Uncoupling Protein 1 Knockout Aggravates Isoproterenol-induced Acute Myocardial Ischemia Via AMPK/mTOR/PPARα Pathways in Rats

Overview

Journal Transgenic Res

Specialty Molecular Biology

Date 2021 Oct 28

PMID 34709566

Citations 9

Authors

Daorong Hou

Heling Fu

Yuan Zheng

Dan Lu

Yuanwu Ma

Yuan Yin

Lianfeng Zhang

Dan Bao

Affiliations

Soon will be listed here.

Abstract

Uncoupling protein 1 (UCP1) was found exclusively in the inner membranes of the mitochondria of brown adipose tissue (BAT). We found that UCP1 was also expressed in heart tissue and significantly upregulated in isoproterenol (ISO)-induced acute myocardial ischemia (AMI) rat model. The present study is to determine the underlying mechanism involved in the UCP1 upregulation in ISO-induced AMI rat model. The Ucp1 rats were generated by CRISPR-Cas9 system and presented decreased BAT volume. 2-months old Sprague Dawley (SD) wild-type (WT) and Ucp1 rats were treated with ISO intraperitoneally 30 mg/kg once a day for 3 consecutive days to establish AMI model. In saline group, the echocardiographic parameters, serum markers of myocardial injury cardiac troponin I (cTnI), creatine kinase isoenzyme MB (CK-MB), oxidant malondialdehyde (MDA), antioxidant superoxide dismutase (SOD) or fibrosis were comparable between WT and Ucp1 rats. ISO treatment induced worse left ventricle (LV) hypertrophy, myocardial fibrosis, increased higher cTnI, CK-MB and MDA and decreased lower SOD level in Ucp1 rats compared with that of WT rats. Ucp1 rats also presented lower myocardial phosphocreatine (PCr)/ATP-ratio, which demonstrated worse cardiac energy regulation defect. ISO treatment induced the phosphorylation of AMP-activated protein kinase (AMPK) activation, subsequently the phosphorylation of mammalian target of rapamycin (mTOR) inhibition and peroxisome proliferators-activated receptor α (PPARα) activation in WT rats, whereas activation of AMPK/mTOR/PPARα pathways significantly inhibited in Ucp1 rats. To sum up, UCP1 knockout aggravated ISO-induced AMI by inhibiting AMPK/mTOR/PPARα pathways in rats. Increasing UCP1 expression in heart tissue may be a cytoprotective therapeutic strategy for AMI.

Citing Articles

Comparative efficacy of sweated and non-sweated Bge. extracts on acute myocardial ischemia via regulating the PPARα/RXRα/NF-κB signaling pathway.

Shan X, Li J, Hong B, Yin H, Lu Z, Wang G Heliyon. 2024; 10(11):e31923.

PMID: 38845919 PMC: 11154627. DOI: 10.1016/j.heliyon.2024.e31923.

mTORC1 hyperactivation and resultant suppression of macroautophagy contribute to the induction of cardiomyocyte necroptosis by catecholamine surges.

Cai M, Wu P, Ni W, Huang D, Wang X Physiol Rep. 2024; 12(5):e15966.

PMID: 38444056 PMC: 10915131. DOI: 10.14814/phy2.15966.

Impact of Epicardial Adipose Tissue on Infarct Size and Left Ventricular Systolic Function in Patients with Anterior ST-Segment Elevation Myocardial Infarction.

Gavara J, Merenciano-Gonzalez H, Llopis-Lorente J, Molina-Garcia T, Perez-Sole N, de Dios E Diagnostics (Basel). 2024; 14(4).

PMID: 38396407 PMC: 10888463. DOI: 10.3390/diagnostics14040368.

Salvianolic acid B promotes angiogenesis and inhibits cardiomyocyte apoptosis by regulating autophagy in myocardial ischemia.

Chen Q, Xu Q, Zhu H, Wang J, Sun N, Bian H Chin Med. 2023; 18(1):155.

PMID: 38017536 PMC: 10685573. DOI: 10.1186/s13020-023-00859-w.

Preventing mitochondrial reverse electron transport as a strategy for cardioprotection.

Prag H, Murphy M, Krieg T Basic Res Cardiol. 2023; 118(1):34.

PMID: 37639068 PMC: 10462584. DOI: 10.1007/s00395-023-01002-4.

