Preliminary Study of Necroptosis in Cardiac Hypertrophy Induced by Pressure Overload_Journal of Biomedical Engineering

Authors：

ZHAOMingyue ¹ , QINYupei ² , LULihui ¹ , TANGXiaoju ¹ , WUWenchao , FUHua ² ,  LIUXiaojing ¹

1. Laboratory of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China;
2. Department of Cardiology, West China Hospital, Sichuan University, Chengdu 610041, China;

Corresponding author：

LIUXiaojing, Email: liuxq@scu.edu.cn

Keywords：

necroptosis; losartan; pressure overload; transverse abdominal aortic constriction

DOI：

10.7507/1001-5515.20150112

Video：

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The aim of this study was to observe whether necroptosis is involved in the process of cardiac hypertrophy induced by pressure overload. SD rats underwent transverse abdominal aortic constriction (TAC) operation for establishing cardiac hypertrophy model. The structure and function of the left ventricle of rats were evaluated via echocardiography, left ventricular mass index, the expression of markers of cardiac hypertrophy and histological detection. Real-time PCR and Western blot were used to measure the gene and protein expression of receptor interacting protein kinase 1 and 3 (RIPK1 and RIPK3, the necroptosis markers) respectively. Four weeks after TAC operation, rat model for cardiac hypertrophy was established. The experimental data showed that the gene and protein expressions of RIPK1 and RIPK3 in the rat heart hypertrophic tissues after TAC for 4 weeks were increased significantly compared with those in the sham group. HE staining showed cardiomyocytes injury and hypertrophy in the hearts of TAC rat models. By transmission electron microscope, we observed that mitochondria of cardiomyocytes were damaged seriously in the TAC models. Treatment with losartan used, the selective antagonist of angiotensinⅡtypeⅠreceptor could improve the cardiac function of TAC rats. Moreover, losartan treatment decreased the expression of RIPK1 and RIPK3 in heart tissues of TAC rats. The results suggest that necroptosis occurrs in the process of cardiac hypertrophy with pressure overload, and losartan could alleviate the cardiac hypertrophy and inhibit necroptosis.

Citation： ZHAOMingyue, QINYupei, LULihui, TANGXiaoju, WUWenchao, FUHua, LIUXiaojing. Preliminary Study of Necroptosis in Cardiac Hypertrophy Induced by Pressure Overload. Journal of Biomedical Engineering, 2015, 32(3): 618-623. doi: 10.7507/1001-5515.20150112 Copy

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4.	ZAKYNTHINOS E, PIERUTSAKOS Ch, KONSTANTINIDIS K, et al. Losartan reduces left ventricular hypertrophy proportionally to blood pressure reduction in hypertensives, but does not affect diastolic cardiac function[J]. Angiology, 2004, 55(6):669-678.
5.	GARCIA-REDONDO A B, BRIONES A M, AVENDANO M S, et al. Losartan and tempol treatments normalize the increased response to Hydrogen peroxide in resistance arteries from hypertensive rats[J]. J Hypertens, 2009, 27(9):1814-1822.
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7.	DEALMEIDA A C, VAN OORT R J, WEHRENS X H. Transverse aortic constriction in mice[J]. J Vis Exp, 2010, (38):doi:10.3791/1729.
8.	CHA Jihei, LEE H R, KIM K C, et al. Changes of gene expressions in spontaneously hypertensive rat model after losartan treatment[J]. Korean Circ J, 2012, 42(11):761-768.
9.	HUAI Yong, WANG Haiyan, ZHAO Lei, et al. Lacidipine inhibits endoplasmic reticulum stress and myocardial remodeling induced by pressure overload in rat heart[J]. Eur J Pharmacol, 2013, 718(1-3):441-447.
10.	FRIMAN S, WALLIN M, GUSTAFSSON B I, et al. Sympathetic nerves do not affect experimental ischemia-reperfusion injury of rat liver[J]. Transplant Proc, 2009, 41(2):743-745.
11.	SATOH K, NIGRO P, ZEIDAN A, et al. Cyclophilin A promotes cardiac hypertrophy in apolipoprotein E-deficient mice[J]. Arterioscler Thromb Vasc Biol, 2011, 31(5):1116-1123.
12.	HAN Wei-dong, XIE Jian-sheng, LI Ling, et al. Necrostatin-1 reverts shikonin-induced necroptosis to apoptosis[J]. Apoptosis, 2009, 14(5):674-686.
13.	李君丽, 廖延标, 陆立慧, 等.visfatin诱导心肌细胞肥大的机制初探[J].生物医学工程学杂志, 2014, 31(2):379-384.
14.	GREEN D R, OBERST A, DILLON C P, et al. RIPK-dependent necrosis and its regulation by caspases:a mystery in five Acts[J]. Mol Cell, 2011, 44(1):9-16.
15.	OROGO A M, GUSTAFSSON A B. Cell death in the myocardium:My heart won't go on[J]. IUBMB Life, 2013, 65(8):651-656.
16.	KOSHINUMA S, MIYAMAE M, KANEDA K, et al. Combination of necroptosis and apoptosis inhibition enhances cardioprotection against myocardial ischemia-reperfusion injury[J]. J Anesth, 2014, 28(2):235-241.
17.	MIHAILOVI AĆU-STANOJEVI AĆU N, MILORADOVI AĆU Z, GRUJI AĆU-MILANOVI AC'U J, et al. Effects of angiotensinⅡtype-1 receptor blocker losartan on age-related cardiovascular risk in spontaneously hypertensive rats[J]. Gen Physiol Biophys, 2009, 28(Spec No):112-118.
18.	PIERDOMENICO M, NEGRONI A, STRONATI L, et al. Necroptosis is active in children with inflammatory bowel disease and contributes to heighten intestinal inflammation[J]. Am J Gastroenterol, 2014, 109(2):279-287.
19.	LIN C H, YANG Huanle, XUE Qianli, et al. Losartan improves measures of activity, inflammation, and oxidative stress in older mice[J]. Exp Gerontol, 2014, 58:174-178.

