Dexmedetomidine improves cardiac function and protects against maladaptive remodeling following myocardial infarction

Han,Hui; Dai,Daopeng; Hu,Jinquan; Zhu,Jinzhou; Lu,Lin; Tao,Guorong; Zhang,Ruiyan

doi:10.3892/mmr.2019.10774

Dexmedetomidine improves cardiac function and protects against maladaptive remodeling following myocardial infarction

Authors:
- Hui Han
- Daopeng Dai
- Jinquan Hu
- Jinzhou Zhu
- Lin Lu
- Guorong Tao
- Ruiyan Zhang
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Affiliations: Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China, Department of Orthopedics, Changzheng Hospital Affiliated with Second Military Medical University, Shanghai 200003, P.R. China, Department of Anesthesiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
Published online on: October 29, 2019 https://doi.org/10.3892/mmr.2019.10774
Pages: 5183-5189
Copyright: © Han et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Dexmedetomidine (DEX), a highly specific and selective α2 adrenergic receptor agonist, has been demonstrated to possess potential cardioprotective effects. However, the mechanisms underlying this process remain to be fully illuminated. In the present study, a myocardial infarction (MI) animal model was generated by permanently ligating the left anterior descending coronary artery in mice. Cardiac function and collagen content were evaluated by transthoracic echocardiography and picrosirius red staining, respectively. Apoptosis was determined by the relative expression levels of Bax and Bcl‑2 and the myocardial caspase‑3 activity. Additionally, nicotinamide adenine dinucleotide phosphate oxidase (NOX)‑derived oxidative stress was evaluated by the relative expression of Nox2 and Nox4, along with the myocardial contents of malondialdehyde (MDA) and superoxide dismutase (SOD) activity. It was demonstrated that intraperitoneal DEX treatment (20 µg/kg/day) improved the systolic function of the left ventricle, and decreased the fibrotic changes in post‑myocardial infarction mice, which was paralleled by a decrease in the levels of apoptosis. Subsequent experiments indicated that the restoration of redox signaling was achieved by DEX administration, and the over‑activation of NOXs, including Nox2 and Nox4, was markedly inhibited. In conclusion, this present study suggested that DEX was cardioprotective and limited the excess production of NOX‑derived ROS in ischemic heart disease, implying that DEX is a promising novel drug, especially for patients who have suffered MI.

