Is miR-21 A Therapeutic Target in Cardiovascular Disease?

Antoinette Holland; Molly Enrick; Arianna Diaz; Liya Yin

doi:10.53941/ijddp.0201003

Abstract

microRNA-21 (miR-21) serves a multitude of functions at the molecular level through its regulation of messenger RNA. Previous research has sparked interest in the role of miR-21 as a potential therapeutic target in cardiovascular diseases. miR-21 expression contributes to the differentiation, proliferation, and maturation of many cell types, such as fibroblasts, endothelial cells, cardiomyocytes, and endothelial progenitor cells. The function of miR-21 depends upon its expression level in the specific cell types and downstream targets, which determine cell fate. Under pathological conditions, the expression level of miR-21 is altered, leading to abnormal gene regulation of downstream signaling and cardiovascular diseases such as hypertension, cardiac hypertrophy and fibrosis, atherosclerosis, and heart failure. Agomirs or antagomirs can be introduced into the respective tissue type to reverse or stop the progression of the disease. Exosomes in the extracellular vesicles, which mediate many cellular events with high biocompatibility, have a high potential of efficiently delivering miR-21 to their targeted cells. The critical role of miR-21 in cardiovascular disease (CVD) is indisputable, but there are controversial reports on the function of miR-21 in the same disease. This discrepancy sparks interest in better understanding the role of miR-21 in different tissues under different stages of various diseases and the mechanism of how miR-21 inhibitors work.

