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http://dx.doi.org/10.4196/kjpp.2019.23.1.37

Nicorandil alleviated cardiac hypoxia/reoxygenation-induced cytotoxicity via upregulating ketone body metabolism and ACAT1 activity  

Bai, Yan Ping (Department of Cardiology, The Affiliated Hospital of Yan'an University)
Han, Lei Sen (Department of Cardiology, The Forth Renmin Hospital of Xi'an)
Publication Information
The Korean Journal of Physiology and Pharmacology / v.23, no.1, 2019 , pp. 37-45 More about this Journal
Abstract
To study the effect of nicorandil pretreatment on ketone body metabolism and Acetyl-CoA acetyltransferase (ACAT1) activity in hypoxia/reoxygenation (H/R)-induced cardiomyocytes. In our study, we applied H9c2 cardiomyocytes cell line to evaluate the cardioprotective effects of nicorandil. We detected mitochondrial viability, cellular apoptosis, reactive oxygen species (ROS) production and calcium overloading in H9c2 cells that exposed to H/R-induced cytotoxicity. Then we evaluated whether nicorandil possibly regulated ketone body, mainly ${\beta}$-hydroxybutyrate (BHB) and acetoacetate (ACAC), metabolism by regulating ACAT1 and Succinyl-CoA:3-ketoacid coenzyme A transferase 1 (OXCT1) protein and gene expressions. Nicorandil protected H9c2 cardiomyocytes against H/R-induced cytotoxicity dose-dependently by mitochondria-mediated anti-apoptosis pathway. Nicorandil significantly decreased cellular apoptotic rate and enhanced the ratio of Bcl-2/Bax expressions. Further, nicorandil decreased the production of ROS and alleviated calcium overloading in H/R-induced H9c2 cells. In crucial, nicorandil upregulated ACAT1 and OXCT1 protein expressions and either of their gene expressions, contributing to increased production of cellular BHB and ACAC. Nicorandil alleviated cardiomyocytes H/R-induced cytotoxicity through upregulating ACAT1/OXCT1 activity and ketone body metabolism, which might be a potential mechanism for emerging study of nicorandil and other $K_{ATP}$ channel openers.
Keywords
Acetyl-CoA acetyltransferase; Hypoxia reoxygenation; Ketone body; Nicorandil; OXCT1;
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1 Cotter DG, Schugar RC, Crawford PA. Ketone body metabolism and cardiovascular disease. Am J Physiol Heart Circ Physiol. 2013;304:H1060-H1076.   DOI
2 Faria MH, Muniz LR, Vasconcelos PR. Ketone bodies metabolism during ischemic and reperfusion brain injuries following bilateral occlusion of common carotid arteries in rats. Acta Cir Bras. 2007;22:125-129.   DOI
3 Tieu K, Perier C, Caspersen C, Teismann P, Wu DC, Yan SD, Naini A, Vila M, Jackson-Lewis V, Ramasamy R, Przedborski S. D-${\beta}$-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J Clin Invest. 2003;112:892-901.   DOI
4 Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese RV Jr, de Cabo R, Ulrich S, Akassoglou K, Verdin E. Suppression of oxidative stress by ${\beta}$-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 2013;339:211-214.   DOI
5 Nagao M, Toh R, Irino Y, Mori T, Nakajima H, Hara T, Honjo T, Satomi-Kobayashi S, Shinke T, Tanaka H, Ishida T, Hirata K. ${\beta}$-Hydroxybutyrate elevation as a compensatory response against oxidative stress in cardiomyocytes. Biochem Biophys Res Commun. 2016;475:322-328.   DOI
