Yonsei Med J.  2010 Nov;51(6):838-844. 10.3349/ymj.2010.51.6.838.

Ethyl Pyruvate Has Anti-Inflammatory and Delayed Myocardial Protective Effects after Regional Ischemia/Reperfusion Injury

Affiliations
  • 1Department of Cardiothoracic and Vascular Surgery, Institute of Health Sciences, Gyeongsang National University, Jinju, Korea.
  • 2Department of Anesthesiology and Pain Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Korea. ilwooshin@gnu.ac.kr

Abstract

PURPOSE
Ethyl pyruvate has anti-inflammatory properties and protects organs from ischemia/reperfusion (I/R)-induced tissue injury. The aim of this study was to determine whether ethyl pyruvate decreases the inflammatory response after regional I/R injury and whether ethyl pyruvate protects against delayed regional I/R injury in an in vivo rat heart model after a 24 hours reperfusion.
MATERIALS AND METHODS
Rats were randomized to receive lactated Ringer's solution or ethyl pyruvate dissolved in Ringer's solution, which was given by intraperitoneal injection 1 hour prior to ischemia. Rats were subjected to 30 min of ischemia followed by reperfusion of the left coronary artery territory. After a 2 hours reperfusion, nuclear factor kappaB, myocardial myeloperoxidase activity, and inflammatory cytokine levels were determined. After the 24 hours reperfusion, the hemodynamic function and myocardial infarct size were evaluated.
RESULTS
At 2 hours after I/R injury, ethyl pyruvate attenuated I/R-induced nuclear factor kappaB translocation and reduced myeloperoxidase activity in myocardium. The plasma circulating levels of inflammatory cytokines decreased significantly in the ethyl pyruvate-treated group. At 24 hours after I/R injury, ethyl pyruvate significantly improved cardiac function and reduced infarct size after regional I/R injury.
CONCLUSION
Ethyl pyruvate has the ability to inhibit neutrophil activation, inflammatory cytokine release, and nuclear factor kappaB translocation. Ethyl pyruvate is associated with a delayed myocardial protective effect after regional I/R injury in an in vivo rat heart model.

Keyword

Ethyl pyruvate; myocardium; reperfusion injury; inflammation

MeSH Terms

Animals
Anti-Inflammatory Agents/*pharmacology
Cell Nucleus/metabolism
Cytoplasm/metabolism
Heart/physiopathology
Inflammation
Male
Myocardial Infarction/prevention & control
Myocardium/*metabolism
NF-kappa B/metabolism
Peroxidase/metabolism
Pyruvates/*pharmacology
Rats
Rats, Sprague-Dawley
Reperfusion Injury/*drug therapy/*metabolism

Figure

  • Fig. 1 Effect of EP on I/R-induced translocation of NF-κB. Representative illustration of NF-NF-κB expression in the cytosolic and nuclear fractions of rat ischemic myocardium by Western blotting. Sham + LR, sham-operated rats in which no tightening of the left coronary artery was performed; sham + EP50, sham-operated rats in which 50 mg/kg EP was administered intraperitoneally 1 hour before ischemic insult; I/R + LR, rats in which 4 mL LR was administered intraperitoneally 1 hour before ischemic insult; I/R + EP50, rats in which 50 mg/kg EP was administered intraperitoneally 1 hour before ischemic insult. NF-NF-κB, nucl-ear factor-NF-κB; NE, nuclear extraction; CE, cytosolic extraction; I/R, ischemia/reperfusion; EP, ethyl pyruvate; LR, lactated Ringer's solution. *p < 0.05 vs. sham + LR. †p < 0.05 vs. sham + EP50. ‡p < 0.05 vs. I/R + LR.

  • Fig. 2 Cardiac production of pro-inflammatory cytokines. Plasma levels of TNF-α and IL-1β at 2 hours post-reperfusion in each group. Values are the mean ± SD (n = 6 in each group). Sham + LR, sham-operated rats in which no tightening of the left coronary artery was performed; sham + EP50, sham-operated rats in which 50 mg/kg EP was administered intraperitoneally 1 hour before ischemic insult; I/R + LR, rats in which 4 mL LR was administered intraperitoneally 1 hour before ischemic insult; I/R + EP50, rats in which 50 mg/kg EP was administered intraperitoneally 1 hour before ischemic insult. TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; I/R, ischemia/reperfusion; EP, ethyl pyruvate; LR, lactated Ringer's solution. *p < 0.05 vs. sham + LR. †p < 0.05 vs. sham + EP50. ‡p < 0.05 vs. I/R + LR.

