Reduced mitochondrial response sensitivity is involved in the anti‑apoptotic effect of dexmedetomidine pretreatment in cardiomyocytes

Weng,Xiaojian; Zhang,Xiaodan; Lu,Xiaofei; Wu,Jin; Li,Shitong

doi:10.3892/ijmm.2018.3384

Reduced mitochondrial response sensitivity is involved in the anti‑apoptotic effect of dexmedetomidine pretreatment in cardiomyocytes

Authors:
- Xiaojian Weng
- Xiaodan Zhang
- Xiaofei Lu
- Jin Wu
- Shitong Li
View Affiliations

Affiliations: Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China, Department of Intensive Care Unit, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
Published online on: January 12, 2018 https://doi.org/10.3892/ijmm.2018.3384
Pages: 2328-2338

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

Dexmedetomidine is a commonly used α2-adrenoceptor agonist, which affects various organs, including providing beneficial effects on the heart. However, the mechanism underlying the cardiac benefit remains to be fully elucidated. In the present study, it was demonstrated that dexmedetomidine pretreatment on primary cultured rat cardiomyocytes protected against reactive oxygen species (ROS)‑induced apoptosis. In terms of the potential mechanism, it was demonstrated that dexmedetomidine inhibited mitochondrial biogenesis and mitochondrial respiratory complexes, but with increased coupling efficiency. However, dexmedetomidine upregulated mitochondrial membrane potential (Δψm) and resisted against the loss of Δψm induced by carbonilcyanide p‑triflouromethoxyphenylhydrazone. Due to the importance of mitochondria affecting ROS, the present study investigated the dexmedetomidine‑suppressed mitochondrial response to H2O2 stimulation, which was explained by suppressed ROS levels and the suppression of the increased oxygen consumption rate. Results demonstrated for the first time, to the best of our knowledge, a novel protective mechanism for dexmedetomidine on cardiomyocytes through the attenuated response of mitochondria towards H2O2, which had a protective effect against ROS‑induced apoptosis.

