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

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. Gαi2G184S/+/DCM double heterozygote mice (TG9+Gαi2G184S/+) had substantially decreased survival compared to DCM animals. Furthermore, heart weight/body weight ratios (HW/BW) were significantly greater in TG9+Gαi2G184S/+ mice as was expression of natriuretic peptide genes. Catecholamine injury in Gαi2G184S/G184S mutant mice produced markedly increased isoproterenol-induced fibrosis and collagen III gene expression vs WT mice. Cardiac fibroblasts from Gαi2G184S/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. 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.

Not all arrestins are created equal: Therapeutic implications of the functional diversity of the β arrestins in the heart

“…However, if this holds true in actual cardiomyocytes in vivo , it might be part of the mechanism for this β-blocker`s cardio-protective effects. However, several studies do not lend support to this notion; sustained β 1 AR activation by catecholamines, markedly more potent activators of β-arrestin-dependent ERKs in the heart than carvedilol, increases cardiac adverse remodeling even in the absence of cardiac injury[26]. Moreover, carvedilol is also a β 2 - and α 1 AR antagonist, which may interfere with its β-arrestin-activating properties in the heart[27].…”

Sarco“MiR” friend or foe: a perspective on the mechanisms of doxorubicin-induced cardiomyopathy

“…On the other hand, β 2 AR is thought to confer cardioprotection (38,42). This prosurvival phenotype is thought to be at least in part associated with its interaction with G i proteins (43). In human end stage heart failure patients, G i proteins, particularly the α-2 subunit (G 1α-2 ), are up-regulated (44).…”

“…Activation of G 1α-2 is slightly more controversial as one group demonstrated that constitutive activation of G 1α-2 in a dilated cardiomyopathy and an isoproterenolinduced heart failure mouse model led to worsening hypertrophy and fibrosis, respectively. The authors postulate that the role of G 1α-2 in fibroblasts as opposed to cardiomyocytes may be the driving force behind these phenotypes (43). To complicate the story even more, recent models have demonstrated reverse phenotypes for the role of β 1 AR and β 2 AR in heart failure whereby β 1 AR is cardioprotective and β 2 AR promotes cardiotoxicity (48).…”

Regulation of G protein subunit composition in cardiomyocytes: pharmacological implications

“…Most prominently, expression of G iα2 is increased in heart failure (El-Armouche et al 2003). It is controversially discussed whether G iα2 signaling is beneficial or detrimental in heart failure (Kaur et al 2012). Accordingly, the role of G iα2 must be studied in greater detail.…”