PPARα activation alleviates damage to the cytoskeleton during acute myocardial ischemia/reperfusion in rats

Yuan,Jie; Mo,Hongdan; Luo,Jing; Zhao,Suhong; Liang,Shuang; Jiang,Yu; Zhang,Maomao

doi:10.3892/mmr.2018.8771

PPARα activation alleviates damage to the cytoskeleton during acute myocardial ischemia/reperfusion in rats

Authors:
- Jie Yuan
- Hongdan Mo
- Jing Luo
- Suhong Zhao
- Shuang Liang
- Yu Jiang
- Maomao Zhang
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Affiliations: Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
Published online on: March 16, 2018 https://doi.org/10.3892/mmr.2018.8771
Pages: 7218-7226
Copyright: © Yuan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The cytoskeleton serves an important role in maintaining cellular morphology and function, and it is a substrate of calpain during myocardial ischemia/reperfusion (I/R) injury (MIRI). Calpain may be activated by endoplasmic reticulum (ER) stress during MIRI. The activation of peroxisome proliferator‑activated receptor α (PPARα) may inhibit ischemia/reperfusion damage by regulating stress reactions. The present study aimed to determine whether the activation of PPARα protects against MIRI‑induced cytoskeletal degradation, and investigated the underlying mechanism involved. Wistar rats were pretreated with or without fenofibrate and subjected to left anterior descending coronary artery ligation for 45 min, followed by 120 min of reperfusion. Calpain activity and the expression of PPARα, desmin and ER stress parameters were evaluated. Electrocardiography was performed and cardiac function was evaluated. The ultrastructure was observed under transmission electron microscopy. I/R significantly induced damage to the cytoskeleton in cardiomyocytes and cardiac dysfunction, all of which were improved by PPARα activation. In addition, I/R increased ER stress and calpain activity, which were significantly decreased in fenofibrate‑pretreated rat heart tissue. The results suggested that PPARα activation may exert a protective effect against I/R in the myocardium, at least in part via ER stress inhibition. Suppression of ER stress may be an effective therapeutic target for protecting the I/R myocardium.