View Figures

View References

1	Bhana N, Goa KL and McClellan KJ: Dexmedetomidine. Drugs. 59:263–270. 2000. View Article : Google Scholar : PubMed/NCBI
2	Martin E, Ramsay G, Mantz J and Sum-Ping ST: The role of the alpha2-adrenoceptor agonist dexmedetomidine in postsurgical sedation in the intensive care unit. J Intensive Care Med. 18:29–41. 2003. View Article : Google Scholar
3	Szumita PM, Baroletti SA, Anger KE and Wechsler ME: Sedation and analgesia in the intensive care unit: Evaluating the role of dexmedetomidine. Am J Health Syst Pharm. 64:37–44. 2007. View Article : Google Scholar
4	Venn RM, Hell J and Grounds RM: Respiratory effects of dexmedetomidine in the surgical patient requiring intensive care. Crit Care. 4:302–308. 2000. View Article : Google Scholar : PubMed/NCBI
5	Hsu YW, Cortinez LI, Robertson KM, Keifer JC, Sum-Ping ST, Moretti EW, Young CC, Wright DR, Macleod DB and Somma J: Dexmedetomidine pharmacodynamics: Part I: Crossover comparison of the respiratory effects of dexmedetomidine and remifentanil in healthy volunteers. Anesthesiology. 101:1066–1076. 2004. View Article : Google Scholar : PubMed/NCBI
6	Lee SH, Lee CY, Lee JG, Kim N, Lee HM and Oh YJ: Intraoperative dexmedetomidine improves the quality of recovery and postoperative pulmonary function in patients undergoing video-assisted thoracoscopic surgery: A CONSORT-prospective, randomized, controlled trial. Medicine. 95:e28542016. View Article : Google Scholar : PubMed/NCBI
7	Ren X, Ma H and Zuo Z: Dexmedetomidine postconditioning reduces brain injury after brain hypoxia-ischemia in neonatal rats. J Neuroimmune Pharmacol. 11:238–247. 2016. View Article : Google Scholar : PubMed/NCBI
8	Sifringer M, von Haefen C, Krain M, Paeschke N, Bendix I, Bührer C, Spies CD and Endesfelder S: Neuroprotective effect of dexmedetomidine on hyperoxia-induced toxicity in the neonatal rat brain. Oxid Med Cell Longev. 2015:5303712015. View Article : Google Scholar : PubMed/NCBI
9	Sun Y, Gao Q, Wu N, Li SD, Yao JX and Fan WJ: Protective effects of dexmedetomidine on intestinal ischemia-reperfusion injury. Exp Ther Med. 10:647–652. 2015. View Article : Google Scholar : PubMed/NCBI
10	Gu H, Liu J and Wu C: Impact of dexmedetomidine versus propofol on cardiac function of children undergoing laparoscopic surgery. Int J Clin Exp Med. 7:5882–5885. 2014.
11	Turan A, Bashour CA, You J, Kirkova Y, Kurz A, Sessler DI and Saager L: Dexmedetomidine sedation after cardiac surgery decreases atrial arrhythmias. J Clin Anesth. 26:634–642. 2014. View Article : Google Scholar : PubMed/NCBI
12	Willigers HM, Prinzen FW, Roekaerts PM, de Lange S and Durieux ME: Dexmedetomidine decreases perioperative myocardial lactate release in dogs. Anesth Analg. 96:657–664, Table of contents. 2003. View Article : Google Scholar : PubMed/NCBI
13	Fu C, Dai X, Yang Y, Lin M, Cai Y and Cai S: Dexmedetomidine attenuates lipopolysaccharide-induced acute lung injury by inhibiting oxidative stress, mitochondrial dysfunction and apoptosis in rats. Mol Med Rep. 15:131–138. 2017. View Article : Google Scholar :
14	Ibacache M, Sanchez G, Pedrozo Z, Galvez F, Humeres C, Echevarria G, Duaso J, Hassi M, Garcia L, Díaz-Araya G and Lavandero S: Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart. Biochim Biophys Acta. 1822:537–545. 2012. View Article : Google Scholar : PubMed/NCBI
15	Maltsev AV, Kokoz YM, Evdokimovskii EV, Pimenov OY, Reyes S and Alekseev AE: Alpha-2 adrenoceptors and imidazoline receptors in cardiomyocytes mediate counterbalancing effect of agmatine on NO synthesis and intracellular calcium handling. J Mol Cell Cardiol. 68:66–74. 2014. View Article : Google Scholar : PubMed/NCBI
16	Kang PM and Izumo S: Apoptosis and heart failure: A critical review of the literature. Circ Res. 86:1107–1113. 2000. View Article : Google Scholar : PubMed/NCBI
17	Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW and Khaw BA: Apoptosis in myocytes in end-stage heart failure. N Engl J Med. 335:1182–1189. 1996. View Article : Google Scholar : PubMed/NCBI
18	Parra V, Eisner V, Chiong M, Criollo A, Moraga F, Garcia A, Härtel S, Jaimovich E, Zorzano A, Hidalgo C and Lavandero S: Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis. Cardiovasc Res. 77:387–397. 2008. View Article : Google Scholar
19	Molkentin JD: Calcineurin, mitochondrial membrane potential, and cardiomyocyte apoptosis. Circ Res. 88:1220–1222. 2001. View Article : Google Scholar : PubMed/NCBI
20	Lyras L, Cairns NJ, Jenner A, Jenner P and Halliwell B: An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer's disease. J Neurochem. 68:2061–2069. 1997. View Article : Google Scholar : PubMed/NCBI
21	Simon HU, Haj-Yehia A and Levi-Schaffer F: Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis. 5:415–418. 2000. View Article : Google Scholar
