miR-22 in Smooth Muscle Cells

HomeCirculationVol. 137, No. 17miR-22 in Smooth Muscle Cells Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBmiR-22 in Smooth Muscle CellsA Potential Therapy for Cardiovascular Disease Zhan-Peng Huang, PhD and Da-Zhi Wang, PhD Zhan-Peng HuangZhan-Peng Huang Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Z.-P.H.). Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, MA (Z.-P.H., D.-Z.W.). Search for more papers by this author and Da-Zhi WangDa-Zhi Wang Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, MA (Z.-P.H., D.-Z.W.). Search for more papers by this author Originally published24 Apr 2018https://doi.org/10.1161/CIRCULATIONAHA.118.033042Circulation. 2018;137:1842–1845Article, see p 1824Cardiovascular disease continues to be the leading cause of death and disability in the United States. Furthermore, >40% of the US adult population is projected to have some form of cardiovascular disease by 2030.1 Vascular smooth muscle cells (VSMCs) are important in atherosclerosis, the major cause of myocardial infarction and stroke. MicroRNAs (miRNAs) are a class of small noncoding ribonucleic acids (RNAs) containing ≈22 nucleotides. Studies using mouse models have shown that miRNAs are essential for cardiovascular development and function.2,3 Furthermore, miRNAs are required for proliferation and differentiation of VSMCs during embryonic development4 and for maintaining vascular contractile function, SMC contractile differentiation, and vascular remodeling in the postnatal stage.5 Numerous studies have linked altered miRNA expression to various diseases, indicating that miRNAs may play important roles in the pathogenesis of cardiovascular disease.In this issue of Circulation, Yang et al linked the function of miR-22 to VSMC phenotype switching.6 They found that miR-22 expression is downregulated in different VSMC phenotype switching models, including injured femoral arteries (in vivo), explanted cultured thoracic aortic tissues (ex vivo), and late passages of cultured VSMCs (in vitro). The regulatory function of miR-22 in VSMC phenotype switching was further demonstrated via both gain- and loss-of-function experiments, in vitro and in vivo. miR-22 enhances the expression of VSMC marker genes and inhibits VSMC proliferation and migration without affecting VSMC apoptosis. Consistent with their prior report,7 the authors identified MECP2 (Methyl CpG-binding Protein 2) as one of the downstream targets of miR-22 for regulating smooth muscle cell (SMC) differentiation. Additionally, they linked the expression and function of HDAC4 (a histone deacetylase) and EVI1 (a transcriptional regulator and oncoprotein) to VSMC phenotype switching by showing that overexpression or knockdown of these miR-22 targets recapitulated miR-22-mediated regulation of VSMC phenotypes.How do miR-22 and its downstream targets regulate the expression of genes related to SMC differentiation? Yang et al provided mechanistic insights and found that EVI1 binds to the promoter regions of several critical genes in VSMC phenotype switching, including SMαA, SM22α, SRF, and myocardin (Myocd), leading to H3K9me3 enrichment in these promoter regions, thereby regulating VSMC gene expression. Interestingly, EVI1 and MECP2, both transcriptional repressors, seem to share a similar molecular mechanism in regulating VSMC phenotype switching and SMC differentiation by repressing the expression of VSMC differentiation genes. Together, this study uncovered an important regulatory function for miR-22 and its molecular mechanisms in VSMC. This study suggests that a miRNA may positively regulate gene expression by directly inhibiting the expression levels of transcriptional repressors or epigenetic silencers.Probably one of the most exciting findings of the Yang et al study is the translational potential of miR-22 in vascular diseases. Using an arterial disease model of wire injury in mouse femoral arteries, they found that miR-22 agomiR (miRNA mimic) inhibits neointima formation in the injured arteries, while locked nucleic acid-miR-22 (miRNA inhibitor) promotes neointimal hyperplasia. These in vivo data suggest that miR-22 promotes the switch from a proliferative, synthetic state of VSMC to a contractile phenotype under pathological conditions. The functional significance of miR-22 in VSMC and arterial disease is further supported by the observation of decreased miR-22 expression, together with increased expression of its target genes, MECP2 and EVI1, in diseased human femoral arteries.miR-22 has been shown to be ubiquitously expressed in multiple cell types and organs. In addition to playing a key role in VSMC remodeling, miR-22 is also an important regulator of cardiac function and remodeling (Figure).8,9 miR-22 null mice develop normally without displaying aberrant physiology under normal conditions. However, miR-22 null mice develop premature cardiac dilation and heart failure under cardiac stress conditions, indicating that miR-22 is indispensable for cardiac remodeling. This conclusion is further supported by studies conducted in cardiomyocyte-specific miR-22 knockout mice.8 Intriguingly, inhibition of miR-22 was reported to enhance fibrogenesis of cardiac fibroblasts, suggesting that miR-22 may also modulate cardiac function by regulating the function of noncardiomyocytes in the heart.10 Recently, miR-22 was demonstrated to be an important regulator of cardiac autophagy during aging.16 Inhibition of miR-22 after myocardial infarction activates cardiac autophagy and prevents postinfarction remodeling in old mice. Several target genes, including Sirt1, HDAC4, PPARα, and PurB, are linked to the function of miR-22 in cardiomyocyte pathophysiology.8,9 These studies indicate that the primary function of miR-22 is involvement in the stress response and remodeling under pathophysiological conditions.Download figureDownload PowerPointFigure. miR-22 as a key regulator of cardiac and vascular remodeling, tumor suppressor or oncogene in a context- and target-dependent manner. Multiple miR-22 targets, including Sirt1, HDAC4, PPARα, and PurB in cardiomyocytes,8,9 