  • Fig. 3 MPO activity was expressed as U/g area at risk (AAR) obtained from the sham + LR, sham + EP50, I/R + LR, and I/R + EP50 groups. Values are the mean ± SD (n = 6 in each group). Sham + LR, sham-operated rats in which no tightening of the left coronary artery was performed; sham + EP50, sham-operated rats in which 50 mg/kg EP was administered intraperitoneally 1 hour before ischemic insult; I/R + LR, rats in which 4 mL LR was administered intraperitoneally 1 hour before ischemic insult; I/R + EP50, rats in which 50 mg/kg EP was administered intraperitoneally 1 hour before ischemic insult. MPO activity, myeloperoxidase activity; I/R, ischemia/reperfusion.; EP, ethyl pyruvate; LR, lactated Ringer's solution. *p < 0.05 vs. sham + LR. †p < 0.05 vs. sham + EP50. ‡p < 0.05 vs. I/R + LR.

  • Fig. 4 Comparison of myocardial infarct size in the I/R + LR, I/R + EP25, and I/R + EP50 groups. Values are means ± SD (n = 15 in each group). I/R + LR, rats in which 4 mL LR was administered intraperitoneally 1 hour before ischemic insult; I/R + EP25, rats in which 25 mg/kg EP was administrated intraperitoneally 1 hour before ischemic insult; I/R + EP50, rats in which 50 mg/kg EP was administered intraperitoneally 1 hour before ischemic insult. I/R, ischemia/reperfusion; LR, lactated Ringer's solution; EP, ethyl pyruvate; AAR, area at risk; LV, left ventricle; IA, infracted area. *p < 0.05 compared to the I/R + LR group.


Cited by  2 articles

Myocardial protective effect by ulinastatin via an anti-inflammatory response after regional ischemia/reperfusion injury in an in vivo rat heart model
Il-Woo Shin, In-Seok Jang, Seung-Min Lee, Kyeong-Eon Park, Seong-Ho Ok, Ju-Tae Sohn, Heon-Keun Lee, Young-Kyun Chung
Korean J Anesthesiol. 2011;61(6):499-505.    doi: 10.4097/kjae.2011.61.6.499.

Lipofundin® MCT/LCT 20% increase left ventricular systolic pressure in an ex vivo rat heart model via increase of intracellular calcium level
Jiyoung Park, Yeon A Kim, Jeong Yeol Han, Sangkyu Jin, Seong-Ho Ok, Ju-Tae Sohn, Heon-Keun Lee, Young-Kyun Chung, Il-Woo Shin
Korean J Anesthesiol. 2016;69(1):57-62.    doi: 10.4097/kjae.2016.69.1.57.