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1	Cahill TJ, Choudhury RP and Riley PR: Heart regeneration and repair after myocardial infarction: Translational opportunities for novel therapeutics. Nat Rev Drug Discov. 16:699–717. 2017. View Article : Google Scholar : PubMed/NCBI
2	Lefer DJ and Marban E: Is cardioprotection dead? Circulation. 136:98–109. 2017. View Article : Google Scholar : PubMed/NCBI
3	Malfitano C, Barboza CA, Mostarda C, da Palma RK, dos Santos CP, Rodrigues B, Freitas SC, Belló-Klein A, Llesuy S, Irigoyen MC and De Angelis K: Diabetic hyperglycemia attenuates sympathetic dysfunction and oxidative stress after myocardial infarction in rats. Cardiovasc Diabetol. 13:1312014. View Article : Google Scholar : PubMed/NCBI
4	Li B, Tian J, Sun Y, Xu TR, Chi RF, Zhang XL, Hu XL, Zhang YA, Qin FZ and Zhang WF: Activation of NADPH oxidase mediates increased endoplasmic reticulum stress and left ventricular remodeling after myocardial infarction in rabbits. Biochim Biophys Acta. 1852:805–815. 2015. View Article : Google Scholar : PubMed/NCBI
5	Yu L, Yang G, Zhang X, Wang P, Weng X, Yang Y, Li Z, Fang M, Xu Y, Sun A and Ge J: Megakaryocytic leukemia 1 (MKL1) bridges epigenetic activation of NADPH oxidase in macrophages to cardiac ischemia-reperfusion injury. Circulation. 138:2820–2836. 2018. View Article : Google Scholar : PubMed/NCBI
6	Cadenas S: ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection. Free Radic Biol Med. 117:76–89. 2018. View Article : Google Scholar : PubMed/NCBI
7	Asensio-Lopez MDC, Lax A, Fernandez Del Palacio MJ, Sassi Y, Hajjar RJ and Pascual-Figal DA: Pharmacological inhibition of the mitochondrial NADPH oxidase 4/PKCalpha/Gal-3 pathway reduces left ventricular fibrosis following myocardial infarction. Transl Res. 199:4–23. 2018. View Article : Google Scholar : PubMed/NCBI
8	Shi S, Liang J, Liu T, Yuan X, Ruan B, Sun L, Tang Y, Yang B, Hu D and Huang C: Depression increases sympathetic activity and exacerbates myocardial remodeling after myocardial infarction: Evidence from an animal experiment. PLoS One. 9:e1017342014. View Article : Google Scholar : PubMed/NCBI
9	Huang BS and Leenen FH: The brain renin-angiotensin-aldosterone system: A major mechanism for sympathetic hyperactivity and left ventricular remodeling and dysfunction after myocardial infarction. Curr Heart Fail Rep. 6:81–88. 2009. View Article : Google Scholar : PubMed/NCBI
10	Xiong L, Liu Y, Zhou M, Wang G, Quan D, Shuai W, Shen C, Kong B, Huang C and Huang H: Targeted ablation of cardiac sympathetic neurons attenuates adverse post-infarction remodeling and left ventricle dysfunction. Exp Physiol. 103:1221–1229. 2018. View Article : Google Scholar : PubMed/NCBI
11	Ji F, Li Z, Nguyen H, Young N, Shi P, Fleming N and Liu H: Perioperative dexmedetomidine improves outcomes of cardiac surgery. Circulation. 127:1576–1584. 2013. View Article : Google Scholar : PubMed/NCBI
12	Menon DV, Wang Z, Fadel PJ, Arbique D, Leonard D, Li JL, Victor RG and Vongpatanasin W: Central sympatholysis as a novel countermeasure for cocaine-induced sympathetic activation and vasoconstriction in humans. J Am Coll Cardiol. 50:626–633. 2007. View Article : Google Scholar : PubMed/NCBI
13	Parati G and Esler M: The human sympathetic nervous system: Its relevance in hypertension and heart failure. Eur Heart J. 33:1058–1066. 2012. View Article : Google Scholar : PubMed/NCBI
14	Sun Z, Zhao T, Lv S, Gao Y, Masters J and Weng H: Dexmedetomidine attenuates spinal cord ischemia-reperfusion injury through both anti-inflammation and anti-apoptosis mechanisms in rabbits. J Transl Med. 16:2092018. View Article : Google Scholar : PubMed/NCBI
15	Yan X, Zhang H, Fan Q, Hu J, Tao R, Chen Q, Iwakura Y, Shen W, Lu L, Zhang Q and Zhang R: Dectin-2 deficiency modulates Th1 differentiation and improves wound healing after myocardial infarction. Circ Res. 120:1116–1129. 2017. View Article : Google Scholar : PubMed/NCBI
16	Sun Y, Jiang C, Jiang J and Qiu L: Dexmedetomidine protects mice against myocardium ischaemic/reperfusion injury by activating an AMPK/PI3K/Akt/eNOS pathway. Clin Exp Pharmacol Physiol. 44:946–953. 2017. View Article : Google Scholar : PubMed/NCBI
