Targeting the microRNA-34a as a Novel Therapeutic Strategy for Cardiovascular Diseases

Abstract

Cardiovascular diseases (CVDs) are still the main cause of morbidity and mortality worldwide and include a group of disorders varying from vasculature, myocardium, arrhythmias and cardiac development. MicroRNAs (miRs) are endogenous non-coding RNAs with 18-23 nucleotides that regulate gene expression. The miR-34 family, including miR-34a/b/c, plays a vital role in the regulation of myocardial physiology and pathophysiological processes. Recently, miR-34a has been implicated in cardiovascular fibrosis, dysfunction and related cardiovascular disorders as an essential regulator. Interestingly, there is a pivotal link among miR-34a, cardiovascular fibrosis, and Smad4/TGF-β1 signaling. Notably, both loss-of-function and gain-of-function approaches identified the critical roles of miR-34a in cardiovascular apoptosis, autophagy, inflammation, senescence and remodeling by modulating multifunctional signaling pathways. In this article, we focus on the current understanding of miR-34a in biogenesis, its biological effects and its implications for cardiac pathologies including myocardial infarction, heart failure, ischaemia reperfusion injury, cardiomyopathy, atherosclerosis, hypertension and atrial fibrillation. Thus, further understanding of the effects of miR-34a on cardiovascular diseases will aid the development of effective interventions. Targeting for miR-34a has emerged as a potential therapeutic target for cardiovascular dysfunction and related diseases.

Keywords: apoptosis; cardiovascular fibrosis; heart dysfunction; microRNA-34a; myocardial remodeling.

Figure 1

Schematic diagram of the activities of miR-34a, and potential binding sites between miR-34a and the target genes. (A) Schematic diagram of the activities, and target genes of miR-34a. (B) The sequence of miR-34a-5p is conserved in humans, mice and rats. The potential miR-34a-5p-binding sites of target genes. FOXM1, Forkhead box M1; FOXO3, Fork head box O3; PTEN, Phosphatase and tensin homologue; SIRT1, Silent information regulator 1.

Figure 2

The regulatory roles and underlying mechanisms of miR-34a in cardiovascular dysfunction and related disorders. MiR-34a has been shown to regulate cellular apoptosis, autophagy, inflammation, senescence and remodeling in various cardiac and vascular tissues and cells through Smad4/TGF-β1, FOXO3/PUMA, Notch1/ETBR, PTEN/PI3K/SIRT1, and FOXM1/NRF2/HO-1 signaling pathways, respectively. EMT, Epithelial-mesenchymal transition; ECM, Extracellular matrix; ETBR, endothelial receptor type B; FOXM1, Forkhead box M1; FOXO3, Forkhead box O3; NRF2, Nuclear factor-E2-related factor 2; PI3K, Phosphatidylinositol 3-kinase; PNUTS, Phosphatase-1 nuclear targeting subunit; PTEN, Phosphatase and tensin homologue; PUMA, p53-up-regulated modulator of apoptosis; SIRT1, Silent information regulator 1; TGF-β1, Transforming growth factor β1.