MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol

Abstract

Rationale: Heart failure 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 heart failure remains to be elucidated. Objective: To clarify the role of miR-33 involved in heart failure. 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 in miR-33–deficient (knockout [KO]) mice. When mice were subjected to transverse aortic constriction, miR-33 expression levels were significantly upregulated in wild-type left ventricles. There was no difference in hypertrophic responses between wild-type and miR-33KO hearts, whereas cardiac fibrosis was ameliorated in miR-33KO hearts compared with wild-type hearts. Despite the ameliorated cardiac fibrosis, miR-33KO mice showed impaired systolic function after transverse aortic constriction. We also found that cardiac fibroblasts were mainly responsible for miR-33 expression in the heart. Deficiency of miR-33 impaired cardiac fibroblast proliferation, which was considered to be caused by altered lipid raft cholesterol content. Moreover, cardiac fibroblast–specific miR-33–deficient mice also showed decreased cardiac fibrosis induced by transverse aortic constriction as systemic miR-33KO mice. Conclusion: 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.

Genetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosis

“…A profibrotic role for miR-33 has been also reported in cardiac fibrosis, as cardiac fibroblast-specific deficiency of miR-33 reduced cardiac fibrosis in response to pressure overload by transverse aortic constriction. The proposed mechanism underlying this response was that deficiency of miR-33 impaired cardiac fibroblast proliferation because of altered lipid raft cholesterol content (58,59). In the kidney, we demonstrate an important role for miR-33 in the regulation of FAO in TECs, which may be relevant to explain its effects on fibrogenesis.…”

MicroRNAs and lipid metabolism

“…In addition the role of miR-33 in regulating lipid accumulation in macrophages and hepatocytes, Nishiga et al reported that miR-33 preserves lipid raft cholesterol content in cardiac fibroblasts through the regulation of ABCA1 expression and maintains adaptive fibrotic response in the remodeling heart [50]. Surprisingly, miR-33 deficient mice showed impaired systolic function after thoracic aortic constriction (TAC).…”

Lipid rafts increase to facilitate ectoderm lineage specification of differentiating embryonic stem cells

“…These results indicated that lipid rafts play a role in RA-induced exit from pluripotency. To verify this indication, we also disrupted rafts via treating the early differentiating cells with cholesterol depletion reagent MBCD [47-50]. Compared to the group treated with RA only (green), cells co-treated with MBCD and RA exhibited delayed pluripotency exit, as revealed by the slower decrease of Oct4 and GFP expression (red, Figure 3f ), supporting that rafts facilitate the early differentiating cells to exit from pluripotency.…”