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1	Westrate LM, Lee JE, Prinz WA and Voeltz GK: Form follows function: The importance of endoplasmic reticulum shape. Annu Rev Biochem. 84:791–811. 2015. View Article : Google Scholar : PubMed/NCBI
2	Yang L, Zhao D, Ren J and Yang J: Endoplasmic reticulum stress and protein quality control in diabetic cardiomyopathy. Biochim Biophys Acta. 1852:209–218. 2015. View Article : Google Scholar : PubMed/NCBI
3	Zhou H, Zhu J, Yue S, Lu L, Busuttil RW, Kupiec-Weglinski JW, Wang X and Zhai Y: The dichotomy of endoplasmic reticulum stress response in liver ischemia-reperfusion injury. Transplantation. 100:365–372. 2016. View Article : Google Scholar : PubMed/NCBI
4	Iurlaro R and Muñoz-Pinedo C: Cell death induced by endoplasmic reticulum stress. FEBS J. 283:2640–2652. 2016. View Article : Google Scholar : PubMed/NCBI
5	Liu J, Ren F, Cheng Q, Bai L, Shen X, Gao F, Busuttil RW, Kupiec-Weglinski JW and Zhai Y: Endoplasmic reticulum stress modulates liver inflammatory immune response in the pathogenesis of liver ischemia and reperfusion injury. Transplantation. 94:211–217. 2012. View Article : Google Scholar : PubMed/NCBI
6	Hou JY, Liu Y, Liu L and Li XM: Protective effect of hyperoside on cardiac ischemia reperfusion injury through inhibition of ER stress and activation of Nrf2 signaling. Asian Pac J Trop Med. 9:76–80. 2016. View Article : Google Scholar : PubMed/NCBI
7	Nakka VP, Gusain A and Raghubir R: Endoplasmic reticulum stress plays critical role in brain damage after cerebral ischemia/reperfusion in rats. Neurotox Res. 17:189–202. 2010. View Article : Google Scholar : PubMed/NCBI
8	Kersten S: Integrated physiology and systems biology of PPARα. Mol Metab. 3:354–371. 2014. View Article : Google Scholar : PubMed/NCBI
9	Nan YM, Wang RQ and Fu N: Peroxisome proliferator-activated receptor α, a potential therapeutic target for alcoholic liver disease. World J Gastroenterol. 20:8055–8060. 2014. View Article : Google Scholar : PubMed/NCBI
10	Su Q, Baker C, Christian P, Naples M, Tong X, Zhang K, Santha M and Adeli K: Hepatic mitochondrial and ER stress induced by defective PPARα signaling in the pathogenesis of hepatic steatosis. Am J Physiol Endocrinol Metabol. 306:E1264–E1273. 2014. View Article : Google Scholar
11	Palomer X, Capdevila-Busquets E, Garreta G, Davidson MM and Vázquez-Carrera M: PPARα attenuates palmitate-induced endoplasmic reticulum stress in human cardiac cells by enhancing AMPK activity. Clin Investig Arterioscler. 26:255–267. 2014.(In Spanish). View Article : Google Scholar : PubMed/NCBI
12	Mo H, Zhao S, Luo J and Yuan J: PPARα activation by fenofibrate protects against acute myocardial ischemia/reperfusion injury by inhibiting mitochondrial apoptosis. Int J Clin Exp Pathol. 9:10955–10964. 2016.
13	Yuan J, Wu J and Han ZG: Fenofibrate improves energy metabolism and attenuates isoproterenol induced acute myocardial ischemic injury in rats via PPAR alpha activation. Zhonghua Xin Xue Guan Bing Za Zhi. 36:847–850. 2008.(In Chinese). PubMed/NCBI
14	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
15	Jones MG, Anderson KM, Wilson PW, Kannel WB, Wagner NB and Wagner GS: Prognostic use of a QRS scoring system after hospital discharge for initial acute myocardial infarction in the Framingham cohort. Am J Cardiol. 66:546–550. 1990. View Article : Google Scholar : PubMed/NCBI
16	Tjandrawidjaja MC, Fu Y, Westerhout CM, Wagner GS, Granger CB and Armstrong PW: APEX-AMI Investigators: Usefulness of the QRS score as a strong prognostic marker in patients discharged after undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Am J Cardiol. 106:630–634. 2010. View Article : Google Scholar : PubMed/NCBI
17	Shiomi H, Kosuge M, Morimoto T, Watanabe H, Taniguchi T, Nakatsuma K, Toyota T, Yamamoto E, Shizuta S, Tada T, et al: QRS score at presentation electrocardiogram is correlated with infarct size and mortality in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention. Circ J. 81:1129–1136. 2017. View Article : Google Scholar : PubMed/NCBI
18	Blunt BC, Creek AT, Henderson DC and Hofmann PA: H2O2 activation of HSP25/27 protects desmin from calpain proteolysis in rat ventricular myocytes. Am J Physiol. 293:1518–1525. 2007.
