RATIONALE:Heart failure (HF) and atherosclerosis share the underlying mechanisms of chronic inflammation followed by fibrosis. A highly conserved microRNA (miR), miR-33 is considered as a potential therapeutic target for atherosclerosis because it regulates lipid metabolism and inflammation. However, the role of miR-33 in HF remains to be elucidated. OBJECTIVE:To clarify the role of miR-33 involved in HF. METHODS AND RESULTS:We first investigated the expression levels of miR-33a/b in human cardiac tissue samples with dilated cardiomyopathy. Increased expression of miR-33a was associated with improving hemodynamic parameters. To clarify the role of miR-33 in remodeling hearts, we investigated the responses to pressure overload by transverse aortic constriction (TAC) in miR-33-deficient (KO) mice. When mice were subjected to TAC, miR-33 expression levels were significantly up-regulated in wild-type (WT) left ventricles. There was no difference in hypertrophic responses between WT and miR-33KO hearts, whereas cardiac fibrosis was ameliorated in miR-33KO hearts compared with WT hearts. Despite the ameliorated cardiac fibrosis, miR-33KO mice showed impaired systolic function after TAC. We also found that cardiac fibroblasts (CFs) were mainly responsible for miR-33 expression in the heart. Deficiency of miR-33 impaired CF proliferation, which was considered to be caused by altered lipid raft cholesterol content. Moreover, CF-specific miR-33-deficient mice also showed decreased cardiac fibrosis induced by TAC as systemic miR-33KO mice. CONCLUSIONS:Our results demonstrate that miR-33 is involved in cardiac remodeling and it preserves lipid raft cholesterol content in fibroblasts and maintains adaptive fibrotic responses in the remodeling heart.