Abstract 337: Cardiac-Specific Deletion of the Small Rho GTPase Cdc42 Shows its Function as an Anti-Hypertrophic Effector.
The small GTPases of the Rho family are molecular switches that respond to membrane bound receptors and/or stretch stimulation, thereby cycling between a GDP-bound inactive conformation to a GTP-bound active conformation. When activated, Rho GTPases play critical roles in affecting cellular morphology, apoptosis, gene expression, and stress signaling pathways. Previous in vitro studies in neonatal cardiomyocytes suggested that Rho GTPases are involved in hypertrophy induced by angiotensin II, phenylephrine or leukocyte inhibitory factor. However, little is known concerning Rho GTPase family member function in vivo. Here, we investigated the function of the GTPase Cdc42 in the heart through a Cre-LoxP conditional deletion strategy. Using an alpha-myosin heavy chain (MHC) cardiac-specific Cre expressing transgene crossed with Cdc42fl/fl mice, Cdc42 protein levels were significantly reduced at 4 weeks of age. Cdc42fl/fl-Cre+ mice displayed a normal span life, but remarkably, presented with mild baseline cardiac hypertrophy. Moreover, when subjected to transverse aortic constriction (TAC) for 2 weeks, Cdc42fl/fl-Cre+ mice developed an exacerbated hypertrophic response compared with control groups. Similarly, 2 weeks chronic infusion with angiotensin II and phenylephrine (respectively 432 μg/kg/day and 100 mg/kg/day) showed significantly greater hypertrophy in Cdc42fl/fl-Cre+ mice compared with controls. Following 8 weeks of TAC, Cdc42fl/fl-Cre+ mice compared with controls, quickly transitioned to heart failure characterized by decreased cardiac function and pulmonary edema. This increase in cardiac growth after TAC and agonist infusion was also associated with an enhanced fibrotic response. At the molecular level, P21 activated kinase (Pak) and c-Jun N-terminal kinase (JNK) phosphorylation were impaired in Cdc42fl/fl-Cre+ mice subjected to TAC. These results suggest that Cdc42 normally functions as an anti-hypertrophic signaling pathway in the heart in association with Pak and JNK downstream signaling.