MicroRNA -148 Alleviates Cardiac Dysfunction, Immune Disorders and Myocardial Apoptosis in Myocardial Ischemia-reperfusion (MI/R) Injury by Targeting Pyruvate Dehydrogenase Kinase (PDK4)

Overview

Journal Bioengineered

Date 2021 Sep 14

PMID 34517782

Citations 8

Authors

Qi Yin

Ping Wang

Xiaohua Wu

Affiliations

Soon will be listed here.

Abstract

Ischemic heart disease in children may be induced by varied factors, and there is no corresponding systematic treatment up to now. This study aims to investigate the effects of microRNA (miR)-148 on myocardial injury in immature rats with myocardial ischemia-reperfusion (MI/R) injury. In this study, MI/R model was established by ligating the coronary artery of heart. The results showed that miR-148 alleviated myocardial injury and rescued relevant parameters (mean ventricular systolic blood pressure (MAP), left ventricular systolic blood pressure (LVSP), heart rate (HR), creatine kinase-MB (CK-MB), cTn1 and Mb in immature rats with MI/R injury. Besides, miR-148 improved the immune dysfunction induced by MI/R through increasing the number of interleukin (IL)-10 cells and reducing the number of inducible nitric oxide synthase (iNOS) cells. In addition, miR-148 relieved the apoptosis of cardiomyocytes induced by MI/R through inhibiting the expression of Bax and elevating the expression of Bcl-2. Further molecular mechanism indicated that pyruvate dehydrogenase kinase 4 (PDK4) was the downstream target of miR-148, which was further confirmed by dual luciferase reporter assay and related expression detection. Accordingly, silenced PDK4 attenuated cardiac dysfunction, immune disorder and myocardial apoptosis in immature rats and enhanced the ability of antioxidant enzymes. What is more, activated SMAD pathway induced by MI/R injury was then blocked by silenced PDK4. Taken together, our study demonstrated that overexpressed miR-148 relieved cardiac dysfunction, immune disorder and cardiomyocyte apoptosis in immature MI/R rats by PDK4 inhibition, which provided novel targets for MI/R injury treatment.

Citing Articles

FGF21 protects against HFpEF by improving cardiac mitochondrial bioenergetics in mice.

Zhang K, Gan J, Wang B, Lei W, Zhen D, Yang J Nat Commun. 2025; 16(1):1661.

PMID: 39955281 PMC: 11829982. DOI: 10.1038/s41467-025-56885-9.

A review of cutting-edge biomarkers for diagnosing coronary artery disease.

Azami P, Mohammadzadeh S, Seirafi S, Razeghian-Jahromi I Medicine (Baltimore). 2025; 104(4):e41377.

PMID: 39854741 PMC: 11771658. DOI: 10.1097/MD.0000000000041377.

Human Breast Milk Exosomes: Affecting Factors, Their Possible Health Outcomes, and Future Directions in Dietetics.

Celik E, Cemali O, Sahin T, Deveci G, Cakir Bicer N, Hirfanoglu I Nutrients. 2024; 16(20).

PMID: 39458514 PMC: 11510026. DOI: 10.3390/nu16203519.

Cardiovascular Disease and miRNAs: Possible Oxidative Stress-Regulating Roles of miRNAs.

Lee S Antioxidants (Basel). 2024; 13(6).

PMID: 38929095 PMC: 11200533. DOI: 10.3390/antiox13060656.

Circulating microRNAs and therapy-associated cardiac events in HER2-positive breast cancer patients: an exploratory analysis from NeoALTTO.

Pizzamiglio S, Ciniselli C, de Azambuja E, Agbor-Tarh D, Moreno-Aspitia A, Suter T Breast Cancer Res Treat. 2024; 206(2):285-294.

PMID: 38689174 PMC: 11182852. DOI: 10.1007/s10549-024-07299-6.

References

Sugden M, Holness M . Therapeutic potential of the mammalian pyruvate dehydrogenase kinases in the prevention of hyperglycaemia. Curr Drug Targets Immune Endocr Metabol Disord. 2002; 2(2):151-65. View

Wang H, Huo X, Yang X, He J, Cheng L, Wang N . STAT3-mediated upregulation of lncRNA HOXD-AS1 as a ceRNA facilitates liver cancer metastasis by regulating SOX4. Mol Cancer. 2017; 16(1):136. PMC: 5558651. DOI: 10.1186/s12943-017-0680-1. View

McCusker C, Doherty N, Molloy B, Rooney N, Mulholland C, Sands A . A randomized controlled trial of interventions to promote adjustment in children with congenital heart disease entering school and their families. J Pediatr Psychol. 2012; 37(10):1089-103. DOI: 10.1093/jpepsy/jss092. View

Toldo S, Mauro A, Cutter Z, Abbate A . Inflammasome, pyroptosis, and cytokines in myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2018; 315(6):H1553-H1568. PMC: 6336966. DOI: 10.1152/ajpheart.00158.2018. View

