Protective Effect and Regulation Mechanism of Oxaloacetate on Myocardial Ischemia Reperfusion Injury in Rats_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

DINGShi-ao ,  MEIJu , BAOChun-rong , ZHANGJun-wen , YANGYang , YUANYuan , YINHang

Department of Cardiothoracic Surgery, Xinhua Hospital, Medical School of Shanghai Jiaotong University, Shanghai 200092, P. R. China;

Corresponding author：

MEIJu, Email: ju_mei63@126.com

Keywords：

Oxaloacetate (OAA); Myocardial ischemia reperfusion injury; Kelch-like ECH-associated protein-1 (Keap1); NF-E2 related factor 2 (Nrf2); Heme oxygenase-1 (HO-1)

DOI：

10.7507/1007-4848.20160064

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Objective To investigate the protective effect and the regulation mechanism of oxaloacetate (OAA) on myocardial ischemia reperfusion injury in rats. Methods Sixty rats, weight ranged from 200 to 250 grams, were randomly divided into 6 groups:a negative control group, a sham operation control group, a model control group, an OAA pretreatment myocardial ischemia-reperfusion model group (three subgroups:15 mg/kg, 60 mg/kg, 240 mg/kg). We established the model of myocardial ischemia reperfusion of rats and recorded the internal pressure of left ventricle (LVSP), the maximal rate of left ventricular pressure change (±dp/dt_max) and left ventricular end diastolic pressure (LVEDP). We restored reperfusion 180 minutes after ligating the left anterior descending coronary artery 30 minutes and determinated cardiac troponin Ⅰ (cTn-I), lactate dehydrogenase (LDH), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px). We took out heart tissues, stained it and calculated the infarcted size. We used the Western blot to detect the expression of NF-E2 related factor 2 (Nrf2), Kelch-like ECH-associated protein-1 (Keap1) and heme oxygenase-1 (HO-1). Results Compared with the sham operation group, heart function indexes in the negative control group had no significant difference (P>0.05). But in the model control group there was a decrease (P<0.05) And the serum levels of LDH, cTn-I, and myocardial infarcted size were significantly increased (P<0.01). Compared with the model control group, heart function indexes in the OAA pretreatment groups improved, the serum LDH, cTn-I activity, and infarct size decreased (P<0.05), SOD and GSH-Px activity increased (P<0.05). And these results were statistically different (P<0.01) in the high dose OAA pretreatment groups. Compared with the model control group, the expression of Keap1 in the OAA pretreatment group was down-regulated (P<0.001) while total Nrf2, nucleus Nrf2 and its downstream HO-1 was up-regulated (P<0.001), which suggested that OAA enhanced antioxidant capacity by (at least in part) Keap1-Nrf2 pathway, resulting in reducing myocardial damage and protecting myocardium after acute myocardial ischemia reperfusion injury. Conclusion Oxaloacetate can provide protective effects on myocardial ischemia reperfusion injury through down-regulating the expression of Keap1 and up-regulating the expression of Nrf2 and its downstream peroxiredoxins to improve antioxidant capacity.

Citation： DINGShi-ao, MEIJu, BAOChun-rong, ZHANGJun-wen, YANGYang, YUANYuan, YINHang. Protective Effect and Regulation Mechanism of Oxaloacetate on Myocardial Ischemia Reperfusion Injury in Rats. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2016, 23(3): 274-279. doi: 10.7507/1007-4848.20160064 Copy

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2.	Deng C, Sun Z, Tong G, et al. Alpha-Lipoic acid reduces infarct size and preserves cardiac function in rat myocardial ischemia/reperfusion injury through activation of PI3K/Akt/Nrf2 pathway. PLoS One, 2013, 8(3): 571-583.
3.	De Vries DK, Kortekaas KA, Tsikas D, et al. Oxidative damage in clinical ischemia/reperfusion injury: a reappraisal. Antioxid Redox Signal, 2013, 19(6): 535-545.
4.	Filep JG. Glucocorticoid protection against myocardial ischemia-reperfusion injury: central role for the PGD2-Nrf2 pathway. Hyper-tension, 2014, 63(1): 22-23.
5.	Katsumata Y, Shinmura K, Sugiura Y, et al. Endogenous prostag-landin D2 and its metabolites protect the heart against ischemia-reperfusion injury by activating Nrf2. Hypertension, 2014, 63(1): 80-87.
6.	Tang X, Liu J, Dong W, et al. The cardioprotective effects of citric Acid and L-malic Acid on myocardial ischemia/reperfusion injury. Evid Based Complement Alternat Med, 2013, 32(2): 220-231.
7.	Meili-Butz S, Niermann T, Fasler-Kan E, et al. Dimethyl fumarate, a small molecule drug for psoriasis, inhibits Nuclear Factor-kappaB and reduces myocardialinfarct size in rats. Eur J Pharmacol, 2008, 586(1-3): 251-258.
8.	Campos F, Sobrino T, Ramos-Cabrer P, et al. Oxaloacetate: a novel neuroprotective for acute ischemic stroke. Int J Biochem Cell Biol, 2012, 44(2): 262-265.
9.	Gurusamy N, Goswami S, Malik G, et al. Oxidative injury induces selective rather than global inhibition of proteasomal activity. J Mol Cell Cardiol, 2008, 44(2): 419-428.
10.	Braunersreuther V, Jaquet V. Reactive oxygen species in myocardial reperfusion injury from physiopathology to therapeutic approa-ches. Curr Pharm Biotechnol, 2012, 13(1): 97-114.
11.	Wang XY, Dong WP, Bi SH, et al. Protective effects of osthole against myocardial ischemia/reperfusion injury in rats. Int J Mol Med, 2013, 32(2): 365-372.
12.	Matysiak R, Błaszczyk J, Obrebska A, et al. Oxidative-reductive balance in patients after acute coronary syndrome that undergo cardiac rehabilitation. Pol Merkur Lekarski, 2014, 37(219): 148-152.
13.	Sykiotis GP,Bohmann D. Stress-activated cap'n'collar transcription factors in aging and human disease. Sci Signal, 2010, 3(112):104-110.
14.	Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci, 2014, 39(4): 199-218.
15.	Li Z, Galli U, Becker LE, et al. Sulforaphane protects hearts from early injury after experimental transplantation. Ann Transplant, 2013, 18(5): 58-66.
16.	Calvert JW, Jha S, Gundewar S, et al. Hydrogen sulfide mediates cardioprotection through Nrf2 signaling. Circ Res, 2009, 105(4): 365-374.
17.	Cui G, Chui WL, Li RA, et al. Cytoprotection of Baicalein Against Oxidative Stress-induced Cardiomyocytes Injury Through the Nrf2/Keap1 Pathway. J Cardiovasc Pharmacol, 2015, 65(1): 39-46.
18.	Ashrafian H, Czibik G, Bellahcene M, et al. Fumarate is cardiopro-tective via activation of the Nrf2 antioxidant pathway. Cell Metab, 2012, 15(3): 361-371.
19.	Hayes JD, McMahon M. NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci, 2009, 34(4): 176-188.
20.	Motohashi H, Yamamoto M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med, 2004, 10(11): 549-557.

