Roles of MicroRNA-122 in Cardiovascular Fibrosis and Related Diseases

Abstract

Fibrotic diseases cause annually more than 800,000 deaths worldwide, where of the majority accounts for cardiovascular fibrosis, which is characterized by endothelial dysfunction, myocardial stiffening and reduced dispensability. MicroRNAs (miRs), small noncoding RNAs, play critical roles in cardiovascular dysfunction and related disorders. Intriguingly, there is a critical link among miR-122, cardiovascular fibrosis, sirtuin 6 (SIRT6) and angiotensin-converting enzyme 2 (ACE2), which was recently identified as a coreceptor for SARS-CoV2 and a negative regulator of the rennin-angiotensin system. MiR-122 overexpression appears to exacerbate the angiotensin II-mediated loss of autophagy and increased inflammation, apoptosis, extracellular matrix deposition, cardiovascular fibrosis and dysfunction by modulating the SIRT6-Elabela-ACE2, LGR4-β-catenin, TGFβ-CTGF and PTEN-PI3K-Akt signaling pathways. More importantly, the inhibition of miR-122 has proautophagic, antioxidant, anti-inflammatory, anti-apoptotic and antifibrotic effects. Clinical and experimental studies clearly demonstrate that miR-122 functions as a crucial hallmark of fibrogenesis, cardiovascular injury and dysfunction. Additionally, the miR-122 level is related to the severity of hypertension, atherosclerosis, atrial fibrillation, acute myocardial infarction and heart failure, and miR-122 expression is a risk factor for these diseases. The miR-122 level has emerged as an early-warning biomarker cardiovascular fibrosis, and targeting miR-122 is a novel therapeutic approach against progression of cardiovascular dysfunction. Therefore, an increased understanding of the cardiovascular roles of miR-122 will help the development of effective interventions. This review summarizes the biogenesis of miR-122; regulatory effects and underlying mechanisms of miR-122 on cardiovascular fibrosis and related diseases; and its function as a potential specific biomarker for cardiovascular dysfunction.

Keywords: ACE2; Cardiovascular dysfunction; Fibrosis; Sirtuin 6; microRNA-122.

Fig. 1

Central roles of miR-122 in HF, hypertension, MI, atherosclerosis and atrial fibrillation. MiR-122 has been shown to promote apoptosis, inflammation, fibrosis, pathological hypertrophy and remodeling in the cardiovascular system; decrease the LVEF, LVFS and cardiac contractility; and increase NT-proBNP and ROS generation, leading to arrhythmia and cardiovascular dysfunction. Therefore, miR-122 can cause cardiovascular fibrosis and heart dysfunction, ultimately resulting in hypertension, atherosclerosis, MI and HF. MI myocardial infarction, HF heart failure, ROS reactive oxygen species, LVFS left ventricular fractional shortening, LVEF left ventricular ejection fraction

Fig. 2

Schematic diagram of the activities, and target genes of miR-122 and potential miR-122-binding sites in these target genes. a Schematic diagram showing the mechanism of miR-122. b APLN, APLNR, SIRT1, SIRT6 and FOXO3 were identified as miR-122 target genes by the use of the publicly available bioinformatics tool Microcosm Targets and microRNA.org. The predicted interactions between miR-122 and the abovementioned targets were shown and analyzed with a miR target gene prediction website (https://www.microrna.org). c The sequence of miR-122 is highly conserved in humans, mice and rats. FOXO3 forkhead box O3, SIRT1 sirtuin 1, SIRT6 sirtuin 6, APLN Apelin, APLNR Apelin receptor

Fig. 3

The regulatory roles and underlying mechanisms of miR-122 in cardiovascular remodeling, fibrosis and dysfunction. MiR-122 plays a role in regulating cell growth, survival, inflammation, ECM deposition, pathological remodeling, cardiovascular fibrosis and dysfunction in RRTECs, HAECs, NRVMs, CMs, AFs, CFs, and HK2 cells by modulating the ANRIL-BRCC3, FOXO3-Calcineurin, Bach-1/HO-1, TGFβ-CTGF-NFAT5 and PTEN-PI3K-Akt signaling pathways, respectively. Furthermore, the inhibition of miR-122 has been shown to modulate cardiac contractility, autophagy, apoptosis, and oxidative stress by regulating of the SIRT6-ELA-ACE2, GATA4-Bax, XIAP-ERK-Caspase, and LGR4-β-catenin signaling, respectively. ACE2 angiotensin-converting enzyme 2, AFs adventitial fibrotic cells, CFs cardiofibroblasts, CMs cardiomyocytes, HAECs, Human aortic endothelial cells, NRVMs neonatal rat cardiomyocytes, RRTECs rat renal tubular epithelial cells, HK2 cells human renal tubular epithelial cells, ANRIL antisense non-coding RNA in the INK4 locus, BRCC3 BRCA1/BRCA2-containing complex subunit 3, NLRP3nod-like receptor protein 3, PTEN gene of phosphate and tension homology deleted on chromosome ten, PI3K phosphatidylinositol 3-kinase, TGF-β transforming growth factor-β, CTGF connective tissue growth factor, NFAT5 nuclear factor of activated T-cell-5, LGR4 leucine-rich repeat-containing G protein-coupled receptor 4, ROS reactive oxygen species, mTOR mammalian target of rapamycin, ECM extracellular matrix, AMPK adenosine 5 ‘-monophosphate-activated protein kinase, GATA4 GATA binding protein 4, SIRT6 sirtuin 6, ELA elabela, ERK extracellular signal-regulated kinase, XIAP X-linked inhibitor of apoptosis protein, FOXO3 forkhead box O3, Bach-1 BTB and CNC homology 1, HO-1 heme oxygenase1, MCP-1 monocyte chemotactic protein 1