19	Turer AT and Hill JA: Pathogenesis of myocardial ischemia-reperfusion injury and rationale for therapy. Am J Cardiol. 106:360–368. 2010. View Article : Google Scholar : PubMed/NCBI
20	Singh RB, Chohan PK, Dhalla NS and Netticadan T: The sarcoplasmic reticulum proteins are targets for calpain action in the ischemic-reperfused heart. J Mol Cell Cardiol. 37:101–110. 2004. View Article : Google Scholar : PubMed/NCBI
21	Kumarapeli AR and Wang X: Genetic modification of the heart: Chaperones and the cytoskeleton. J Mol Cell Cardiol. 37:1097–1109. 2004.PubMed/NCBI
22	Chohan PK, Singh RB, Dhalla NS and Netticadan T: L-arginine administration recovers sarcoplasmic reticulum function in ischemic reperfused hearts by preventing calpain activation. Cardiovasc Res. 69:152–163. 2006. View Article : Google Scholar : PubMed/NCBI
23	Zhang CM, Gao L, Zheng YJ and Yang HT: Berbamine protects the heart from ischemia/reperfusion injury by maintaining cytosolic Ca(2+) homeostasis and preventing calpain activation. Circ J. 76:1993–2002. 2012. View Article : Google Scholar : PubMed/NCBI
24	French JP, Quindry JC, Falk DJ, Staib JL, Lee Y, Wang KKW and Powers SK: Ischemia-reperfusion-induced calpain activation and SERCA2a degradation are attenuated by exercise training and calpain inhibition. Am J Physiol Heart Circulat Physiol. 290:128–136. 2006. View Article : Google Scholar
25	Wilding JR, Joubert F, de Araujo C, Fortin D, Novotova M, Veksler V and Ventura-Clapier R: Altered energy transfer from mitochondria to sarcoplasmic reticulum after cytoarchitectural perturbations in mice hearts. J Physiol. 575:191–200. 2006. View Article : Google Scholar : PubMed/NCBI
26	Calaghan SC, Guennec JYL and White E: Cytoskeletal modulation of electrical and mechanical activity in cardiac myocytes. Prog Biophys Mol Biol. 84:29–59. 2004. View Article : Google Scholar : PubMed/NCBI
27	Krebs J, Agellon LB and Michalak M: Ca²⁺ homeostasis and endoplasmic reticulum (ER) stress: An integrated view of calcium signaling. Biochem Biophys Res Communicat. 460:114–121. 2015. View Article : Google Scholar
28	Kim J, Choi TG, Ding Y, Kim Y, Ha KS, Lee KH, Kang I, Ha J, Kaufman RJ, Lee J, et al: Overexpressed cyclophilin B suppresses apoptosis associated with ROS and Ca2+ homeostasis after ER stress. J Cell Sci. 121:3636–3648. 2008. View Article : Google Scholar : PubMed/NCBI
29	Li Y, Zhu W, Tao J, Xin P, Liu M, Li J and Wei M: Fasudil protects the heart against ischemia-reperfusion injury by attenuating endoplasmic reticulum stress and modulating SERCA activity: The differential role for PI3K/Akt and JAK2/STAT3 signaling pathways. PLoS One. 7:e481152012. View Article : Google Scholar : PubMed/NCBI
30	Armstrong SC, Shivell CL and Ganote CE: Sarcolemmal blebs and osmotic fragility as correlates of irreversible ischemic injury in preconditioned isolated rabbit cardiomyocytes ☆. J Mol Cell Cardiol. 33:149–160. 2001. View Article : Google Scholar : PubMed/NCBI
31	Pavli M, Farmaki E, Merkourea S, Vastardis H, Sklavounou A, Tzerbos F and Chatzistamou I: Endoplasmic reticulum stress-associated chaperones, Bip/GRP78 and calnexin are overexpressed in keratocystic odontogenic tumours. J Oral Maxillofac Res. 5:e32014.PubMed/NCBI
32	Minamino T, Komuro I and Kitakaze M: Endoplasmic reticulum stress as a therapeutic target in cardiovascular disease. Circ Res. 107:1071–1082. 2010. View Article : Google Scholar : PubMed/NCBI
33	Lam VH, Zhang L, Huqi A, Fukushima A, Tanner BA, Onay-Besikci A, Keung W, Kantor PF, Jaswal JS, Rebeyka IM and Lopaschuk GD: Activating PPARα prevents post-ischemic contractile dysfunction in hypertrophied neonatal hearts. Circ Res. 117:41–51. 2015. View Article : Google Scholar : PubMed/NCBI
34	Pantazi E, Folch-Puy E, Bejaoui M, Panisello A, Varela AT, Rolo AP, Palmeira CM and Roselló-Catafau J: PPARα agonist WY-14643 induces SIRT1 activity in rat fatty liver ischemia-reperfusion injury. Biomed Res Int. 2015:8946792015. View Article : Google Scholar : PubMed/NCBI
35	Luciani DS, Gwiazda KS, Yang TL, Kalynyak TB, Bychkivska Y, Frey MH, Jeffrey KD, Sampaio AV, Underhill TM and Johnson JD: Roles of IP3R and RyR Ca2+ channels in endoplasmic reticulum stress and beta-cell death. Diabetes. 58:422–432. 2009. View Article : Google Scholar : PubMed/NCBI