6 Thaler S, Choragiewicz TJ, Rejdak R, Fiedorowicz M, Turski WA, Tulidowicz-Bielak M, Zrenner E, Schuettauf F, Zarnowski T. Neuroprotection by acetoacetate and ${\beta}$-hydroxybutyrate against NMDAinduced RGC damage in rat--possible involvement of kynurenic acid. Graefes Arch Clin Exp Ophthalmol. 2010;248:1729-1735.   DOI
7 Massieu L, Haces ML, Montiel T, Hernandez-Fonseca K. Acetoacetate protects hippocampal neurons against glutamate-mediated neuronal damage during glycolysis inhibition. Neuroscience. 2003; 120:365-378.   DOI
8 Schugar RC, Moll AR, Andre d'Avignon D, Weinheimer CJ, Kovacs A, Crawford PA. Cardiomyocyte-specific deficiency of ketone body metabolism promotes accelerated pathological remodeling. Mol Metab. 2014;3:754-769.   DOI
9 Li W, Wu N, Shu W, Jia D, Jia P. Pharmacological preconditioning and postconditioning with nicorandil attenuates ischemia/reperfusion-induced myocardial necrosis and apoptosis in hypercholesterolemic rats. Exp Ther Med. 2015;10:2197-2205.   DOI
10 Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357:1121-1135.   DOI
11 Silachev DN, Plotnikov EY, Pevzner IB, Zorova LD, Babenko VA, Zorov SD, Popkov VA, Jankauskas SS, Zinchenko VP, Sukhikh GT, Zorov DB. The mitochondrion as a key regulator of ischaemic tolerance and injury. Heart Lung Circ. 2014;23:897-904.   DOI
12 Abete P, Testa G, Cacciatore F, Della-Morte D, Galizia G, Langellotto A, Rengo F. Ischemic preconditioning in the younger and aged heart. Aging Dis. 2011;2:138-148.
13 Kloner RA, Rezkalla SH. Preconditioning, postconditioning and their application to clinical cardiology. Cardiovasc Res. 2006;70:297-307.   DOI
14 Fukao T, Mitchell G, Sass JO, Hori T, Orii K, Aoyama Y. Ketone body metabolism and its defects. J Inherit Metab Dis. 2014;37:541-551.   DOI
15 Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol Metab. 2014;25:42-52.   DOI
16 Ishii H, Ichimiya S, Kanashiro M, Amano T, Imai K, Murohara T, Matsubara T. Impact of a single intravenous administration of nicorandil before reperfusion in patients with ST-segment-elevation myocardial infarction. Circulation. 2005;112:1284-1288.   DOI
17 Wu H, Ye M, Yang J, Ding J, Yang J, Dong W, Wang X. Nicorandil protects the heart from ischemia/reperfusion injury by attenuating endoplasmic reticulum response-induced apoptosis through PI3K/Akt signaling pathway. Cell Physiol Biochem. 2015;35:2320-2332.   DOI
18 Dhalla NS, Elmoselhi AB, Hata T, Makino N. Status of myocardial antioxidants in ischemia-reperfusion injury. Cardiovasc Res. 2000; 47:446-456.   DOI
19 Aubert G, Martin OJ, Horton JL, Lai L, Vega RB, Leone TC, Koves T, Gardell SJ, Kruger M, Hoppel CL, Lewandowski ED, Crawford PA, Muoio DM, Kelly DP. The failing heart relies on ketone bodies as a fuel. Circulation. 2016;133:698-705.   DOI
20 Bedi KC Jr, Snyder NW, Brandimarto J, Aziz M, Mesaros C, Worth AJ, Wang LL, Javaheri A, Blair IA, Margulies KB, Rame JE. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation. 2016;133:706-716.   DOI
21 Camberos-Luna L, Geronimo-Olvera C, Montiel T, Rincon-Heredia R, Massieu L. The ketone body, ${\beta}$-hydroxybutyrate stimulates the autophagic flux and prevents neuronal death induced by glucose deprivation in cortical cultured neurons. Neurochem Res. 2016;41: 600-609.   DOI
22 Crawford PA, Crowley JR, Sambandam N, Muegge BD, Costello EK, Hamady M, Knight R, Gordon JI. Regulation of myocardial ketone body metabolism by the gut microbiota during nutrient deprivation. Proc Natl Acad Sci U S A. 2009;106:11276-11281.   DOI