Downregulation of MiR-214 Promotes Dilated Cardiomyopathy Progression Through PDE5A-Mediated CGMP Regulation

Overview

Journal Sci Rep

Specialty Science

Date 2024 Nov 14

PMID 39543318

Authors

Jingjing Yan

Xinzhou Wang

Panxia Cao

Qiaozhi Li

Hong Wu

Affiliations

Soon will be listed here.

Abstract

Dilated cardiomyopathy (DCM) is a myocardial disorder resulting in a substantial decline in cardiac function and potentially leading to heart failure. This research combines bioinformatics analysis with empirical validation to explore the roles and mechanisms of miR-214 in DCM. Using the DEseq2 R package, a total of 125 differentially expressed circulating miRNAs (DE c-miRNAs) and 784 DE genes (DEGs) were identified. Cross-analysis between target genes of DE c-miRNAs and DEGs identified 124 common genes, and protein-protein interaction analysis of common genes identified 11 hub genes. Twelve DE c-miRNAs were further verified by quantifying their levels in the serum of DCM patients and healthy individuals. miR-214 levels were significantly decreased in serum from DCM patients, positively correlated with left ventricular ejection fraction and left ventricular fractional shortening. Further analysis showed that miR-214 directly targets and negatively regulates phosphodiesterase 5 A (PDE5A). Elevated PDE5A expression reduced cGMP levels; however, using sildenafil, a PDE5A inhibitor, reversed this effect, substantiating the regulatory mechanism of miR-214 on cGMP via PDE5A. These results provide new potential targets for the diagnosis and treatment of DCM.

References

Rani D, Kasala A, Dhandapany P, Muthusami U, Kunnoth S, Rathinavel A . Novel Mutations in Indian Population with Cardiomyopathies. Pharmgenomics Pers Med. 2023; 16:883-893. PMC: 10518145. DOI: 10.2147/PGPM.S407179. View

Zernecke A, Weber C . Chemokines in the vascular inflammatory response of atherosclerosis. Cardiovasc Res. 2009; 86(2):192-201. DOI: 10.1093/cvr/cvp391. View

Lu T, Rothenberg M . MicroRNA. J Allergy Clin Immunol. 2017; 141(4):1202-1207. PMC: 5889965. DOI: 10.1016/j.jaci.2017.08.034. View

Lee M, Sulistyowati E, Hsu J, Huang B, Dai Z, Wu B . KMUP-1 Ameliorates Ischemia-Induced Cardiomyocyte Apoptosis through the NO⁻cGMP⁻MAPK Signaling Pathways. Molecules. 2019; 24(7). PMC: 6479774. DOI: 10.3390/molecules24071376. View

Chen Y, Wang X . miRDB: an online database for prediction of functional microRNA targets. Nucleic Acids Res. 2019; 48(D1):D127-D131. PMC: 6943051. DOI: 10.1093/nar/gkz757. View

St Hilaire C, Ziegler S, Markello T, Brusco A, Groden C, Gill F . NT5E mutations and arterial calcifications. N Engl J Med. 2011; 364(5):432-42. PMC: 3049958. DOI: 10.1056/NEJMoa0912923. View

Yu L, Shi X, Han C, Rao C, Wang J . A rapid reporter assay for recombinant human brain natriuretic peptide (rhBNP) by GloSensor technology. J Pharm Anal. 2018; 8(5):297-301. PMC: 6190497. DOI: 10.1016/j.jpha.2018.04.003. View

Becker J, Chatterjee S, Robinson T, Bennett J, Panakova D, Galindo C . Differential activation of natriuretic peptide receptors modulates cardiomyocyte proliferation during development. Development. 2013; 141(2):335-45. PMC: 3879815. DOI: 10.1242/dev.100370. View

Takimoto E, Champion H, Belardi D, Moslehi J, Mongillo M, Mergia E . cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism. Circ Res. 2004; 96(1):100-9. DOI: 10.1161/01.RES.0000152262.22968.72. View

10.

Duan Q, Yang L, Gong W, Chaugai S, Wang F, Chen C . MicroRNA-214 Is Upregulated in Heart Failure Patients and Suppresses XBP1-Mediated Endothelial Cells Angiogenesis. J Cell Physiol. 2015; 230(8):1964-73. PMC: 4911176. DOI: 10.1002/jcp.24942. View

11.

Mori M, Ludwig R, Garcia-Martin R, Brandao B, Kahn C . Extracellular miRNAs: From Biomarkers to Mediators of Physiology and Disease. Cell Metab. 2019; 30(4):656-673. PMC: 6774861. DOI: 10.1016/j.cmet.2019.07.011. View

12.

Amin M, Trevelyan C, Turner N . MicroRNA-214 in Health and Disease. Cells. 2021; 10(12). PMC: 8699121. DOI: 10.3390/cells10123274. View

13.

Jiang J, Wakimoto H, Seidman J, Seidman C . Allele-specific silencing of mutant Myh6 transcripts in mice suppresses hypertrophic cardiomyopathy. Science. 2013; 342(6154):111-4. PMC: 4100553. DOI: 10.1126/science.1236921. View

14.

Zaragoza C, Saura M, Hernandez I, Ramirez-Carracedo R, Garcia-Garcia F, Zamorano J . Differential expression of circulating miRNAs as a novel tool to assess BAG3-associated familial dilated cardiomyopathy. Biosci Rep. 2019; 39(3). PMC: 6418398. DOI: 10.1042/BSR20180934. View

15.

Zhang Y, Wang J, Wang X, Li A, Lei Z, Li D . TXNIP aggravates cardiac fibrosis and dysfunction after myocardial infarction in mice by enhancing the TGFB1/Smad3 pathway and promoting NLRP3 inflammasome activation. Acta Biochim Biophys Sin (Shanghai). 2023; 55(12):1950-1960. PMC: 10753373. DOI: 10.3724/abbs.2023150. View

16.

Zhou J, Tian G, Quan Y, Kong Q, Huang F, Li J . The long noncoding RNA THBS1-AS1 promotes cardiac fibroblast activation in cardiac fibrosis by regulating TGFBR1. JCI Insight. 2023; 8(6). PMC: 10070117. DOI: 10.1172/jci.insight.160745. View

17.

MacFarland R, Zelus B, Beavo J . High concentrations of a cGMP-stimulated phosphodiesterase mediate ANP-induced decreases in cAMP and steroidogenesis in adrenal glomerulosa cells. J Biol Chem. 1991; 266(1):136-42. View

18.

. Dilated cardiomyopathy. Nat Rev Dis Primers. 2019; 5(1):33. DOI: 10.1038/s41572-019-0088-x. View

19.

Song Y, Zhao L, Wang B, Sun J, Hu J, Zhu X . The circular RNA TLK1 exacerbates myocardial ischemia/reperfusion injury via targeting miR-214/RIPK1 through TNF signaling pathway. Free Radic Biol Med. 2020; 155:69-80. DOI: 10.1016/j.freeradbiomed.2020.05.013. View

20.

Wugeng S, Zan S, Liu Y, Bai Y, Hu A, Wei X . MicroRNA-214-3p protects against myocardial ischemia-reperfusion injury by targeting demethylase lysine demethylase 3A. Regen Ther. 2023; 23:17-24. PMC: 10066509. DOI: 10.1016/j.reth.2023.01.008. View