MicroRNA-133a Protects Against Myocardial Fibrosis and Modulates Electrical Repolarization Without Affecting Hypertrophy in Pressure-Overloaded Adult Hearts

Abstract

Rationale: MicroRNA (miR)-133a regulates cardiac and skeletal muscle differentiation and plays an important role in cardiac development. Because miR-133a levels decrease during reactive cardiac hypertrophy, some have considered that restoring miR-133a levels could suppress hypertrophic remodeling. Objective: To prevent the "normal" downregulation of miR-133a induced by an acute hypertrophic stimulus in the adult heart. Methods and Results: miR-133a is downregulated in transverse aortic constriction (TAC) and isoproterenolinduced hypertrophy, but not in 2 genetic hypertrophy models. Using MYH6 promoter-directed expression of a miR-133a genomic precursor, increased cardiomyocyte miR-133a had no effect on postnatal cardiac development assessed by measures of structure, function, and mRNA profile. However, increased miR-133a levels increased QT intervals in surface electrocardiographic recordings and action potential durations in isolated ventricular myocytes, with a decrease in the fast component of the transient outward K ؉ current, I to,f , at baseline. Transgenic expression of miR-133a prevented TAC-associated miR-133a downregulation and improved myocardial fibrosis and diastolic function without affecting the extent of hypertrophy. I to,f downregulation normally observed post-TAC was prevented in miR-133a transgenic mice, although action potential duration and QT intervals did not reflect this benefit. miR-133a transgenic hearts had no significant alterations of basal or post-TAC mRNA expression profiles, although decreased mRNA and protein levels were observed for the I to,f auxiliary KChIP2 subunit, which is not a predicted target. Conclusions: These results reveal striking differences between in vitro and in vivo phenotypes of miR expression, and further suggest that mRNA signatures do not reliably predict either direct miR targets or major miR effects. (Circ Res. 2010;106:166-175.)

Early and Short-term Triiodothyronine Supplementation Prevents Adverse Postischemic Cardiac Remodeling: Role of Transforming Growth Factor-β1 and Antifibrotic miRNA Signaling

“…Both miR-30 and miR-133 condition the protein level of CTGF, and their decrease after myocardial damage leads to fibrosis and conduction anomalies (10,46). In agreement with these findings reported by other authors, we found that the T3-dependent miRNA modulation was accompanied by decreased MMP-2 and CTGF expression 3 d post-I/R.…”

MicroRNAs: um novo paradigma no tratamento e diagnóstico da insuficiência cardíaca?

“…So far, there seems to be about 150-200 miRNAs expressed in the cardiovascular system. Many of these miRNAs are dynamically regulated in response to acute cardiac stress and in some cases during long-term compensatory response of the heart to a chronic injury or hemodynamic overload 13,14 . Therefore, there is growing evidence that the expression of miRNAs is an important part of the mechanism of response to acute stress of the heart, contributing both to cardiac homeostasis and to the heart disease.…”

“…In a recent study, the expression of miR-133 was induced in a rat model subjected to acute hypertrophic stimulus. Although the weight of the heart has not been standardized, other aspects of hypertrophy, such as apoptosis and fibrosis were restored to basal levels 14 .…”

Cardinal roles of miRNA in cardiac development and disease

“…They are also upregulated during cardiac hypertrophy and failure, and have been implicated in arrhythmogenesis [56]. The downregulation of miR-133 during cardiac hypertrophy is also associated with a decrease in K cnip2, the I to,f accessory subunit, albeit via an indirect mechanism, and is accordingly, responsible for prolongation of the QT interval [57]. Taken together, miR-1 and miR-133 are multifaceted molecules involved in hypertrophic and ischemic heart by targeting of a spectrum of mRNAs.…”