References

Planavila A, Redondo I, Hondares E, Vinciguerra M, Munts C, Iglesias R . Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat Commun. 2013; 4:2019. DOI: 10.1038/ncomms3019. View

Virtue S, Feldmann H, Christian M, Tan C, Masoodi M, Dale M . A new role for lipocalin prostaglandin d synthase in the regulation of brown adipose tissue substrate utilization. Diabetes. 2012; 61(12):3139-47. PMC: 3501861. DOI: 10.2337/db12-0015. View

Ma L, Wang R, Wang H, Zhang Y, Zhao Z . Long-term caloric restriction activates the myocardial SIRT1/AMPK/PGC-1α pathway in C57BL/6J male mice. Food Nutr Res. 2020; 64. PMC: 7007760. DOI: 10.29219/fnr.v64.3668. View

Sack M . Mitochondrial depolarization and the role of uncoupling proteins in ischemia tolerance. Cardiovasc Res. 2006; 72(2):210-9. DOI: 10.1016/j.cardiores.2006.07.010. View

Mourouzis I, Giagourta I, Galanopoulos G, Mantzouratou P, Kostakou E, Kokkinos A . Thyroid hormone improves the mechanical performance of the post-infarcted diabetic myocardium: a response associated with up-regulation of Akt/mTOR and AMPK activation. Metabolism. 2013; 62(10):1387-93. DOI: 10.1016/j.metabol.2013.05.008. View

Stanford K, Middelbeek R, Townsend K, An D, Nygaard E, Hitchcox K . Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest. 2012; 123(1):215-23. PMC: 3533266. DOI: 10.1172/JCI62308. View

Townsend K, Tseng Y . Brown adipose tissue: Recent insights into development, metabolic function and therapeutic potential. Adipocyte. 2013; 1(1):13-24. PMC: 3661118. DOI: 10.4161/adip.18951. View

Villarroya F, Iglesias R, Giralt M . PPARs in the Control of Uncoupling Proteins Gene Expression. PPAR Res. 2007; 2007:74364. PMC: 1779581. DOI: 10.1155/2007/74364. View

Li Q, Li N, Cui H, Tian X, Jin C, Chen G . Tongxinluo exerts protective effects via anti-apoptotic and pro-autophagic mechanisms by activating AMPK pathway in infarcted rat hearts. Exp Physiol. 2017; 102(4):422-435. DOI: 10.1113/EP086192. View

10.

Liu S, Roberts D, Kharitonenkov A, Zhang B, Hanson S, Li Y . Endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue. Sci Rep. 2013; 3:2767. PMC: 3783882. DOI: 10.1038/srep02767. View

11.

Chen W, Liu H, Chen Y, Sha Y, Ma Q, Zhu P . Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018; 47(5):2067-2076. DOI: 10.1159/000491474. View

12.

Yang F, Zhang L, Gao Z, Sun X, Yu M, Dong S . Exogenous H2S Protects Against Diabetic Cardiomyopathy by Activating Autophagy via the AMPK/mTOR Pathway. Cell Physiol Biochem. 2017; 43(3):1168-1187. DOI: 10.1159/000481758. View

13.

Hoerter J, Gonzalez-Barroso M, Couplan E, Mateo P, Gelly C, Cassard-Doulcier A . Mitochondrial uncoupling protein 1 expressed in the heart of transgenic mice protects against ischemic-reperfusion damage. Circulation. 2004; 110(5):528-33. DOI: 10.1161/01.CIR.0000137824.30476.0E. View

14.

Yang G, Fang Z, Liu Y, Zhang H, Shi X, Ji Q . Protective effects of chinese traditional medicine buyang huanwu decoction on myocardial injury. Evid Based Complement Alternat Med. 2009; 2011:930324. PMC: 3138753. DOI: 10.1093/ecam/nep013. View

15.

Holloway C, Dass S, Suttie J, Rider O, Cox P, Cochlin L . Exercise training in dilated cardiomyopathy improves rest and stress cardiac function without changes in cardiac high energy phosphate metabolism. Heart. 2012; 98(14):1083-90. DOI: 10.1136/heartjnl-2012-302145. View

16.

Shi X, Zhu H, Zhang Y, Zhou M, Tang D, Zhang H . XuefuZhuyu decoction protected cardiomyocytes against hypoxia/reoxygenation injury by inhibiting autophagy. BMC Complement Altern Med. 2017; 17(1):325. PMC: 5477241. DOI: 10.1186/s12906-017-1822-0. View

17.

Bienengraeber M, Ozcan C, Terzic A . Stable transfection of UCP1 confers resistance to hypoxia/reoxygenation in a heart-derived cell line. J Mol Cell Cardiol. 2003; 35(7):861-5. DOI: 10.1016/s0022-2828(03)00147-0. View

18.

Sadek H, Humphries K, Szweda P, Szweda L . Selective inactivation of redox-sensitive mitochondrial enzymes during cardiac reperfusion. Arch Biochem Biophys. 2002; 406(2):222-8. DOI: 10.1016/s0003-9861(02)00446-0. View

19.

Zhang X, Wang Q, Wang X, Chen X, Shao M, Zhang Q . Tanshinone IIA protects against heart failure post-myocardial infarction via AMPKs/mTOR-dependent autophagy pathway. Biomed Pharmacother. 2019; 112:108599. DOI: 10.1016/j.biopha.2019.108599. View

20.

Nagoor Meeran M, Stanely Mainzen Prince P, Basha R . Preventive effects of N-acetyl cysteine on lipids, lipoproteins and myocardial infarct size in isoproterenol induced myocardial infarcted rats: an in vivo and in vitro study. Eur J Pharmacol. 2011; 677(1-3):116-22. DOI: 10.1016/j.ejphar.2011.11.043. View