1. Rodrigo R, Prieto JC, Castillo R. Cardioprotection against ischemia/reperfusion by vitamins C and E plus n-3 fatty acids: molecular mechanisms and potential clinical applications. Clin Sci (Lond), 2013, 124(1): 1-15.
2. Deng C, Sun Z, Tong G, et al. Alpha-Lipoic acid reduces infarct size and preserves cardiac function in rat myocardial ischemia/reperfusion injury through activation of PI3K/Akt/Nrf2 pathway. PLoS One, 2013, 8(3): 571-583.
3. De Vries DK, Kortekaas KA, Tsikas D, et al. Oxidative damage in clinical ischemia/reperfusion injury: a reappraisal. Antioxid Redox Signal, 2013, 19(6): 535-545.
4. Filep JG. Glucocorticoid protection against myocardial ischemia-reperfusion injury: central role for the PGD2-Nrf2 pathway. Hyper-tension, 2014, 63(1): 22-23.
5. Katsumata Y, Shinmura K, Sugiura Y, et al. Endogenous prostag-landin D2 and its metabolites protect the heart against ischemia-reperfusion injury by activating Nrf2. Hypertension, 2014, 63(1): 80-87.
6. Tang X, Liu J, Dong W, et al. The cardioprotective effects of citric Acid and L-malic Acid on myocardial ischemia/reperfusion injury. Evid Based Complement Alternat Med, 2013, 32(2): 220-231.
7. Meili-Butz S, Niermann T, Fasler-Kan E, et al. Dimethyl fumarate, a small molecule drug for psoriasis, inhibits Nuclear Factor-kappaB and reduces myocardialinfarct size in rats. Eur J Pharmacol, 2008, 586(1-3): 251-258.
8. Campos F, Sobrino T, Ramos-Cabrer P, et al. Oxaloacetate: a novel neuroprotective for acute ischemic stroke. Int J Biochem Cell Biol, 2012, 44(2): 262-265.
9. Gurusamy N, Goswami S, Malik G, et al. Oxidative injury induces selective rather than global inhibition of proteasomal activity. J Mol Cell Cardiol, 2008, 44(2): 419-428.
10. Braunersreuther V, Jaquet V. Reactive oxygen species in myocardial reperfusion injury from physiopathology to therapeutic approa-ches. Curr Pharm Biotechnol, 2012, 13(1): 97-114.
11. Wang XY, Dong WP, Bi SH, et al. Protective effects of osthole against myocardial ischemia/reperfusion injury in rats. Int J Mol Med, 2013, 32(2): 365-372.
12. Matysiak R, Błaszczyk J, Obrebska A, et al. Oxidative-reductive balance in patients after acute coronary syndrome that undergo cardiac rehabilitation. Pol Merkur Lekarski, 2014, 37(219): 148-152.
13. Sykiotis GP,Bohmann D. Stress-activated cap'n'collar transcription factors in aging and human disease. Sci Signal, 2010, 3(112):104-110.
14. Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci, 2014, 39(4): 199-218.
15. Li Z, Galli U, Becker LE, et al. Sulforaphane protects hearts from early injury after experimental transplantation. Ann Transplant, 2013, 18(5): 58-66.
16. Calvert JW, Jha S, Gundewar S, et al. Hydrogen sulfide mediates cardioprotection through Nrf2 signaling. Circ Res, 2009, 105(4): 365-374.
17. Cui G, Chui WL, Li RA, et al. Cytoprotection of Baicalein Against Oxidative Stress-induced Cardiomyocytes Injury Through the Nrf2/Keap1 Pathway. J Cardiovasc Pharmacol, 2015, 65(1): 39-46.
18. Ashrafian H, Czibik G, Bellahcene M, et al. Fumarate is cardiopro-tective via activation of the Nrf2 antioxidant pathway. Cell Metab, 2012, 15(3): 361-371.
19. Hayes JD, McMahon M. NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci, 2009, 34(4): 176-188.
20. Motohashi H, Yamamoto M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med, 2004, 10(11): 549-557.

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Protective Effect and Regulation Mechanism of Oxaloacetate on Myocardial Ischemia Reperfusion Injury in Rats

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