Year of Publication

2008

Degree Name

Doctor of Philosophy (PhD)

Document Type

Dissertation

College

Pharmacy

Department

Pharmaceutical Sciences

First Advisor

Dr. Steven R. Post

Abstract

A key cardiovascular signaling molecule involved in both physiologic and pathologic regulation of cardiomyocytes is the small molecular weight G-protein, Ras. Differential effects of Ras are mediated by multiple effector molecules, including the RalGEFs which activate Ral. Studies performed in cardiomyocytes have indicated a role for Ral in cardiac hypertrophic signaling and the RalGEF family member, Rgl2, was shown to specifically interact with Ras in the heart. Therefore, I hypothesized that Rgl2 was an important Ras effector that would regulate cardiomyocyte signaling.

To elucidate the potential importance of Rgl2 in regulating cardiomyocyte signaling, a gain-of-function approach was utilized in which NRVMs were infected with an adenovirus to increase Rgl2 expression. Using this approach, I found that Rgl2 increased Ral-GTP levels, Ras-GTP levels, and PI3-kinase-Akt signaling, but decreased ERK phosphorylation. Overall, my results suggest a model in which Rgl2 disrupts Ras-Raf and Ras-RasGAP interaction to decrease ERK phosphorylation and increase Ras-GTP, respectively. Furthermore, Rgl2-induced Ral activation promotes the enhanced PI3- kinase-Akt signaling. The physiologic consequence of Rgl2 signaling is difficult to predict, but the increase in PI3-kinase-Akt signaling would be expected to promote cardiomyocyte survival and enhance cardiac function, both of which are characteristic of physiologic hypertrophy.

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