1. BERNARDO B C, WEEKS K L, PRETORIUS L A. Molecular distinction between physiological and pathological cardiac hypertrophy:Experimental findings and therapeutic strategies[J]. Pharmacol Ther, 2010, 128(1):191-227.
2. LUEDDE M, LUTZ M, CARTER N, et al. RIP3, a kinase promoting necroptotic cell death, mediates adverse remodelling after myocardial infarction[J]. Cardiovasc Res, 2014, 103(2):206-216.
3. GUO F, SUN Y B, SU L, et al. Losartan attenuates paraquat-induced pulmonary fibrosis in rats[J]. Hum Exp Toxicol, 2014:doi:10.1177/0960327114543840.
4. ZAKYNTHINOS E, PIERUTSAKOS Ch, KONSTANTINIDIS K, et al. Losartan reduces left ventricular hypertrophy proportionally to blood pressure reduction in hypertensives, but does not affect diastolic cardiac function[J]. Angiology, 2004, 55(6):669-678.
5. GARCIA-REDONDO A B, BRIONES A M, AVENDANO M S, et al. Losartan and tempol treatments normalize the increased response to Hydrogen peroxide in resistance arteries from hypertensive rats[J]. J Hypertens, 2009, 27(9):1814-1822.
6. PARK C S, CHA H, KWON E J, et al. The chemical chaperone 4-phenylbutyric acid attenuates pressure-overload cardiac hypertrophy by alleviating endoplasmic reticulum stress[J]. Biochem Biophys Res Commun, 2012, 421(3):578-584.
7. DEALMEIDA A C, VAN OORT R J, WEHRENS X H. Transverse aortic constriction in mice[J]. J Vis Exp, 2010, (38):doi:10.3791/1729.
8. CHA Jihei, LEE H R, KIM K C, et al. Changes of gene expressions in spontaneously hypertensive rat model after losartan treatment[J]. Korean Circ J, 2012, 42(11):761-768.
9. HUAI Yong, WANG Haiyan, ZHAO Lei, et al. Lacidipine inhibits endoplasmic reticulum stress and myocardial remodeling induced by pressure overload in rat heart[J]. Eur J Pharmacol, 2013, 718(1-3):441-447.
10. FRIMAN S, WALLIN M, GUSTAFSSON B I, et al. Sympathetic nerves do not affect experimental ischemia-reperfusion injury of rat liver[J]. Transplant Proc, 2009, 41(2):743-745.
11. SATOH K, NIGRO P, ZEIDAN A, et al. Cyclophilin A promotes cardiac hypertrophy in apolipoprotein E-deficient mice[J]. Arterioscler Thromb Vasc Biol, 2011, 31(5):1116-1123.
12. HAN Wei-dong, XIE Jian-sheng, LI Ling, et al. Necrostatin-1 reverts shikonin-induced necroptosis to apoptosis[J]. Apoptosis, 2009, 14(5):674-686.
13. 李君丽, 廖延标, 陆立慧, 等.visfatin诱导心肌细胞肥大的机制初探[J].生物医学工程学杂志, 2014, 31(2):379-384.
14. GREEN D R, OBERST A, DILLON C P, et al. RIPK-dependent necrosis and its regulation by caspases:a mystery in five Acts[J]. Mol Cell, 2011, 44(1):9-16.
15. OROGO A M, GUSTAFSSON A B. Cell death in the myocardium:My heart won't go on[J]. IUBMB Life, 2013, 65(8):651-656.
16. KOSHINUMA S, MIYAMAE M, KANEDA K, et al. Combination of necroptosis and apoptosis inhibition enhances cardioprotection against myocardial ischemia-reperfusion injury[J]. J Anesth, 2014, 28(2):235-241.
17. MIHAILOVI AĆU-STANOJEVI AĆU N, MILORADOVI AĆU Z, GRUJI AĆU-MILANOVI AC'U J, et al. Effects of angiotensinⅡtype-1 receptor blocker losartan on age-related cardiovascular risk in spontaneously hypertensive rats[J]. Gen Physiol Biophys, 2009, 28(Spec No):112-118.
18. PIERDOMENICO M, NEGRONI A, STRONATI L, et al. Necroptosis is active in children with inflammatory bowel disease and contributes to heighten intestinal inflammation[J]. Am J Gastroenterol, 2014, 109(2):279-287.
19. LIN C H, YANG Huanle, XUE Qianli, et al. Losartan improves measures of activity, inflammation, and oxidative stress in older mice[J]. Exp Gerontol, 2014, 58:174-178.

Journal of Biomedical Engineering

Preliminary Study of Necroptosis in Cardiac Hypertrophy Induced by Pressure Overload

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