MicroRNAs in cardiovascular disease: from pathogenesis to prevention and treatment

Abstract

The management of cardiovascular risk through lifestyle modification and pharmacotherapy is paramount to the prevention of cardiovascular disease. Epidemiological studies have identified obesity, dyslipidemia, diabetes, and hypertension as interrelated factors that negatively affect cardiovascular health. Recently, genetic and pharmacological evidence in model systems has implicated microRNAs as dynamic modifiers of disease pathogenesis. An expanded understanding of the function of microRNAs in gene regulatory networks associated with cardiovascular risk will enable identification of novel genetic mechanisms of disease and inform the development of innovative therapeutic strategies.

Figure 1. miRNA regulation of blood pressure.

Pathological changes in vascular tone and RAAS signaling underlie primary arterial hypertension. miR-143 and miR-145 promote a contractile VSMC phenotype and are required for maintenance of normal vascular tone and RAAS-induced vasoconstriction. Human genome-wide association studies have identified SNPs in the miRNA binding sites of several RAAS-associated genes that correlate with a dysregulation of blood pressure.

Figure 2. Role of miR-33 and miR-122 in hepatic lipid metabolism.

The SREBF locus encodes the lipogenic transcription factor SREBP and miR-33, which represses mRNA transcripts of genes in the fatty acid (FA) β-oxidation and cholesterol efflux pathways. miR-122 promotes lipid synthesis by supporting the expression of lipid biosynthetic genes, and dampens fatty acid oxidation by inhibiting phosphorylation of AMPKa by an unknown mechanism.

Figure 3. miRNA modulation of insulin signaling and metabolic homeostasis.

(A) miRNAs regulate pancreatic insulin secretion and the insulin signaling cascade in peripheral tissues. Pathological changes in the expression of these miRNAs contribute to the type II diabetic phenotype. (B) Modulation of Med13 expression in the heart by the cardiac-specific miRNA, miR-208a, regulates whole body metabolism and adiposity.

Figure 4. miRNAs in cardiovascular pathology.

(A) miRNAs in endothelial cells act as paracrine signals to preserve vascular structure under normal conditions and to promote cell survival following injury. VSMC miRNAs modulate the smooth muscle response to injury. These mechanisms are dysregulated during atherosclerosis. (B) Cardiomyocyte and fibroblast miRNAs regulate cellular survival and pathological responses to multiple cardiac stressors.