References

1.
Tsao C.W.; Aday A.W.; Almarzooq Z.I.; et al. Heart disease and stroke statistics-2022 update: a report from the American heart association. Circulation, 2022, 145(8): e153-e639.
2.
O'Brien J.; Hayder H.; Zayed Y.; et al. Overview of microRNA biogenesis, mechanisms of actions, and circulation. Front. Endocrinol., 2018, 9: 402.
3.
Ben-Nun D.; Buja L.M.; Fuentes F. Prevention of heart failure with preserved ejection fraction (HFpEF): reexamining microrna-21 inhibition in the era of oligonucleotide-based therapeutics. Cardiovasc. Pathol., 2020, 49: 107243.
4.
Cheng Y.H.; Zhang C.X. MicroRNA-21 in cardiovascular disease. J. Cardiovasc. Transl. Res., 2010, 3(3): 251-255.
5.
Kumarswamy R.; Volkmann I.; Thum T. Regulation and function of mirna-21 in health and disease. RNA Biology, 2011, 8(5): 706-713.
6.
Morrisey E.E. The magic and mystery of miR-21. J. Clin. Invest., 2010, 120(11): 3817-3819.
7.
Dai B.B.; Wang F.; Nie X.; et al. The cell type-specific functions of mir-21 in cardiovascular diseases. Front. Genet., 2020, 11: 563166.
8.
Sekar D.; Venugopal B.; Sekar P.; et al. Role of microRNA 21 in diabetes and associated/related diseases. Gene, 2016, 582(1): 14-18.
9.
Matsumoto T.; Hwang P.M. Resizing the genomic regulation of restenosis. Circ. Res., 2007, 100(11): 1537-1539.
10.
Telkoparan-Akillilar P.; Cevik D. Identification of miR-17, miR-21, miR-27a, miR-106b and miR-222 as endoplasmic reticulum stress-related potential biomarkers in circulation of patients with atherosclerosis. Mol. Biol. Rep., 2021, 48(4): 3503-3513.
11.
Canfrán-Duque A.; Rotllan N.; Zhang X.B.; et al. Macrophage deficiency of miR-21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis. EMBO Mol. Med., 2017, 9(9): 1244-1262.
12.
Sun P.; Tang L.N.; Li G.Z.; et al. Effects of MiR-21 on the proliferation and migration of vascular smooth muscle cells in rats with atherosclerosis via the Akt/ERK signaling pathway. Eur. Rev. Med. Pharmacol. Sci., 2019, 23(5): 2216-2222.
13.
Ji R.R.; Cheng Y.H.; Yue J.M.; et al. MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA in vascular neointimal lesion formation. Circ. Res., 2007, 100(11): 1579-1588.
14.
Neth P.; Nazari-Jahantigh M.; Schober A.; et al. MicroRNAs in flow-dependent vascular remodelling. Cardiovasc. Res., 2013, 99(2): 294-303.
15.
Silacci P.; Formentin K.; Bouzourène K.; et al. Unidirectional and oscillatory shear stress differentially modulate NOS Ⅲ gene expression. Nitric. Oxide., 2000, 4(1): 47-56.
16.
Kuang D.B.; Zhou J.P.; Yu L.Y.; et al. DDAH1-V3 transcript might act as miR-21 sponge to maintain balance of DDAH1-V1 in cultured HUVECs. Nitric. Oxide., 2016, 60: 59-68.
17.
Weber M.; Baker M.B.; Moore J.P.; et al. MiR-21 is induced in endothelial cells by shear stress and modulates apoptosis and eNOS activity. Biochem. Biophys. Res. Commun., 2010, 393(4): 643-648.
18.
Zuo K.Q.; Li M.Q.; Zhang X.P.; et al. MiR-21 suppresses endothelial progenitor cell proliferation by activating the TGFβ signaling pathway via downregulation of WWP1. Int. J. Clin. Exp. Pathol., 2015, 8(1):414-422.
19.
Sabatel C.; Malvaux L.; Bovy N.; et al. MicroRNA-21 exhibits antiangiogenic function by targeting RhoB expression in endothelial cells. PLoS One, 2011, 6(2): e16979.
20.
Liu L.Z.; Li C.Y.; Chen Q.; et al. MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1α expression. PLoS One, 2011, 6(4): e19139.
21.
Kanugula A.K.; Adapala R.K.; Jamaiyar A.; et al. Endothelial TRPV4 channels prevent tumor growth and metastasis via modulation of tumor angiogenesis and vascular integrity. Angiogenesis, 2021, 24(3): 647-656.
22.
Zhang Y.; Liu Y.J.; Liu T.; et al. Plasma microRNA-21 is a potential diagnostic biomarker of acute myocardial infarction. Eur. Rev. Med. Pharmacol. Sci., 2016, 20(2): 323-329.
