Date of Award

January 2013

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Jeffrey R. Bender

Subject Area(s)

Medicine, Cellular biology, Immunology

Abstract

STATIN INHIBITION OF MACROPHAGE INTEGRIN-INDUCED RAC2-MYOSIN IIA INTERACTION: AN ANTI-INFLAMMATORY EFFECT.

Kenneth E. Ike, Alan Morrison, and Jeffrey R. Bender. Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, School of Medicine, New Haven, CT.

HMG-CoA reductase inhibitors (statins) are pharmaceuticals that are utilized for the treatment of lipid disorders along with the primary and secondary prevention of coronary heart disease. HMG-CoA reductase is the rate-limiting enzyme in cholesterol synthesis, converting HMG-CoA to mevalonate. The isoprenoid products, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), are derived from the mevalonate pathway and serve as substrates in the prenylation of 2% of cellular proteins including the Rho family of low molecular weight G-proteins which mediate multiple cellular signals. Prenylation is an important post-translational modification of proteins that plays a role in the subcellular localization of proteins to certain hydrophobic (membrane) compartments. This localization can affect overall protein function. We demonstrate that manipulation of the prenylation state of Rac2 alters the formation of a signaling complex between Rac2 and Myosin IIA that forms via Beta2 integrin engagement coupled to chemokine (CCL2, MCP-1) stimulation. This complex appears critical to the translocation of the RNA binding protein, HuR, from the nucleus to the cytosol whereby it functions to exact its effects on mRNA stability. HuR translocation prolongs the half-life of transcripts encoding critical inflammatory, immune and angiogenic cytokines like TNF-alpha;, INF-gamma;, and VEGF-A. This pathway may represent a pleiotropic effect of statin therapy and may serve as a target for future small molecule therapeutics with anti-inflammatory potential.

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This is an Open Access Thesis.

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