeutic strategies to prevent or treat heart failure.
Finally, one must keep in mind that although the experimental work on Gαq has advanced our basic knowledge on possible signaling pathways that may lead to diverse cardiac pathologies in human heart failure, there is a paucity of information as to whether the human cardiac Gαq system is essential for normal development and adult cardiac function, critical in initiation of pathology, important in propagation or maintenance of cardiac remodeling, and amenable to specific pharmacological intervention. Of interest in this respect is a recent report citing lack of differences in Gαq levels in normal and heart-failure cardiac samples but a decrease in RGS2 (regulator of G protein signaling protein) in the heart-failure specimens.13
Taken together, the present information on the role of Gαq as a causative mechanism in human heart failure is only suggestive at best. Additional research on these issues is critical to progress toward translational medicine targeting the Gαq-signaling pathway.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
- © 2000 American Heart Association, Inc.
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Takeishi Y, Jalili T, Hoit BD, Kirkpatrick DL, Wagoner LE, Abraham WT, Walsh RA. Alterations in Ca2+ cycling proteins and Gαq signaling after left ventricle assist device support in failing human hearts. Cardiovasc Res. 2000;45:883–888.