Gαl i2 signaling: Friend or foe in cardiac injury and heart failure?

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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Receptors coupled to G proteins have many effects on the heart. Enhanced signaling by Gα s and Gα q leads to cardiac injury and heart failure, while Gα i2 signaling in cardiac myocytes can protect against ischemic injury and β- adrenergic-induced heart failure. We asked whether enhanced Gα i2 signaling in mice could protect against heart failure using a point mutation in Gα i2 (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 catecholamineinduced cardiac injury. Gα i2 G184S/+/DCM double heterozygote mice (TG9+Gα i2 G184S/+) had substantially decreased survival compared to DCM animals. Furthermore, heart weight/body weight ratios (HW/BW) were significantly greater in TG9+Gα i2 G184S/+ mice as was expression of natriuretic peptide genes. Catecholamine injury in Gα i2 G184S/G184S mutant mice produced markedly increased isoproterenolinduced fibrosis and collagen III gene expression vs WT mice. Cardiac fibroblasts from Gα i2 G184S/G184S 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. Gα i2 signaling in cardiac myocytes protects against ischemic injury but enhancing Gα i2 signaling overall may have detrimental effects in heart failure, perhaps through actions on cardiac fibroblasts.

Original languageEnglish
Pages (from-to)443-453
Number of pages11
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume385
Issue number5
DOIs
StatePublished - May 2012

Keywords

  • Angiotensin
  • Cardiac fibroblasts
  • Isoproterenol
  • RGS

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