Krüppel-like factor 5 (KLF5) is a zinc-finger-type transcription factor that mediates the tissue remodeling in cardiovascular diseases, such as atherosclerosis, restenosis, and cardiac hypertrophy. Our previous studies have shown that KLF5 is induced by angiotensin II (AII), although the precise molecular mechanism is not yet known. Here we analyzed regulatory single nucleotide polymorphisms (SNPs) within the KLF5 locus to identify clinically relevant signaling pathways linking AII and KLF5. One SNP was located at -1282 bp and was associated with an increased risk of hypertension: subjects with the A/A and A/G genotypes at -1282 were at significantly higher risk for hypertension than those with the G/G genotype. Interestingly, a reporter construct corresponding to the -1282G genotype showed much weaker responses to AII than a construct corresponding to -1282A. Electrophoretic mobility shift, chromatin immunoprecipitation, and reporter assays collectively showed that the -1282 SNP is located within a functional myocyte enhancer factor 2 (MEF2) binding site, and that the -1282G genotype disrupts the site and reduces the AII responsiveness of the promoter. Moreover, MEF2 activation via reactive oxygen species and p38 mitogen-activated protein kinase induced KLF5 expression in response to AII, and KLF5 and MEF2 were coexpressed in coronary atherosclerotic plaques. These results suggest that a novel signaling and transcription network involving MEF2A and KLF5 plays an important role in the pathogenesis of cardiovascular diseases such as hypertension.