Alpha Omega Alpha Honor Medical Society

2010 Research Abstract

MEK1 and Myocardin Dependent Regulation of Hic-5 Expression in Cardiac Hypertrophy

Investigator: Ashish Rastogi, Albany Medical College
Mentor: Rebecca S. Keller, PhD, Albany Medical College

Cardiovascular disease remains the major cause of death in the United States. Therefore, identifying molecular mechanisms involved in the development of cardiac hypertrophy, an early indicator of cardiovascular disease, is essential. Published data from our lab showed that Hic-5 expression was upregulated in response to a hypertrophic agent, phenylephrine (PE), and in a mouse model of pathologic hypertrophy. Additionally, the MEK inhibitor, U0126, inhibited the PE induction of Hic-5. Myocardin, a transcription factor, is downstream of MEK signaling and has been implicated in the pathogenesis of cardiac hypertrophy as well. Thus, we hypothesized that both MEK and myocardin dependent signaling were sufficient and necessary for Hic-5 expression. To test the sufficiency of MEK signaling on Hic-5 expression, constitutively-active constructs of upstream molecules (ca-RAS or ca-RAC) were overexpressed in neonatal rat ventricular myocytes (NRVM). Similarly, to test sufficiency of myocardin signaling on Hic-5 expression, myocardin was overexpressed in NRVM. To test the necessity of MEK signaling, MEK1 expression was knocked down via siRNA in the presence of PE or ca-RAS. Similarly, to test the necessity of myocardin for Hic-5 expression, we subjected NRVM to a myocardin siRNA in the presence of PE. We found that ca-RAS was able to induce Hic-5 expression in the presence but not in the absence of MEK1 (p<0.05). ca-RAC, alternatively, did not induce Hic-5. However, ca-RAC did promote ERK-phosphorylation which is downstream of MEK signaling (p<0.05). These data suggest that Hic-5 expression is dependent on MEK1 activity but not ERK-phosphorylation. We also found that myocardin overexpression increased Hic-5 expression levels whereas knockdown of myocardin inhibited PE induced Hic-5 induction. These findings suggest a novel signaling pathway in which Hic-5 is downstream of both MEK1 and myocardin signaling, leading to pathological cardiac hypertrophy and thus implicates Hic-5 as a possible future pharmacological target for therapy.

Updated on June 8, 2011.


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