SIRT1 confers protection against ischemia/reperfusion injury in cardiomyocytes via regulation of uncoupling protein 2 expression

Deng,Min; Wang,Daxin; He,Shenghu; Xu,Rixin; Xie,Yong

doi:10.3892/mmr.2017.7452

SIRT1 confers protection against ischemia/reperfusion injury in cardiomyocytes via regulation of uncoupling protein 2 expression

Authors:
- Min Deng
- Daxin Wang
- Shenghu He
- Rixin Xu
- Yong Xie
View Affiliations

Affiliations: Department of Cardiology, Subei People's Hospital, Medical College of Yangzhou University, Yangzhou, Jiangsu 225001, P.R. China
Published online on: September 11, 2017 https://doi.org/10.3892/mmr.2017.7452
Pages: 7098-7104

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The development of a novel targeted therapy for acute myocardial infarction (AMI) remains a major hurdle in the treatment of cardiovascular disease. Previous studies indicate that mitochondrial uncoupling protein 2 (UCP‑2) is involved in the progression of AMI. The present study uses lentivirus knockdown of Sirtuin 1 (SIRT1) in H9c2 cells under hypoxia conditions, and revealed that levels of SIRT1 are accompanied by the expression of UCP‑2. Therefore, it was hypothesized that SIRT1 might be important in the development of myocardial infarction. The present study demonstrated that: i) exogenous expression of SIRT1 in vitro induced resistance to hypoxic injury in H9c2 cells, coinciding with a reduction in expression of UCP‑2; ii) knockdown of UCP‑2 conferred resistance to hypoxic injury in H9c2; iii) intraperitoneal injection of resveratrol and the resultant increase in SIRT1 levels may protect against ischemia/reperfusion injury in vivo, concomitant with decreased expression of UCP‑2. These findings provide direct evidence that the SIRT1/UCP‑2 axis might be important in myocardial infarction, and suggest that this axis may be a novel therapeutic target for the treatment of cardiovascular disease.

View Figures

View References

1	Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, et al: Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet. 380:2095–2128. 2012. View Article : Google Scholar : PubMed/NCBI
2	Evans ZP, Palanisamy AP, Sutter AG, Ellett JD, Ramshesh VK, Attaway H, Schmidt MG, Schnellmann RG and Chavin KD: Mitochondrial uncoupling protein-2 deficiency protects steatotic mouse hepatocytes from hypoxia/reoxygenation. Am J Physiol Gastrointest Liver Physiol. 302:G336–G342. 2012. View Article : Google Scholar : PubMed/NCBI
3	Echtay KS: Mitochondrial uncoupling proteins-what is their physiological role? Free Radical Biol Med. 43:1351–1371. 2007. View Article : Google Scholar
4	Haigis MC and Guarente LP: Mammalian sirtuins-emerging roles in physiology, aging, and calorie restriction. Genes Dev. 20:2913–2921. 2006. View Article : Google Scholar : PubMed/NCBI
5	Verdin E, Hirschey MD, Finley LW and Haigis MC: Sirtuin regulation of mitochondria: Energy production, apoptosis, and signaling. Trends Biochem Sci. 35:669–675. 2010. View Article : Google Scholar : PubMed/NCBI
6	Bordone L, Motta MC, Picard F, Robinson A, Jhala US, Apfeld J, McDonagh T, Lemieux M, McBurney M, Szilvasi A, et al: Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol. 4:e312006. View Article : Google Scholar : PubMed/NCBI
7	Shalwala M, Zhu S-G, Das A, Salloum FN, Xi L and Kukreja RC: Sirtuin 1 (SIRT1) activation mediates sildenafil induced delayed cardioprotection against ischemia-reperfusion injury in mice. PLoS One. 9:e869772014. View Article : Google Scholar : PubMed/NCBI
8	Chiu PY, Luk KF, Leung HY, Ng KM and Ko KM: Schisandrin B stereoisomers protect against hypoxia/reoxygenation-induced apoptosis and inhibit associated changes in Ca2+-induced mitochondrial permeability transition and mitochondrial membrane potential in H9c2 cardiomyocytes. Life Sci. 82:1092–1101. 2008. View Article : Google Scholar : PubMed/NCBI
9	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
10	Yuan Y, Yao YF, Hu SN, Gao J and Zhang LL: MiR-133a is functionally involved in doxorubicin-resistance in breast cancer Cells MCF-7 via its regulation of the expression of uncoupling protein 2. PLoS One. 10:e01298432015. View Article : Google Scholar : PubMed/NCBI
11	Bodyak N, Rigor DL, Chen YS, Han Y, Bisping E, Pu WT and Kang PM: Uncoupling protein 2 modulates cell viability in adult rat cardiomyocytes. Am J Physiol Heart Circ Physiol. 293:H829–H835. 2007. View Article : Google Scholar : PubMed/NCBI
12	D'Onofrio N, Vitiello M, Casale R, Servillo L, Giovane A and Balestrieri ML: Sirtuins in vascular diseases: Emerging roles and therapeutic potential. Biochim Biophys Acta. 1852:1311–1322. 2015. View Article : Google Scholar : PubMed/NCBI
13	Li C, Wang L, Zheng L, Zhan X, Xu B, Jiang J and Wu C: SIRT1 expression is associated with poor prognosis of lung adenocarcinoma. Onco Targets Ther. 8:977–984. 2015. View Article : Google Scholar : PubMed/NCBI
14	Orozco-Solis R, Ramadori G, Coppari R and Sassone-Corsi P: SIRT1 relays nutritional inputs to the circadian clock through the Sf1 neurons of the ventromedial hypothalamus. Endocrinology. 156:2174–2184. 2015. View Article : Google Scholar : PubMed/NCBI
15	Teshima Y, Akao M, Jones SP and Marbán E: Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes. Circ Res. 93:192–200. 2003. View Article : Google Scholar : PubMed/NCBI
16	Deng S, Yang Y, Han Y, Li X, Wang X, Li X, Zhang Z and Wang Y: UCP2 inhibits ROS-mediated apoptosis in A549 under hypoxic conditions. PLoS One. 7:e307142012. View Article : Google Scholar : PubMed/NCBI
17	McLeod CJ, Aziz A, Hoyt RF Jr, McCoy JP Jr and Sack MN: Uncoupling proteins 2 and 3 function in concert to augment tolerance to cardiac ischemia. J Biol Chem. 280:33470–33476. 2005. View Article : Google Scholar : PubMed/NCBI
18	Kukat A, Dogan SA, Edgar D, Mourier A, Jacoby C, Maiti P, Mauer J, Becker C, Senft K, Wibom R, et al: Loss of UCP2 attenuates mitochondrial dysfunction without altering ROS production and uncoupling activity. PLoS Genet. 10:e10043852014. View Article : Google Scholar : PubMed/NCBI
19	Della-Morte D, Dave KR, DeFazio RA, Bao YC, Raval AP and Perez-Pinzon MA: Resveratrol pretreatment protects rat brain from cerebral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway. Neuroscience. 159:993–1002. 2009. View Article : Google Scholar : PubMed/NCBI
20	Teshima Y, Akao M, Jones SP and Marban E: Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes. Circ Res. 93:192–200. 2003. View Article : Google Scholar : PubMed/NCBI