G-proteins in growth and apoptosis: lessons from the heart

Abstract

The acute contractile function of the heart is controlled by the e ects of released nonepinephrine (NE) on cardiac adrenergic receptors. NE can also act in a more chronic fashion to induce cardiomyocyte growth, characterized by cell enlargement (hypertrophy), increased protein synthesis, alterations in gene expression and addition of sarcomeres. These responses enhance cardiomyocyte contractile function and thus allow the heart to compensate for increased stress. The hypertrophic e ects of NE are mediated through Gq-coupled a 1 -adrenergic receptors and are mimicked by the actions of other neurohormones (endothelin, prostaglandin F 2a angiotensin II) that also act on Gq-coupled receptors. Activation of phospholipase C by Gq is necessary for these responses, and protein kinase C and MAP kinases have also been implicated. Gq stimulated cardiac hypertrophy is also evident in transgenic mouse models. In contrast, stimulation of G s -coupled b-adrenergic receptors or G i -coupled receptors do not directly e ect cardiomyocyte hypertrophy. Apoptosis is also induced by G-protein-coupled receptor stimulation in cardiomyocytes. Sustained or excessive activation of either Gq-or Gs-signaling pathways results in apoptotic loss of cardiomyocytes both in vitro and in vivo. Apoptosis is associated with decreased ventricular function in the failing heart. Cardiomyocytes provide an ideal model system for understanding the basis for G-protein mediated hypertrophy and apoptosis, and the mechanisms responsible for the transition from compensatory to deleterious levels of signaling. This information may prove critical for designing interventions that prevent the pathophysiological consequences of heart failure. Oncogene (2001) 20, 1626 ± 1634.

Convergence of Protein Kinase C and JAK-STAT Signaling on Transcription Factor GATA-4

“…Similarly, the various signaling pathways activated by AII have all been implicated in cardiac hypertrophy, apoptosis, or both (1,24,46). Their importance in mediating specific AII effects as well as their involvement in AII regulation of cardiac genes has not been firmly elucidated.…”

UTP Transactivates Epidermal Growth Factor Receptors and Promotes Cardiomyocyte Hypertrophy Despite Inhibiting Transcription of the Hypertrophic Marker Gene, Atrial Natriuretic Peptide

“…Hypertrophy in response to pressure overload involves heterotrimeric G proteins of the G q/11 class (1) and activation of G q is sufficient to cause hypertrophy in vivo (2), as well as in cell models (3). In keeping with this, activation of G q -coupled receptors including ␣ 1 -adrenergic receptors (␣ 1 -AR), 1 ET A receptors or AT 1 receptors on neonatal rat ventricular myocytes (NRVM) causes increased growth of the cardiomyocytes, as well as increasing transcription from "hypertrophic" marker genes, such as ANP and MLC2 (3). Signaling pathways associated with increased protein synthesis, and hence cell size, are known to be partly independent of those causing re-expression of ANP and MLC2, but both can be activated by G q (4).…”

Determination of the Exact Molecular Requirements for Type 1 Angiotensin Receptor Epidermal Growth Factor Receptor Transactivation and Cardiomyocyte Hypertrophy

“…G␣ q/11 is a well-established mediator of cardiac hypertrophy, 10 so we hypothesized that G-protein coupling to the Figure 4A). 17 [Y215F]AT 1 was confirmed as a G proteinuncoupled mutant with robust expression ( Figure S2 and Table S1) and, although [Y215F]AT 1 was described previously with reduced radioligand affinity, we found no statistically significant difference in affinity compared with WT, and the Ang II concentrations used herein are sufficient to ensure almost complete receptor occupancy at either receptor.…”

“…Recent studies suggested a G protein-independent pathway for growth activation, 6 -9 despite evidence that G␣ q/11 , a heterotrimeric G protein that couples to the AT 1 R, is essential for hypertrophy. 10 Indeed, others indicate that G-protein coupling to AT 1 R is required for EGFR transactivation in COS-7 and vascular smooth muscle cells. [11][12][13] Meanwhile, evidence for ␤-arrestin-dependent functional selectivity of the Ang II analog sarcosine, 1 isoleucine, 4 isoleucine, 8 Ang II (SII Ang II), 14 ␤-arrestin-mediated EGFR transactivation by ␤ 1 -adrenoceptors independent of G-protein coupling, 15 and the very recent demonstration of ␤-arrestin-dependent hypertrophy resulting from mechanical stretch 16 suggests that ␤-arrestin scaffolding of extracellular signal-regulated kinase (ERK) 1/2 may contribute to transactivation and/or cardiac hypertrophy.…”