Induction of autophagy contributes to the myocardial protection of valsartan against ischemia‑reperfusion injury

Wu,Xiaoqian; He,Lishan; Cai,Yi; Zhang,Guiping; He,Yulian; Zhang,Zhijia; He,Xiaoen; He,Yanhua; Zhang,Genshui; Luo,Jiandong

doi:10.3892/mmr.2013.1708

Induction of autophagy contributes to the myocardial protection of valsartan against ischemia‑reperfusion injury

Authors:
- Xiaoqian Wu
- Lishan He
- Yi Cai
- Guiping Zhang
- Yulian He
- Zhijia Zhang
- Xiaoen He
- Yanhua He
- Genshui Zhang
- Jiandong Luo
View Affiliations

Affiliations: Department of Pharmacology, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China
Published online on: September 30, 2013 https://doi.org/10.3892/mmr.2013.1708
Pages: 1824-1830

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 mechanisms underlying the myocardial protection of valsartan against ischemia/reperfusion (I/R) injury are complicated and remain unclear. The aim of this study was to investigate whether autophagy machinery was involved in the protection against I/R injury that is induced by valsartan. In vivo rat hearts were subjected to ischemia by 30 min ligation of the left anterior descending coronary artery, followed by a 120 min reperfusion. 3‑methyladenine (3‑MA), a specific inhibitor on autophagic sequestration, was used to inhibit autophagy. The hemodynamics, infarct size of the ventricle and LC3B protein were measured. Western blot analysis was performed to investigate the mechanism by which autophagy was induced by valsartan. Valsartan preconditioning resulted in a significant decrease in infarct size and induced autophagy in the rat heart subjected to I/R injury. The hemodynamics assay showed that the valsartan‑induced cardiac functional recovery was attenuated by 3‑MA. By contrast, 3‑MA decreased the improvement induced by valsartan on the histology and infarction of the rat heart subjected to I/R injury. Valsartan preconditioning induced autophagy via the AKT/mTOR/S6K pathway, independent of Beclin1. In conclusion, valsartan preconditioning induced autophagy via the AKT/mTOR/S6K pathway, which contributed to the myocardial protection against I/R injury.

