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(Circulation Research. 2000;87:1085.)
© 2000 American Heart Association, Inc.

Editorial

G Proteins and Heart Failure

Is Gq a Novel Target for Heart Failure?

Giora Z. Feuerstein, Dennis Rozanski

From the Department of Cardiovascular Disease Research, DuPont Pharmaceuticals, Wilmington, Del.

Correspondence to G.Z. Feuerstein, Cardiovascular Disease Research, Experimental Station, Building 400-3255, Route 141 & Henry Clay Road, DuPont Pharmaceuticals, Wilmington, DE 19880. E-mail giora.z.feuerstein{at}dupontpharma.com

Key Words: heart failure • G protein • Gq • G protein–coupled receptors

	Introduction

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Gproteins (GTP-binding proteins) are heterodimeric protein complexes consisting of , ß, and subunits. G proteins transduce signals from 7-transmembrane receptors (also known as G protein–coupled receptors [GPCRs]) to effector molecules. There are 20 distinct G subunits (40 000 molecular weight), 6 distinct ß subunits (35 000 molecular weight), and 12 subunits (8 000 molecular weight). The G is the major determinant of signaling selectivity, which is largely executed via one of the four major subfamilies: (1) G s: activation of adenylate cyclase; (2) G i/o: inhibition of adenylate cyclase; (3) Gq (Gq, G₁₁, G₁₄, G_15/16): activation of phospholipase C; and (4) G_12/13: 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 G proteins occurs in heart failure, eg, increase in Gi.² Third, there are proven benefits of specific antagonists of GPCRs, eg, angiotensin II AT₁ receptors and ß-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 Gq subtype of the G proteins in cardiac pathology, because Gq has been recognized as an important component of the signaling induced by agonists of the ₁-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 F₂, and thromboxane A₂ (coronary smooth muscle constriction). Reports from different laboratories and models have demonstrated cardiac hypertrophy associated with Gq signaling along with reactivation of embryonic genes, such as atrial natriuretic factor, skeletal -actin, and ß-myosin heavy chain. Furthermore, transient expression of a constitutively active mutant of Gq 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 Gq 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 Gq overexpression in these transgenic models.

Most intriguing in this respect are observations that even transient overexpression of a constitutively active Gq 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 Gq 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 Gq signaling leading to cardiac hypertrophy, dilatation, failure, and apoptosis are poorly understood. The Gq-signaling pathway leading to hypertrophy has been linked to phospholipase C, A₂, and D as well as protein kinase C (isoforms //), 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 Gq-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 Gq 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 Gq 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 Gq signaling and mitochondrial integrity; the discrete molecular mechanisms that link Gq activation to mitochondrial membrane damage remain to be investigated.

Enhancing the knowledge of the Gq 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 Gq-mediated signaling generated in the heart by transgenic techniques (by overexpressing the carboxyl-terminal peptide of the Gq subunit, thereby inducing a dominant-negative effect) resulted in significant abolition of cardiac hypertrophy in response to pressure overload.¹¹ These data show that Gq 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 Gq.¹² Elucidation of specific sequences in these domains that interact with specific Gq 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 Gq 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 Gq 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 Gq 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 Gq 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 Gq-signaling pathway.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction References

 

1. Offermanns S. New insights into the in vivo function of the heterotrimeric G-proteins through gene deletion studies. Naunyn Schmiedebergs Arch Pharmacol. 1999;360:5–13.[Medline] [Order article via Infotrieve]
2. Colucci WS, Braunwald E. Pathophysiology of heart failure. In: Braunwald E, ed. Heart Disease, a Textbook of Cardiovascular Medicine. Philadelphia, Pa: WB Saunders; 1997:394–420.
3. Colucci WS. Heart failure: cardiac function and dysfunction. In: Braunwald E, ed. Atlas of Heart Diseases. Philadelphia, Pa: Current Medicine; 1999.
4. Mende U, Kagen A, Cohen A, Aramburu A, Schoen FJ, Neer EJ. Transient cardiac expression of constitutively active Gq leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways. Proc Natl Acad Sci U S A. 1998;95:13893–13898.[Abstract/Free Full Text]
5. SakataY, Hiot B, Liggett SB, Walsh RA, Dorn GW. Decompensation of pressure overload hypertrophy in Gq-overexpressing mice. Circ Res. 1998;97:1488–1495.
6. Adams JW, Sakata Y, Davis MG, Sah VP, Wang Y, Liggett SB, Chien KR, Brown JH, Dorn GW. Enhanced Gq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure. Proc Natl Acad Sci U S A. 1998;95:10140–10145.[Abstract/Free Full Text]
7. Mende U, Kagen A, Meister M, Neer EJ. Signal transduction in atria and ventricles of mice with transient cardiac expression of activated G protein q. Circ Res. 1999;85:1085–1091.[Abstract/Free Full Text]
8. Ju H, Zhao S, Tappia PS, Panagia V, Dixon CM. Expression of Gq and PLC-ß in scar and border tissue in heart failure due to myocardial infarction. Circulation. 1998;97:892–899.[Abstract/Free Full Text]
9. Yatani A, Frank K, Sako H, Kranias EG, Dorn GW. Cardiac specific overexpression of Gq alters excitation-contraction coupling in isolated cardiac myocytes. J Mol Cell Cardiol. 1999;31:1327–1336.[Medline] [Order article via Infotrieve]
10. Adams JW, Pagel AL, Means CK, Oksenberg D, Armstrong RC, Brown JH. Cardiomyocyte apoptosis induced by Gq signaling is mediated by permeability transition pore formation and activation of the mitochondrial death pathway. Circ Res. 2000;87:1180–1187.[Abstract/Free Full Text]
11. Akhter SA, Lutrell LM, Rockman HA, Iaccarino G, Lefkowitz RJ, Koch WJ. Targeting the receptor-Gq interface to inhibit in vivo pressure overload myocardial hypertrophy. Science. 1998;280:574–577.[Abstract/Free Full Text]
12. Kostenis E, Gomeza J, Lerche C, Wess J. Genetic analysis of receptor-Gq coupling selectivity. J Biol Chem. 1997;272:23675–23681.[Abstract/Free Full Text]
13. Takeishi Y, Jalili T, Hoit BD, Kirkpatrick DL, Wagoner LE, Abraham WT, Walsh RA. Alterations in Ca²⁺ cycling proteins and Gq signaling after left ventricle assist device support in failing human hearts. Cardiovasc Res. 2000;45:883–888.[Abstract/Free Full Text]

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