23.
Wang F.; Long G.W.; Zhao C.X.; et al. Atherosclerosis-related circulating mirnas as novel and sensitive predictors for acute myocardial infarction. PLoS One, 2014, 9(9): e105734.
24.
Roy S.; Khanna S.; Hussain S.R.A.; et al. MicroRNA expression in response to murine myocardial infarction: miR-21 regulates fibroblast metalloprotease-2 via phosphatase and tensin homologue. Cardiovasc. Res., 2009, 82(1): 21-29.
25.
Dong S.M.; Cheng Y.H.; Yang J.; et al. MicroRNA expression signature and the role of microRNA-21 in the early phase of acute myocardial infarction. J. Biol. Chem., 2009, 284(43): 29514-29525.
26.
Yang F.; Liu W.W.; Yan X.J.; et al. Effects of mir-21 on cardiac microvascular endothelial cells after acute myocardial infarction in rats: role of phosphatase and tensin homolog (PTEN)/vascular endothelial growth factor (VEGF) signal pathway. Med. Sci. Monit., 2016, 22: 3562-3575.
27.
Jayawardena E.; Medzikovic L.; Ruffenach G.; et al. Role of mirna-1 and mirna-21 in acute myocardial ischemia-reperfusion injury and their potential as therapeutic strategy. Int. J. Mol. Sci., 2022, 23(3): 1512.
28.
Piché M.E.; Tchernof A.; Després J.P. Obesity phenotypes, diabetes, and cardiovascular diseases. Circ. Res., 2020, 126(11): 1477-1500.
29.
Rai A.K.; Lee B.; Gomez R.; et al. Current status and potential therapeutic strategies for using non-coding RNA to treat diabetic cardiomyopathy. Front. Physiol., 2021, 11: 612722.
30.
Guglielmi V.; D'adamo M.; Menghini R.; et al. Microrna 21 is up-regulated in adipose tissue of obese diabetic subjects. Nutr. Healthy Aging, 2017, 4(2): 141-145.
31.
Kantharidis P.; Wang B.; Carew R.M.; et al. Diabetes complications: the microRNA perspective. Diabetes, 2011, 60(7): 1832-1837.
32.
Scisciola L.; Benedetti R.; Chianese U.; et al. The pivotal role of mirna-21 in myocardial metabolic flexibility in response to short- and long-term high glucose treatment: evidence in human cardiomyocyte cell line. Diabetes Res. Clin. Pract., 2022, 191: 110066.
33.
Juguilon C.; Wang Z.Y.; Wang Y.; et al. Mechanism of the switch from no to H2O2 in endothelium-dependent vasodilation in diabetes. Basic Res. Cardiol., 2022, 117(1): 2.
34.
Li X.C.; Meng C.; Han F.; et al. Vildagliptin attenuates myocardial dysfunction and restores autophagy via mir-21/spry1/erk in diabetic mice heart. Front. Pharmacol., 2021, 12: 634365.
35.
Dai B.B.; Li H.P.; Fan J.H.; et al. Mir-21 protected against diabetic cardiomyopathy induced diastolic dysfunction by targeting gelsolin. Cardiovasc. Diabetol., 2018, 17(1): 123.
36.
Tochhawng L.; Deng S.; Pugalenthi G.; et al. Gelsolin-Cu/ZnSOD interaction alters intracellular reactive oxygen species levels to promote cancer cell invasion. Oncotarget, 2016, 7(33): 52832-52848.
37.
Seeger T.; Fischer A.; Muhly-Reinholz M.; et al. Long-term inhibition of miR-21 leads to reduction of obesity in db/db mice. Obesity, 2014, 22(11): 2352-2360.
38.
Li H.P.; Zhang X.R.; Wang F.; et al. MicroRNA-21 lowers blood pressure in spontaneous hypertensive rats by upregulating mitochondrial translation. Circulation, 2016, 134(10): 734-751.
39.
Zhang C.X. MicroRNAs: role in cardiovascular biology and disease. Clin. Sci., 2008, 114(12): 699-706.
40.
Hinkel R.; Ramanujam D.; Kaczmarek V.; et al. AntimiR-21 prevents myocardial dysfunction in a pig model of ischemia/reperfusion injury. J. Am. Coll. Cardiol., 2020, 75(15): 1788-1800.
41.
Thum T.; Gross C.; Fiedler J.; et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature, 2008, 456(7224): 980-984.
42.
Yan M.W.; Chen C.; Gong W.; et al. miR-21-3p regulates cardiac hypertrophic response by targeting histone deacetylase-8. Cardiovasc. Res., 2015, 105(3): 340-352.
43.