View Figures

View References

1	Tritto I, Zuchi C, Vitale S and Ambrosio G: Therapy against reperfusion-induced microvascular injury. Curr Pharm Des. 19:4586–4596. 2013. View Article : Google Scholar : PubMed/NCBI
2	Cianchetti S, Del Fiorentino A, Colognato R, Di Stefano R, Franzoni F and Pedrinelli R: Anti-inflammatory and anti-oxidant properties of telmisartan in cultured human umbilical vein endothelial cells. Atherosclerosis. 198:22–28. 2008. View Article : Google Scholar : PubMed/NCBI
3	Varagic J, Frohlich ED, Susic D, et al: AT1 receptor antagonism attenuates target organ effects of salt excess in SHRs without affecting pressure. Am J Physiol Heart Circ Physiol. 294:H853–H858. 2008. View Article : Google Scholar : PubMed/NCBI
4	Yang J, Jiang H, Yang J, Ding JW, Chen LH, Li S and Zhang XD: Valsartan preconditioning protects against myocardial ischemia-reperfusion injury through TLR4/NF-kappaB signaling pathway. Mol Cell Biochem. 330:39–46. 2009. View Article : Google Scholar
5	Sawicki G, Menon V and Jugdutt BI: Improved balance between TIMP-3 and MMP-9 after regional myocardial ischemia-reperfusion during AT1 receptor blockade. J Card Fail. 10:442–449. 2004. View Article : Google Scholar : PubMed/NCBI
6	Iekushi K, Taniyama Y, Azuma J, et al: Novel mechanisms of valsartan on the treatment of acute myocardial infarction through inhibition of the antiadhesion molecule periostin. Hypertension. 49:1409–1414. 2007. View Article : Google Scholar : PubMed/NCBI
7	Kundu M and Thompson CB: Autophagy: basic principles and relevance to disease. Annu Rev Pathol. 3:427–455. 2008. View Article : Google Scholar : PubMed/NCBI
8	Levine B and Kroemer G: Autophagy in the pathogenesis of disease. Cell. 132:27–42. 2008. View Article : Google Scholar : PubMed/NCBI
9	Oka T, Hikoso S, Yamaguchi O, et al: Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature. 485:251–255. 2012. View Article : Google Scholar : PubMed/NCBI
10	Ma X, Liu H, Foyil SR, et al: Impaired autophagosome clearance contributes to cardiomyocyte death in ischemia/reperfusion injury. Circulation. 125:3170–3181. 2012. View Article : Google Scholar : PubMed/NCBI
11	Buss SJ, Muenz S, Riffel JH, et al: Beneficial effects of Mammalian target of rapamycin inhibition on left ventricular remodeling after myocardial infarction. J Am Coll Cardiol. 54:2435–2446. 2009. View Article : Google Scholar : PubMed/NCBI
12	Marin TM, Keith K, Davies B, et al: Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Invest. 121:1026–1043. 2011. View Article : Google Scholar : PubMed/NCBI
13	Sala-Mercado JA, Wider J, Undyala VV, et al: Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia-reperfusion injury. Circulation. 122:S179–S184. 2010. View Article : Google Scholar : PubMed/NCBI
14	Zhai P, Sciarretta S, Galeotti J, Volpe M and Sadoshima J: Differential roles of GSK-3β during myocardial ischemia and ischemia/reperfusion. Circ Res. 109:502–511. 2011.
15	Wu X, Cheng J, Li P, et al: Mechano-sensitive transcriptional factor Egr-1 regulates insulin-like growth factor-1 receptor expression and contributes to neointima formation in vein grafts. Arterioscler Thromb Vasc Biol. 30:471–476. 2010. View Article : Google Scholar : PubMed/NCBI
16	Wu X, Huang H, Tang F, Le K, Xu S and Liu P: Regulated expression of endothelial lipase in atherosclerosis. Mol Cell Endocrinol. 315:233–238. 2010. View Article : Google Scholar : PubMed/NCBI
17	Mizushima N: Autophagy: process and function. Genes Dev. 21:2861–2873. 2007. View Article : Google Scholar
18	Wang P, Guan YF, Du H, Zhai QW, Su DF and Miao CY: Induction of autophagy contributes to the neuroprotection of nicotinamide phosphoribosyltransferase in cerebral ischemia. Autophagy. 8:77–87. 2012. View Article : Google Scholar : PubMed/NCBI
19	Gustafsson AB and Gottlieb RA: Autophagy in ischemic heart disease. Circ Res. 104:150–158. 2009. View Article : Google Scholar : PubMed/NCBI
20	Matsui Y, Takagi H, Qu X, et al: Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res. 100:914–922. 2007. View Article : Google Scholar : PubMed/NCBI
21	Aoki H, Takada Y, Kondo S, Sawaya R, Aggarwal BB and Kondo Y: Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways. Mol Pharmacol. 72:29–39. 2007. View Article : Google Scholar : PubMed/NCBI
22	Shinojima N, Yokoyama T, Kondo Y and Kondo S: Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy. 3:635–637. 2007. View Article : Google Scholar : PubMed/NCBI
23	Ganley IG, Lam du H, Wang J, Ding X, Chen S and Jiang X: ULK1. ATG13FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem. 284:12297–12305. 2009. View Article : Google Scholar : PubMed/NCBI
24	Kim J, Kundu M, Viollet B and Guan KL: AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 13:132–141. 2011. View Article : Google Scholar : PubMed/NCBI
25	Egan DF, Shackelford DB, Mihaylova MM, et al: Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 331:456–461. 2011. View Article : Google Scholar : PubMed/NCBI
26	Stephan JS, Yeh YY, Ramachandran V, Deminoff SJ and Herman PK: The Tor and PKA signaling pathways independently target the Atg1/Atg13 protein kinase complex to control autophagy. Proc Natl Acad Sci USA. 106:17049–17054. 2009. View Article : Google Scholar : PubMed/NCBI
27	Nicklin P, Bergman P, Zhang B, et al: Bidirectional transport of amino acids regulates mTOR and autophagy. Cell. 136:521–534. 2009. View Article : Google Scholar : PubMed/NCBI
28	Yu L, McPhee CK, Zheng L, et al: Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature. 465:942–946. 2010. View Article : Google Scholar : PubMed/NCBI
29	Zou M, Lu N, Hu C, et al: Beclin 1-mediated autophagy in hepatocellular carcinoma cells: implication in anticancer efficiency of oroxylin A via inhibition of mTOR signaling. Cell Signal. 24:1722–1732. 2012. View Article : Google Scholar : PubMed/NCBI
30	Zou Z, Wu L, Ding H, et al: MicroRNA-30a sensitizes tumor cells to cis-platinum via suppressing beclin 1-mediated autophagy. J Biol Chem. 287:4148–4156. 2012. View Article : Google Scholar : PubMed/NCBI
31	Ugland H, Naderi S, Brech A, Collas P and Blomhoff HK: cAMP induces autophagy via a novel pathway involving ERK, cyclin E and Beclin 1. Autophagy. 7:1199–1211. 2011. View Article : Google Scholar : PubMed/NCBI