[Cardiovascular research in the era of genome medicine and EBM]

In the postgenome era, medical science should aim at elucidating the physiological functions as well as pathophysiological roles of genetics in a variety of diseases. The latter is especially important in clinical medicine for investigating the biological background of diseases. The cardiovascular system undergoes phenotypic modulation in response to environmental factors such as hemodynamic stress, aging, inflammation, and various life style influences including smoking and obesity. We have been focusing on transcriptional mechanisms by which cardiovascular cells change the profiles of gene expression in response to metabolic and mechanical stresses. We isolated a DNA-binding factor, Krüppel-like factor 5 (KLF5), as a transcription factor of the embryonic isoform of smooth muscle myosin heavy chain gene(SMemb), whose expression is induced in phenotypically modulated smooth muscle cell and cardiac fibroblasts. Recently, by developing KLF5 gene knockout mice, we have found that KLF5 is an essential regulator of cardiovascular remodeling. We have further found that differential chemical modifications and protein-protein interactions regulate this family of factors. To understand genome functions in the pathogenesis of cardiovascular diseases, we are constructing an original database system by filing complicated clinical parameters for genetic association studies. DNA samples obtained from the participants have reached approximately one thousand. Using them, we have analyzed over 50 genetic polymorphisms implicated in atherosclerotic diseases. Among the many SNPs analyzed in our study, we have shown that polymorphisms in the MMP-1 and MMP-3 promoters are associated with disease susceptibility to myocardial infarction.