Date of Award

2008

Degree Type

Dissertation

Department

Chemistry

First Advisor

Wang, Qing

Subject Headings

Coronary heart disease -- Genetic aspects, Myocardial infarction -- Genetic aspects, Medical genetics, CAD, MI, Atheroscleorsis, In vivo mouse model, Mef2a

Abstract

Coronary artery disease (CAD) and myocardial infarction (MI) are the leading cause of death in developed countries. Genetic factors play an important role in the pathogenesis of CAD and MI. The revolutionary advances in molecular genetics have provided new insights into the genetic pathways involved in this disease. Recently, our laboratory used linkage analysis to map the first disease-causing gene for CAD and MI to chromosome 15q26 in a large family and subsequently mutation analysis identified a 7-amio acid deletion in MEF2A, a gene encoding a transcription factor. Later we identified three novel mutations N263S, P279L, G283D in four other patients or families, which has validated our initial finding of MEF2A as a gene for CAD and MI. We recently screened another set of 200 CAD and MI patients using the single strand conformation polymorphism (SSCP) method and found another variant, T215A, in the sixth coding exon of MEF2FA in one CAD patient. The T215A mutation is clustered close to the major transcriptional activation domain of MEF2A.We then performed functional studies using the luciferase assay and found that the mutation significantly reduced the transcriptional activity of MEF2A and acted by a loss of function mechanism as the earlier mutations. To further investigate the role of MEF2A in atherogenesis, we studied knockout mice targeted to the mouse Mef2a gene and created a novel Mef2a+/- Apoe-/- knockout mouse strain. We then analyzed diet-induced atherosclerosis and spontaneous lesion formation in the Mef2a and Mef2a+/- Apoe-/- mice. A total of 39 Mef2a knockout mice, including 20 males (8 wild type Mef2a+/+ and 12 heterozygous Mef2a+/-) and 19 females (9 wild type Mef2a+/+ and 10 heterozygous Mef2a+/-) were fed on atherogenic/paigen diet for 38 weeks. A total of 47 Mef2a +/+, Mef2a+/- mice on Apoe-/- knockout background, including 26 males (15 wild type and 11 heterozygous) and 21 females (9 wild type and 12 heterozygous) were maintained on a Western-type diet for 12 weeks. The mice were analyzed

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