Reference

1. Mallet RT, Sun J, Knott EM, Sharma AB, Olivencia-Yurvati AH. Metabolic cardioprotection by pyruvate: recent progress. Exp Biol Med (Maywood). 2005. 230:435–443.
Article
2. Brand KA, Hermfisse U. Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species. FASEB J. 1997. 11:388–395.
Article
3. Dobsak P, Courderot-Masuyer C, Zeller M, Vergely C, Laubriet A, Assem M, et al. Antioxidative properties of pyruvate and protection of the ischemic rat heart during cardioplegia. J Cardiovasc Pharmacol. 1999. 34:651–659.
Article
4. Yu YM, Kim JB, Lee KW, Kim SY, Han PL, Lee JK. Inhibition of the cerebral inchemic injury by ethyl pyruvate with a wide therapeutic window. Stroke. 2005. 36:2238–2243.
Article
5. Cicalese L, Lee K, Schraut W, Watkins S, Borle A, Stanko R. Pyruvate prevents ischemia-reperfusion mucosal injury of rat small intestine. Am J Surg. 1996. 171:97–100.
6. Sileri P, Schena S, Morini S, Rastellini C, Pham S, Benedetti E, et al. Pyruvate inhibits hepatic ischemia-reperfusion injury in rats. Transplantation. 2001. 72:27–30.
Article
7. Fink MP. Ethyl pyruvate. Curr Opin Anaesthesiol. 2008. 21:160–167.
Article
8. Taylor MD, Grand TJ, Cohen JE, Hsu V, Liao GP, Zentko S, et al. Ethyl pyruvate enhances ATP levels, reduces oxidative stress and preserves cardiac function in a rat model of off-pump coronary bypass. Heart Lung Circ. 2005. 14:25–31.
Article
9. Woo YJ, Taylor MD, Cohen JE, Jayasankar V, Bish LT, Burdick J, et al. Ethyl pyruvate preserves cardiac function and attenuates oxidative injury after prolonged myocardial ischemia. J Thorac Cardiovasc Surg. 2004. 127:1262–1269.
Article
10. Kim HS, Cho IH, Kim JE, Shin YJ, Jeon JH, Kim Y, et al. Ethyl pyruvate has an anti-inflammatory effect by inhibiting ROS-dependent STAT signaling in activated microglia. Free Radic Biol Med. 2008. 45:950–963.
11. Kim JB, Yu YM, Kim SW, Lee JK. Anti-inflammatory mechanism is involved in ethyl pyruvate-mediated efficacious neuroprotection in the postischemic brain. Brain Res. 2005. 1060:188–192.
12. Yang R, Han X, Delude RL, Fink MP. Ethyl pyruvate ameliorates acute alcohol-induced liver injury and inflammation in mice. J Lab Clin Med. 2003. 142:322–331.
Article
13. Shin IW, Jang IS, Lee SH, Baik JS, Park KE, Sohn JT, et al. Propofol has delayed myocardial protective effects after a regional ischemia/reperfusion injury in an in vivo rat heart model. Korean J Anesthesiol. 2010. 58:378–382.
Article
14. Jin YC, Kim CW, Kim YM, Nizamutdinova IT, Ha YM, Kim HJ, et al. Cryptotanshinone, a lipophilic compound of Salvia miltiorrhiza root, inhibits TNF-alpha-induced expression of adhesion molecules in HUVEC and attenuates rat myocardial ischemia/ reperfusion injury in vivo. Eur J Pharmacol. 2009. 614:91–97.
Article
15. Gwechenberger M, Mendoza LH, Youker KA, Frangogiannis NG, Smith CW, Michael LH, et al. Cardiac myocytes produce interleukin-6 in culture and in viable border zone of reperfused infarctions. Circulation. 1999. 99:546–551.
Article
16. Ulloa L, Ochani M, Yang H, Tanovic M, Halperin D, Yang R, et al. Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc Natl Acad Sci U S A. 2002. 99:12351–12356.
Article
17. Zingarelli B, Hake PW, Yang Z, O'Connor M, Denenberg A, Wong HR. Absence of inducible nitric oxide synthase modulates early reperfusion-induced NF-kappaB and AP-1 activation and enhances myocardial damage. FASEB J. 2002. 16:327–342.
18. Chandrasekar B, Freeman GL. Induction of nuclear factor kappaB and activation protein 1 in postischemic myocardium. FEBS Lett. 1997. 401:30–34.
Article
19. Barnes PJ, Karin M. Nuclear factor-kappaB; a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997. 336:1066–1071.
Article
20. Han Y, Englert JA, Yang R, Delude RL, Fink MP. Ethyl pyruvate inhibits nuclear factor-kappaB-dependent signaling by directly targeting p65. J Pharmacol Exp Ther. 2005. 312:1097–1105.
Article
21. Tsung A, Kaizu T, Nakao A, Shao L, Bucher B, Fink MP, et al. Ethyl pyruvate ameliorates liver ischemia-reperfusion injury by decreasing hepatic necrosis and apoptosis. Transplantation. 2005. 79:196–204.
Article
22. Reade MC, Fink MP. Bench-to-bedside review: Amelioration of acute renal impairment using ethyl pyruvate. Crit Care. 2005. 9:556–560.
23. Hansen PR. Role of neutrophils in myocardial ischemia and reperfusion. Circulation. 1995. 91:1872–1885.
Article
24. Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res. 2002. 53:31–47.
Article
25. Goldmann BU, Rudolph V, Rudolph TK, Holle AK, Hillebrandt M, Meinertz T, et al. Neutrophil activation precedes myocardial injury in patients with acute myocardial infarction. Free Radic Biol Med. 2009. 47:79–83.
Article
26. Zhao ZQ, Nakamura M, Wang NP, Velez DA, Hewan-Lowe KO, Guyton RA, et al. Dynamic progression of contractile and endothelial dysfunction and infarct extension in the late phase of reperfusion. J Surg Res. 2000. 94:133–144.
Article
27. Zhao ZQ, Velez DA, Wang NP, Hewan-Lowe KO, Nakamura M, Guyton RA, et al. Progressively developed myocardial apoptotic cell death during late phase of reperfusion. Apoptosis. 2001. 6:279–290.
Full Text Links
  • YMJ
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr