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Gαi2 signaling: friend or foe in cardiac injury and heart failure?

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Abstract

Receptors coupled to G proteins have many effects on the heart. Enhanced signaling by Gαs and Gαq leads to cardiac injury and heart failure, while Gαi2 signaling in cardiac myocytes can protect against ischemic injury and β-adrenergic-induced heart failure. We asked whether enhanced Gαi2 signaling in mice could protect against heart failure using a point mutation in Gαi2 (G184S), which prevents negative regulation by regulators of G protein signaling. Contrary to our expectation, it worsened effects of a genetic dilated cardiomyopathy (DCM) and catecholamine-induced cardiac injury. Gα G184S/+i2 /DCM double heterozygote mice (TG9+Gα G184S/+i2 ) had substantially decreased survival compared to DCM animals. Furthermore, heart weight/body weight ratios (HW/BW) were significantly greater in TG9+Gα G184S/+i2 mice as was expression of natriuretic peptide genes. Catecholamine injury in Gα G184S/G184Si2 mutant mice produced markedly increased isoproterenol-induced fibrosis and collagen III gene expression vs WT mice. Cardiac fibroblasts from Gα G184S/G184Si2 mice also showed a serum-dependent increase in proliferation and ERK phosphorylation, which were blocked by pertussis toxin and a mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor. Gαi2 signaling in cardiac myocytes protects against ischemic injury but enhancing Gαi2 signaling overall may have detrimental effects in heart failure, perhaps through actions on cardiac fibroblasts.

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Acknowledgments

This study supported by National Institutes of Health grant R01-GM39561 (R.R.N.) and the University of Michigan Comprehensive Cancer Center (National Institutes of Health grant P30-CA46592). PYJ is a Scholar of the Child Health Research Center of Excellence in Developmental Biology at Washington University School of Medicine (National Institutes of Health K12-HD001487).

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Authors and Affiliations

  1. Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, MI, 48109-0632, USA

    Kuljeet Kaur, Sergio Parra, Rong Chen, Raelene A. Charbeneau, Susan M. Wade & Richard R. Neubig

  2. Departments of Pediatrics and Genetics, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Patrick Y. Jay

  3. Department of Internal Medicine (Cardiovascular Medicine), The University of Michigan Medical School, 1150 W. Medical Center Drive 1303 MSRB III, Ann Arbor, MI, 48109-0632, USA

    Richard R. Neubig

  4. Center for Chemical Genomics, The University of Michigan Medical School, Ann Arbor, MI, 48109-0632, USA

    Richard R. Neubig

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  1. Kuljeet Kaur
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  2. Sergio Parra
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Correspondence to Richard R. Neubig.

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Kaur, K., Parra, S., Chen, R. et al. Gαi2 signaling: friend or foe in cardiac injury and heart failure?. Naunyn-Schmiedeberg's Arch Pharmacol 385, 443–453 (2012). https://doi.org/10.1007/s00210-011-0705-z

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