EVI1, MECP2, and HDAC4 in SMCs,7 OGN and TGFβR1 in cardiac fibroblasts,10,11 Sirt1, CDK6, Sp1, and CCNA2 in most cancer cells,12,13 and pTEN and ERα in cancer cells of chronic lymphocytic leukemia and hepatitis B virus-related liver cancer,14,15 have been reported.While the Yang et al study has provided compelling evidence to link the function of miR-22 to 2 downstream targets, MECP2 and EVI1, via regulation of histone methylation and consequent control of genes required for VSMC phenotype switching, additional investigation could further strengthen this functional and mechanistic connection. For example, it will be important to test whether restoring the expression of MECP2 and EVI1 is able to fully or partially correct the transcriptome and rescue the phenotype in miR-22 gain-of-function VSMCs. Furthermore, it remains unclear how MECP2 and EVI1 regulate histone methylation, especially H3K9me3, at VSMC gene promoters. An unbiased chromatin immunoprecipitation sequencing could be applied to investigate how miR-22 affects H3K9me3 in gene promoter regions genome-wide. Along with RNA-sequencing analysis, this will help us to better dissect the role of miR-22 in epigenetic regulation of gene expression in VSMC phenotype switching, which will allow a deeper understanding of how the specificity of epigenetic and transcriptional regulation is determined. Whole-genome transcriptome analyses in miR-22 overexpressed and knockdown VSMCs will provide an overview of how miR-22 alters gene expression and signaling pathways during VSMC remodeling. In the Yang et al study, a model of wire-induced injury in femoral arteries was used to define the function of miR-22 in vascular disease. Given that atherosclerosis is often caused by high cholesterol, mouse models with high cholesterol in the blood, such as ApoE mutant mice, will be essential to confirm the observations reported here.Other than in the cardiovascular system, miR-22 has also been extensively studied in tumorigenesis.17 The expression and function of this miRNA in cancer is quite complicated. MiR-22 has been reported to be either a tumor suppressor or an oncomiR in different cancers and tumors (Figure). One of the main targets of miR-22 in tumorigenesis is phosphatase and tensin homolog (pTEN), a repressor of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway.14 Interestingly, pTEN is also a miR-22 target during cardiac hypertrophy.18 Studies have shown that pTEN plays an important role in VSMC biology by inhibiting cell proliferation and migration, which is similar to the function of miR-22 in VSMCs. Future studies are warranted to determine the relationship between miR-22 and pTEN in regulating VSMC phenotype switching. Although a single miRNA may exert different biological functions in different cell populations, miR-22 inhibits cell proliferation and migration in both VSMCs and cancer cells. Whether this miR-22 function is mediated by similar targets or signaling pathways in VSMCs and cancer cells remains to be answered.The current study provides an attractive target, miR-22, for therapeutic application in coronary atherosclerosis. MiR-22-coated stents could potentially prevent in-stent restenosis, which is an unsolved problem for current clinical treatment. This strategy restricts miRNA to local SMCs and largely avoids potential side effects from nonspecific uptake of miRNA into other cell populations or organs, because miR-22 can also serve as an oncogene. Future studies are warranted to demonstrate proof-of-concept evidence for this strategy and determine the lowest effective dosage for therapeutic application. In addition, unbiased approaches must be used to investigate transcriptome changes and the dynamic changes in histone modifications when miR-22 is overexpressed in VSMCs. These data will provide us a chance to more finely define the molecular mechanism of miR-22 in regulating VSMC phenotype switching and explore the potential side effects of miR-22 gain-of-function in VSMCs, which is a prerequisite for therapeutic application of miR-22 in cardiovascular disease. With whole genome data, we could identify the unwanted dysregulated signaling pathways that mediate undesirable side effects of miR-22. Therefore, an improved strategy for the future could incorporate specific small interfering RNAs to target unwanted signaling pathways, mitigating the side effects of miR-22 therapy without affecting its efficacy.AcknowledgmentsWe thank members of the Wang laboratory for discussions.Sources of FundingThis work was supported by the American Heart Association, Muscular Dystrophy Association, and the National Institute of Health (HL085635, HL116919, HL125925) (to Dr Wang). Z-P Huang is supported by the Hundred Talents Program of Sun Yat-sen University and an American Heart Association Scientist Development Grant.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.http://circ.ahajournals.orgZhan-Peng Huang, PhD, Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Rd Guangzhou, Guangdong, 510080, China; or Da-Zhi Wang, PhD, Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, 320 Longwood Avenue, Boston, MA 02115. E-mail [email protected] or [email protected]References1. 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Varzideh F, Kansakar U, Donkor K, Wilson S, Jankauskas S, Mone P, Wang X, Lombardi A and Santulli G (2022) Cardiac Remodeling After Myocardial Infarction: Functional Contribution of microRNAs to Inflammation and Fibrosis, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2022.863238, 9 Santeford A, Lee A, Sene A, Hassman L, Sergushichev A, Loginicheva E, Artyomov M, Ruzycki P and Apte R (2021) Loss of Mir146b with aging contributes to inflammation and mitochondrial dysfunction in thioglycollate-elicited peritoneal macrophages, eLife, 10.7554/eLife.66703, 10 April 24, 2018Vol 137, Issue 17 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.033042PMID: 29685931 Originally publishedApril 24, 2018 KeywordsmicroRNAgene regulationvascular smooth musclenon-coding RNAEditorialssmooth musclegene therapycardiovascular diseasePDF download Advertisement SubjectsBasic Science Research