MicroRNA-133: Biomarker and Mediator of Cardiovascular Diseases

Abstract

If we consider the molecular size of major nucleic acids and the time elapsed since we knew about their existence, microRNAs (miRs) comparatively appear as recently discovered and structurally small pieces of genetic material, but we should make no mistake to underestimate these modest but powerful molecules. Regulating no less than half of the transcriptome, their influence is a key for the fine-tuning of almost any biological process. miRs are considered elements that add precision and robustness to a myriad of physiological and pathological processes and commonly function as components of cellular networks by buffering extremes in gene expression. Their small size limits the side effects of these molecules and eases a pervasive behavior that explains their presence in different body fluids but also opens a complete new field of clinical opportunities for diagnostic, prognostic, or risk stratification applications which benefit from the possibility of bedside measurement.

From a purely investigational perspective, miRs constitute also a very useful tool. Their pleiotropic repressing effect on various, often functionally related, target mRNAs gives us clues on the molecular mechanisms underlying many pathological phenomena. On the other hand, since mRNA complementarity is dictated by a relatively short sequence (seed region) of nucleotides in the miR, computer-based prediction of miR targets is readily available. Additionally, “the control on the controllers” is tempting with the aim of modifying favorably the natural history of miR-related diseases. Several techniques to block or overexpress miRs have been launched, and, even though there are significant difficulties and drawbacks in their administration, some of them are starting to be used in human therapeutics.

miR-133 is muscle specific and one of the most abundant miRs in the heart. It plays major roles in the developing heart on cell differentiation into muscle tissue and also in later stages of cardiac morphogenesis. It is included among the handful of molecules able to cooperate for the experimental reprogrammation of fibroblasts into cardiac-like myocytes. miR-133 participates in the molecular pathology of myocardial hypertrophy, be it primary or secondary, in the transition and evolution of cardiac failure, in myocardial fibrosis and in cardiac cell apoptosis. In stable coronary artery disease and, particularly, in the acute coronary events, miR-133 levels decrease in the myocardium and increase in the circulation proportionally to the extent of the infarcted area. The value of circulating levels of miR-133 as a diagnostic and prognostic biomarker in these patients during the acute ischemic episode and after primary revascularization has already been established. Finally, research studies undertaken during the last 5 years show that dysregulation of miR-133 contributes to the pathological vascular remodeling underlying essential hypertension, vascular calcification, atherosclerosis, and aneurysmal disease.

At this time, it could be said that miRs are ready for prime time for diagnostic and prognostic purposes in the clinical arena, but more is coming on miR molecular manipulation with miR mimics and anti-miRs and even more with targeting of miR-related pathways. Meanwhile, other future uses of miRs in the fields of regenerative medicine and tissue engineering await for further refinement before they can be clinically applicable.