17	Han H, Zhu J, Zhu Z, Ni J, Du R, Dai Y, Chen Y, Wu Z, Lu L and Zhang R: p-Cresyl sulfate aggravates cardiac dysfunction associated with chronic kidney disease by enhancing apoptosis of cardiomyocytes. J Am Heart Assoc. 4:e0018522015. View Article : Google Scholar : PubMed/NCBI
18	Hu J, Deng G, Tian Y, Pu Y, Cao P and Yuan W: An in vitro investigation into the role of bone marrowderived mesenchymal stem cells in the control of disc degeneration. Mol Med Rep. 12:5701–5708. 2015. View Article : Google Scholar : PubMed/NCBI
19	Yang B, Ye D and Wang Y: Caspase-3 as a therapeutic target for heart failure. Expert Opin Ther Targets. 17:255–263. 2013. View Article : Google Scholar : PubMed/NCBI
20	Wang J, Wang H, Hao P, Xue L, Wei S, Zhang Y and Chen Y: Inhibition of aldehyde dehydrogenase 2 by oxidative stress is associated with cardiac dysfunction in diabetic rats. Mol Med. 17:172–179. 2011. View Article : Google Scholar : PubMed/NCBI
21	Dong J, Guo X, Yang S and Li L: The effects of dexmedetomidine preconditioning on aged rat heart of ischaemia reperfusion injury. Res Vet Sci. 114:489–492. 2017. View Article : Google Scholar : PubMed/NCBI
22	Nguyen V, Tiemann D, Park E and Salehi A: Alpha-2 agonists. Anesthesiol Clin. 35:233–245. 2017. View Article : Google Scholar : PubMed/NCBI
23	Liu W, Yu W, Weng Y, Wang Y and Sheng M: Dexmedetomidine ameliorates the inflammatory immune response in rats with acute kidney damage. Exp Ther Med. 14:3602–3608. 2017. View Article : Google Scholar : PubMed/NCBI
24	Zhang X, Wang J, Qian W, Zhao J, Sun L, Qian Y and Xiao H: Dexmedetomidine inhibits tumor necrosis factor-alpha and interleukin 6 in lipopolysaccharide-stimulated astrocytes by suppression of c-Jun N-terminal kinases. Inflammation. 37:942–949. 2014. View Article : Google Scholar : PubMed/NCBI
25	Hou L, Guo J, Xu F, Weng X, Yue W and Ge J: Cardiomyocyte dimethylarginine dimethylaminohydrolase1 attenuates left-ventricular remodeling after acute myocardial infarction: Involvement in oxidative stress and apoptosis. Basic Res Cardiol. 113:282018. View Article : Google Scholar : PubMed/NCBI
26	Becher UM, Ghanem A, Tiyerili V, Furst DO, Nickenig G and Mueller CF: Inhibition of leukotriene C4 action reduces oxidative stress and apoptosis in cardiomyocytes and impedes remodeling after myocardial injury. J Mol Cell Cardiol. 50:570–577. 2011. View Article : Google Scholar : PubMed/NCBI
27	Jimenez-Fernandez S, Gurpegui M, Díaz-Atienza F, Perez-Costillas L, Gerstenberg M and Correll CU: Oxidative stress and antioxidant parameters in patients with major depressive disorder compared to healthy controls before and after antidepressant treatment: Results from a meta-analysis. J Clin Psychiatry. 76:1658–1667. 2015. View Article : Google Scholar : PubMed/NCBI
28	Yu Q, Lee CF, Wang W, Karamanlidis G, Kuroda J, Matsushima S, Sadoshima J and Tian R: Elimination of NADPH oxidase activity promotes reductive stress and sensitizes the heart to ischemic injury. J Am Heart Assoc. 3:e0005552014. View Article : Google Scholar : PubMed/NCBI
29	Cave AC, Brewer AC, Narayanapanicker A, Ray R, Grieve DJ, Walker S and Shah AM: NADPH oxidases in cardiovascular health and disease. Antioxid Redox Signal. 8:691–728. 2006. View Article : Google Scholar : PubMed/NCBI
30	Matsushima S, Tsutsui H and Sadoshima J: Physiological and pathological functions of NADPH oxidases during myocardial ischemia-reperfusion. Trends Cardiovasc Med. 24:202–205. 2014. View Article : Google Scholar : PubMed/NCBI
31	Imamura M, Lander HM and Levi R: Activation of histamine H3-receptors inhibits carrier-mediated norepinephrine release during protracted myocardial ischemia. Comparison with adenosine A1-receptors and alpha2-adrenoceptors. Circ Res. 78:475–481. 1996. View Article : Google Scholar : PubMed/NCBI
32	Zefirov TL, Khisamieva LI, Ziyatdinova NI and Zefirov AL: Selective blockade of α₂-adrenoceptor subtypes modulates contractility of rat myocardium. Bull Exp Biol Med. 162:177–179. 2016. View Article : Google Scholar : PubMed/NCBI