Patrick D.M.; Montgomery R.L.; Qi X.X.; et al. Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice. J. Clin. Invest., 2010, 120(11): 3912-3916.
44.
Kamps J.A.; Krenning G. Micromanaging cardiac regeneration: targeted delivery of microRNAs for cardiac repair and regeneration. World J. Cardiol., 2016, 8(2): 163-179.
45.
Van Rooij E.; Purcell A.L.; Levin A.A. Developing microRNA therapeutics. Circ. Res., 2012, 110(3): 496-507.
46.
Huang C.K.; Bär C.; Thum T. miR-21, mediator, and potential therapeutic target in the cardiorenal syndrome. Front. Pharmacol., 2020, 11: 726.
47.
Guo J.F.; Song W.P.; Boulanger J.; et al. Dysregulated expression of microRNA-21 and disease-related genes in human patients and in a mouse model of alport syndrome. Hum. Gene Ther., 2019, 30(7): 865-881.
48.
Ramanujam D.; Schön A.P.; Beck C.; et al. MicroRNA-21-dependent macrophage-to-fibroblast signaling determines the cardiac response to pressure overload. Circulation, 2021, 143(15): 1513-1525.
49.
Moghaddam A.S.; Afshari J.T.; Esmaeili S.A.; et al. Cardioprotective microRNAs: lessons from stem cell-derived exosomal microRNAs to treat cardiovascular disease. Atherosclerosis, 2019, 285: 1-9.
50.
Song Y.; Zhang C.; Zhang J.X.; et al. Localized injection of miRNA-21-enriched extracellular vesicles effectively restores cardiac function after myocardial infarction. Theranostics, 2019, 9(8): 2346-2360.
51.
Khatri N.; Rathi M.; Baradia D.; et al. In vivo delivery aspects of miRNA, shRNA and siRNA. Crit. Rev. Ther. Drug Carrier Syst., 2012, 29(6): 487-527.
52.
De Jong O.G.; Van Balkom B.W.; Schiffelers R.M.; et al. Extracellular vesicles: potential roles in regenerative medicine. Front. Immunol., 2014, 5: 608..
53.
Johnson T.K.; Zhao L.N.; Zhu D.H.; et al. Exosomes derived from induced vascular progenitor cells promote angiogenesis in vitro and in an in vivo rat hindlimb ischemia model. Am. J. Physiol.: Heart Circ. Physiol., 2019, 317(4): H765-H776.
54.
Yin L.Y.; Ohanyan V.; Chilian W.M.; et al. The role of MSC derived exosomes on cardiac microvascular dysfunction. Int. J. Cardiol., 2021, 344: 36-37.
55.
Wang H.Y.; Xie Y.L.; Salvador A.M.; et al. Exosomes: multifaceted messengers in atherosclerosis. Curr. Atheroscler. Rep., 2020, 22(10): 57.
56.
Qiao L.; Hu S.Q.; Liu S.Y.; et al. microRNA-21-5p dysregulation in exosomes derived from heart failure patients impairs regenerative potential. J. Clin. Invest., 2019, 129(6): 2237-2250.
57.
Luo Q.C.; Guo D.F.; Liu G.R.; et al. Exosomes from MiR-126-overexpressing ADSCs are therapeutic in relieving acute myocardial ischaemic injury. Cell. Physiol. Biochem., 2017, 44(6): 2105-2116.
58.
Muthu S.; Bapat A.; Jain R.; et al. Exosomal therapy-a new frontier in regenerative medicine. Stem Cell Invest., 2021, 8: 7.
59.
Gray W.D.; French K.M.; Ghosh-Choudhary S.; et al. Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology. Circ. Res., 2015, 116(2): 255-263.
60.
Sahoo S.; Losordo D.W. Exosomes and cardiac repair after myocardial infarction. Circ. Res., 2014, 114(2): 333-344.
61.
Wang K.; Jiang Z.; Webster K.A.; et al. Enhanced cardioprotection by human endometrium mesenchymal stem cells driven by exosomal MicroRNA-21. Stem Cells Transl. Med., 2017, 6(1): 209-222.
62.
Bang C.; Batkai S.; Dangwal S.; et al. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J. Clin. Invest., 2014, 124(5): 2136-2146.
63.
Small E.M.; Olson E.N. Pervasive roles of microRNAs in cardiovascular biology. Nature, 2011, 469(7330): 336-342.
64.
Laggerbauer B.; Engelhardt S. MicroRNAs as therapeutic targets in cardiovascular disease. J. Clin. Invest., 2022, 132(11): e159179.

Scilight Press

Author Information

Abstract

Keywords

References

About Scilight

Journals

Publishing Policies

Contact Us