22	Finkel T: Signal transduction by reactive oxygen species in non-phagocytic cells. J Leukoc Biol. 65:337–340. 1999. View Article : Google Scholar : PubMed/NCBI
23	Tian Z, Miyata K, Kadomatsu T, Horiguchi H, Fukushima H, Tohyama S, Ujihara Y, Okumura T, Yamaguchi S, Zhao J, et al: ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism. Nat Commun. 7:130162016. View Article : Google Scholar : PubMed/NCBI
24	Eguchi M, Liu Y, Shin EJ and Sweeney G: Leptin protects H9c2 rat cardiomyocytes from H₂O₂-induced apoptosis. FEBS J. 275:3136–3144. 2008. View Article : Google Scholar : PubMed/NCBI
25	Tian Z, Miyata K, Tazume H, Sakaguchi H, Kadomatsu T, Horio E, Takahashi O, Komohara Y, Araki K, Hirata Y, et al: Perivascular adipose tissue-secreted angiopoietin-like protein 2 (Angptl2) accelerates neointimal hyperplasia after endovascular injury. J Mol Cell Cardiol. 57:1–12. 2013. View Article : Google Scholar : PubMed/NCBI
26	Housmans PR: Effects of dexmedetomidine on contractility, relaxation, and intracellular calcium transients of isolated ventricular myocardium. Anesthesiology. 73:919–922. 1990. View Article : Google Scholar : PubMed/NCBI
27	Cadenas E, Boveris A, Ragan CI and Stoppani AO: Production of superoxide radicals and hydrogen peroxide by NADH-ubiquinone reductase and ubiquinol-cytochrome c reductase from beef-heart mitochondria. Arch Biochem Biophys. 180:248–257. 1977. View Article : Google Scholar : PubMed/NCBI
28	Hinkle PC, Butow RA, Racker E and Chance B: Partial resolution of the enzymes catalyzing oxidative phosphorylation. XV Reverse electron transfer in the flavin-cytochrome Beta region of the respiratory chain of beef heart submitochondrial particles. J Biol Chem. 242:5169–5173. 1967.PubMed/NCBI
29	Lee HC and Wei YH: Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress. Int J Biochem Cell Biol. 37:822–834. 2005. View Article : Google Scholar : PubMed/NCBI
30	Ly JD, Grubb DR and Lawen A: The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis. 8:115–128. 2003. View Article : Google Scholar : PubMed/NCBI
31	Dispersyn G, Nuydens R, Connors R, Borgers M and Geerts H: Bcl-2 protects against FCCP-induced apoptosis and mitochondrial membrane potential depolarization in PC12 cells. Biochim Biophys Acta. 1428:357–371. 1999. View Article : Google Scholar : PubMed/NCBI
32	Deng X, Gao F and May WS Jr: Bcl2 retards G1/S cell cycle transition by regulating intracellular ROS. Blood. 102:3179–3185. 2003. View Article : Google Scholar : PubMed/NCBI
33	Tang XQ, Feng JQ, Chen J, Chen PX, Zhi JL, Cui Y, Guo RX and Yu HM: Protection of oxidative preconditioning against apoptosis induced by H₂O₂ in PC12 cells: Mechanisms via MMP, ROS, and Bcl-2. Brain Res. 1057:57–64. 2005. View Article : Google Scholar : PubMed/NCBI
34	Perry SW, Norman JP, Barbieri J, Brown EB and Gelbard HA: Mitochondrial membrane potential probes and the proton gradient: A practical usage guide. Biotechniques. 50:98–115. 2011. View Article : Google Scholar : PubMed/NCBI
35	Zorov DB, Juhaszova M and Sollott SJ: Mitochondrial ROS-induced ROS release: An update and review. Biochim Biophys Acta. 1757:509–517. 2006. View Article : Google Scholar : PubMed/NCBI
36	Sansbury BE, Riggs DW, Brainard RE, Salabei JK, Jones SP and Hill BG: Responses of hypertrophied myocytes to reactive species: Implications for glycolysis and electrophile metabolism. Biochem J. 435:519–528. 2011. View Article : Google Scholar : PubMed/NCBI
37	Peng K, Qiu Y, Li J, Zhang ZC and Ji FH: Dexmedetomidine attenuates hypoxia/reoxygenation injury in primary neonatal rat cardiomyocytes. Exp Ther Med. 14:689–695. 2017. View Article : Google Scholar : PubMed/NCBI
38	Horbinski C and Chu CT: Kinase signaling cascades in the mitochondrion: A matter of life or death. Free Radic Biol Med. 38:2–11. 2005. View Article : Google Scholar
39	Wang H, Zhang S, Xu S and Zhang L: The efficacy and mechanism of dexmedetomidine in myocardial apoptosis via the renin-angiotensin-aldosterone system. J Renin Angiotensin Aldosterone Syst. 16:1274–1280. 2015. View Article : Google Scholar
40	Tsuruta F, Masuyama N and Gotoh Y: The phosphatidylinositol 3-kinase (PI3K)-Akt pathway suppresses Bax translocation to mitochondria. J Biol Chem. 277:14040–14047. 2002. View Article : Google Scholar : PubMed/NCBI
41	Kennedy SG, Kandel ES, Cross TK and Hay N: Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol Cell Biol. 19:5800–5810. 1999. View Article : Google Scholar : PubMed/NCBI
42	Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP and Wang X: Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science. 275:1129–1132. 1997. View Article : Google Scholar : PubMed/NCBI
43	Oliva CR, Moellering DR, Gillespie GY and Griguer CE: Acquisition of chemoresistance in gliomas is associated with increased mitochondrial coupling and decreased ROS production. PLoS One. 6:e246652011. View Article : Google Scholar : PubMed/NCBI