The role of microRNAs in cardiac development and regenerative capacity

Abstract

The mammalian heart has long been considered to be a postmitotic organ. It was thought that, in the postnatal period, the heart underwent a transition from hyperplasic growth (more cells) to hypertrophic growth (larger cells) due to the conversion of cardiomyocytes from a proliferative state to one of terminal differentiation. This hypothesis was gradually disproven, as data were published showing that the myocardium is a more dynamic tissue in which cardiomyocyte karyokinesis and cytokinesis produce new cells, leading to the hyperplasic regeneration of some of the muscle mass lost in various pathological processes. microRNAs have been shown to be critical regulators of cardiomyocyte differentiation and proliferation and may offer the novel opportunity of regenerative hyperplasic therapy. Here we summarize the relevant processes and recent progress regarding the functions of specific microRNAs in cardiac development and regeneration.

Keywords: cardiac regeneration; heart development; heart failure; microRNA; myocardial infarction.

Fig. 1.

Illustration of the process of microRNA (miRNA) biogenesis and function, described in overview and biogenesis of mirna. DGCR8, DiGeorge syndrome critical region gene 8; RISC, RNA-induced silencing complex; pri-miRNA, primary miRNA; UTR, untranslated region.

Fig. 2.

The four major stages of human cardiac development, along with miRNAs known to play a role. Tbx5, T-box gene family member 5; ROBO1, roundabout axon guidance receptor, homolog 1; slit2, slit homolog 2; cspg2, chondroitin sulfate proteoglycan 2; Hand2, heart and neural crest derivatives-expressed protein 2; MEF2, myocyte enhancer factor-2; SRF, serum response factor; Bim, Bcl-2-like protein 11; BMP 2/4, bone morphogenetic proteins 2 and 4; ISL1, ISL LIM homeobox 1; TBX1, T-box gene family member 1; Chek1, checkpoint kinase 1; Thrap1, thyroid hormone receptor-associated protein 1; Myh6, α-myosin heavy chain; Myh7, β-myosin heavy chain; Myh7b, myosin heavy chain 7b; ADD3, adducin 3; FOG-2, zinc finger protein, friend of GATA family member 2; A, atrium; V, ventricle; CT, Conus truncus; RA, right atrium; LA, left atrium; AS, aortic sac; RV, right ventricle; LV, left ventricle; AVV, atrioventricular valve; Ao, aorta; PA, pulmonary artery.

Fig. 3.

The three major strategies for hyperplasic cardiac regeneration via miRNAs, along with miRNAs of interest in the field. CRF, corticotropin releasing factor; CDK2, cyclin-dependent kinase 2; Akt3, protein kinase Bγ; FNTb, farnesyltransferase, CAAX box, β; SMARCA5, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 5; Nkx2.5, NK2 homeobox 5; Sox6, sex determining region Y-box 6; ROD1, regulator of differentiation 1; Sox2, sex determining region Y-box 2; Klf4, Kruppel-like factor 4; OSKM: Oct4, Sox2, Klf4, Myc.