Revisited and revised: is RhoA always a villain in cardiac pathophysiology?

Abstract

The neonatal rat ventricular myocyte model of hypertrophy has provided tremendous insight with regard to signaling pathways regulating cardiac growth and gene expression. Many mediators thus discovered have been successfully extrapolated to the in vivo setting, as assessed using genetically engineered mice and physiological interventions. Studies in neonatal rat ventricular myocytes demonstrated a role for the small G-protein RhoA and its downstream effector kinase, Rho-associated coiled-coil containing protein kinase (ROCK), in agonist-mediated hypertrophy. Transgenic expression of RhoA in the heart does not phenocopy this response, however, nor does genetic deletion of ROCK prevent hypertrophy. Pharmacologic inhibition of ROCK has effects most consistent with roles for RhoA signaling in the development of heart failure or responses to ischemic damage. Whether signals elicited downstream of RhoA promote cell death or survival and are deleterious or salutary is, however, context and cell-type dependent. The concepts discussed above are reviewed, and the hypothesis that RhoA might protect cardiomyocytes from ischemia and other insults is presented. Novel RhoA targets including phospholipid regulated and regulating enzymes (Akt, PI kinases, phospholipase C, protein kinases C and D) and serum response element-mediated transcriptional responses are considered as possible pathways through which RhoA could affect cardiomyocyte survival.

Fig. 1

GPCRs signaling in hypertrophy, survival, and failure. Dashed lines indicate pathways that the authors do not consider to be predominant. Abbreviations: NE norepinephrine, PE phenylephrine, ET-1 endothelin-1, S1P sphingosine 1-phosphate, LPA lysophosphatidic acid, I/R ischemia/reperfusion, InsP3 inositol-1,4,5-triphosphate, DAG diacylglycerol, PLC phospholipase C, RhoGEF rho guanine nucleotide exchange factor, PKC, protein kinase C, CaMK, calcium–calmodulin-dependent kinase, CaN, calcineurin, ROCK rho-associated coiled-coil containing protein kinase, FAK focal adhesion kinase, PLD phospholipase D

Fig. 2

RhoA is activated by ischemia/reperfusion in the perfused mouse heart. Isolated adult mouse hearts were retrograde perfused using the Langendorff method. Hearts were subjected to continuous perfusion (Ctrl), ischemia (Isch) for 30 min, or ischemia for 30 min and reperfusion for 60 min (I/R). Hearts were frozen, homogenized, and assessed for total RhoA in the lysate and activated RhoA based on pull-down with GST-rhotekin

Fig. 3

RhoA-mediated protective signaling through Akt

Fig. 4

RhoA-mediated protective signaling through phospholipid regulatory enzymes