Friedrich M, Pracht K, Mashreghi M, Jack H, Radbruch A, Seliger B . The role of the miR-148/-152 family in physiology and disease. Eur J Immunol. 2017; 47(12):2026-2038. DOI: 10.1002/eji.201747132. View

Zhang J, Ying Z, Tang Z, Long L, Li K . MicroRNA-148a promotes myogenic differentiation by targeting the ROCK1 gene. J Biol Chem. 2012; 287(25):21093-101. PMC: 3375532. DOI: 10.1074/jbc.M111.330381. View

Li T, Xu J, Qin X, Hou Z, Guo Y, Liu Z . Glucose oxidation positively regulates glucose uptake and improves cardiac function recovery after myocardial reperfusion. Am J Physiol Endocrinol Metab. 2017; 313(5):E577-E585. DOI: 10.1152/ajpendo.00014.2017. View

Klett H, Jurgensen L, Most P, Busch M, Gunther F, Dobreva G . Delineating the Dynamic Transcriptome Response of mRNA and microRNA during Zebrafish Heart Regeneration. Biomolecules. 2019; 9(1). PMC: 6359357. DOI: 10.3390/biom9010011. View

Farid W, Pan Q, van der Meer A, de Ruiter P, Ramakrishnaiah V, De Jonge J . Hepatocyte-derived microRNAs as serum biomarkers of hepatic injury and rejection after liver transplantation. Liver Transpl. 2011; 18(3):290-7. DOI: 10.1002/lt.22438. View

10.

Mokhtari-Zaer A, Marefati N, Atkin S, Butler A, Sahebkar A . The protective role of curcumin in myocardial ischemia-reperfusion injury. J Cell Physiol. 2018; 234(1):214-222. DOI: 10.1002/jcp.26848. View

11.

An X, Ma H, Liu Y, Li F, Song Y, Li G . Effects of miR-101-3p on goat granulosa cells and ovarian development via . J Anim Sci Biotechnol. 2020; 11:102. PMC: 7557009. DOI: 10.1186/s40104-020-00506-6. View

12.

Marin-Juez R, El-Sammak H, Helker C, Kamezaki A, Mullapuli S, Bibli S . Coronary Revascularization During Heart Regeneration Is Regulated by Epicardial and Endocardial Cues and Forms a Scaffold for Cardiomyocyte Repopulation. Dev Cell. 2019; 51(4):503-515.e4. PMC: 6982407. DOI: 10.1016/j.devcel.2019.10.019. View

13.

Spijkerboer A, Utens E, Bogers A, Helbing W, Verhulst F . A historical comparison of long-term behavioral and emotional outcomes in children and adolescents after invasive treatment for congenital heart disease. J Pediatr Surg. 2008; 43(3):534-9. DOI: 10.1016/j.jpedsurg.2007.10.037. View

14.

Bhaskar S, Stanwell P, Cordato D, Attia J, Levi C . Reperfusion therapy in acute ischemic stroke: dawn of a new era?. BMC Neurol. 2018; 18(1):8. PMC: 5771207. DOI: 10.1186/s12883-017-1007-y. View

15.

Jiang C, Gong F . [Regulation and mechanism of miR-148a on cardiomyocyte differentiation induced by 5-aza in mesenchymal stem cells]. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2018; 33(6):514-518. DOI: 10.12047/j.cjap.5601.2017.122. View

16.

Liu L, Rowe G, Yang S, Li J, Damilano F, Chan M . PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy. Circ Res. 2017; 121(12):1370-1378. PMC: 5722682. DOI: 10.1161/CIRCRESAHA.117.311456. View

17.

Chen Y, Song Y, Wang Z . The microRNA-148/152 family: multi-faceted players. Mol Cancer. 2013; 12:43. PMC: 3671164. DOI: 10.1186/1476-4598-12-43. View

18.

Jiao H, Chen R, Jiang Z, Zhang L, Wang H . miR-22 protect PC12 from ischemia/reperfusion-induced injury by targeting p53 upregulated modulator of apoptosis (PUMA). Bioengineered. 2020; 11(1):209-218. PMC: 7039629. DOI: 10.1080/21655979.2020.1729321. View

19.

Bedke T, Muscate F, Soukou S, Gagliani N, Huber S . Title: IL-10-producing T cells and their dual functions. Semin Immunol. 2019; 44:101335. DOI: 10.1016/j.smim.2019.101335. View

20.

Xue R, Lei S, Xia Z, Wu Y, Meng Q, Zhan L . Selective inhibition of PTEN preserves ischaemic post-conditioning cardioprotection in STZ-induced Type 1 diabetic rats: role of the PI3K/Akt and JAK2/STAT3 pathways. Clin Sci (Lond). 2015; 130(5):377-92. DOI: 10.1042/CS20150496. View