Role of PI3K/AKT/mTOR Pathway Associated Oxidative Stress and Cardiac Dysfunction in Takotsubo Syndrome

Author(s): Shan Mao, Xianghong Luo, Yu Li, Chaorong He, Fuhua Huang, Cunhua Su*

Journal Name: Current Neurovascular Research

Volume 17 , Issue 1 , 2020

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Abstract:

Introduction: Takotsubo syndrome (TTS) is a stress-induced cardiomyopathy, but the accurate cause of this syndrome is still unknown.

Methods: β-adrenergic agonist isoproterenol (ISO) is used to establish the TTS rats model. TTS rats were treated with or without LY294002 or Rapamycin. The rat cardiomyoblast cell line H9C2 was subjected to infect with constitutively active Akt (myr-Akt) or dominant-negative mutant Akt (dn-Akt) and then, treated with ISO. Cell apoptosis was assessed using the Bax/ Bcl-2 ratio. In addition, reactive oxygen species (ROS) levels were measured using dihydroethidium (DHE). Mitochondrial superoxide generation and membrane potential were assayed by MitoSOX and JC-1 fluorescence intensity.

Results: ISO might induce the erratic acute cardiac dysfunction and overexpression of PI3K/AKT/mTOR. Moreover, it also increased the oxidative stress and apoptosis in TTS rats. The Akt inhibitor significantly reversed the cardiac injury effect, which triggered by ISO treatment. In H9C2 cells, the inhibition of Akt provides a protective role against ISO-induced injury by reducing oxidative stress, apoptosis and mitochondrial dysfunction.

Conclusion: This study provided new insight into the protective effects of myocardial dysfunction in TTS rats via chronic inhibition of the PI3K/AKT/mTOR expression, which could reduce mitochondrial ROS and oxidative stress-induced apoptosis. PI3K/AKT/mTOR inhibitor could be a therapeutic target to treat cardiovascular dysfunction induced by stress cardiomyopathy.

Keywords: Takotsubo syndrome, PI3K/AKT/mTOR signaling pathway, ROS, mitochondrial dysfunction, stress, adrenoceptor.

[1]
Ueyama, T.; Senba, E.; Kasamatsu, K. Molecular mechanism of emotional stress-induced and catecholamine-induced heart attack. J Cardiovasc Pharmacol 2003; 41(Suppl. 1): S115-8. www.ncbi.nlm.nih.gov/pubmed/12688407
[PMID: 12688407]
[2]
Akashi, Y.J.; Musha, H.; Kida, K. Reversible ventricular dysfunction takotsubo cardiomyopathy. Eur. J. Heart Fail., 2005, 7(7), 1171-1176.
[http://dx.doi.org/10.1016/j.ejheart.2005.03.011] [PMID: 16397924]
[3]
Tsuchihashi, K.; Ueshima, K.; Uchida, T. Angina pectoris-myocardial infarction investigations in Japan. Transient left ventricular apical ballooning without coronary artery stenosis: A novel heart syndrome mimicking acute myocardial infarction. J. Am. Coll. Cardiol., 2001, 38(1), 11-18.
[http://dx.doi.org/10.1016/S0735-1097(01)01316-X] [PMID: 11451258]
[4]
Prasad, A.; Lerman, A.; Rihal, C.S. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): A mimic of acute myocardial infarction. Am. Heart J., 2008, 155(3), 408-417.
[http://dx.doi.org/10.1016/j.ahj.2007.11.008] [PMID: 18294473]
[5]
Bybee, K.A.; Kara, T.; Prasad, A. Systematic review: transient left ventricular apical ballooning: A syndrome that mimics ST-segment elevation myocardial infarction. Ann. Intern. Med., 2004, 141(11), 858-865.
[http://dx.doi.org/10.7326/0003-4819-141-11-200412070-00010] [PMID: 15583228]
[6]
Littlejohn, F.C.; Syed, O.; Ornstein, E.; Connolly, E.S.; Heyer, E.J. Takotsubo cardiomyopathy associated with anesthesia: three case reports. Cases J., 2008, 1(1), 227.
[http://dx.doi.org/10.1186/1757-1626-1-227] [PMID: 18842143]
[7]
Nef, H.M.; Möllmann, H.; Akashi, Y.J.; Hamm, C.W. Mechanisms of stress (Takotsubo) cardiomyopathy. Nat. Rev. Cardiol., 2010, 7(4), 187-193.
[http://dx.doi.org/10.1038/nrcardio.2010.16] [PMID: 20195267]
[8]
Ueyama, T.; Kawabe, T.; Hano, T. Upregulation of heme oxygenase-1 in an animal model of Takotsubo cardiomyopathy. Circ. J., 2009, 73(6), 1141-1146.
[http://dx.doi.org/10.1253/circj.CJ-08-0988] [PMID: 19372624]
[9]
Komamura, K.; Fukui, M.; Iwasaku, T.; Hirotani, S.; Masuyama, T. Takotsubo cardiomyopathy: Pathophysiology, diagnosis and treatment. World J. Cardiol., 2014, 6(7), 602-609.
[http://dx.doi.org/10.4330/wjc.v6.i7.602] [PMID: 25068020]
[10]
Nirmala, C.; Puvanakrishnan, R. Protective role of curcumin against isoproterenol induced myocardial infarction in rats. Mol. Cell. Biochem., 1996, 159(2), 85-93.
[http://dx.doi.org/10.1007/BF00420910] [PMID: 8858558]
[11]
Sharma, M.; Kishore, K.; Gupta, S.K.; Joshi, S.; Arya, D.S. Cardioprotective potential of Ocimum sanctum in isoproterenol induced myocardial infarction in rats. Mol. Cell. Biochem., 2001, 225(1), 75-83.
[http://dx.doi.org/10.1023/A:1012220908636] [PMID: 11716367]
[12]
Chaanine, A.H.; Hajjar, R.J. AKT signalling in the failing heart. Eur. J. Heart Fail., 2011, 13(8), 825-829.
[http://dx.doi.org/10.1093/eurjhf/hfr080] [PMID: 21724622]
[13]
Franke, T.F. Intracellular signaling by Akt: Bound to be specific. Sci. Signal., 2008, 1(24), pe29.
[http://dx.doi.org/10.1126/scisignal.124pe29] [PMID: 18560018]
[14]
Duronio, V. The life of a cell: Apoptosis regulation by the PI3K/PKB pathway. Biochem. J., 2008, 415(3), 333-344.
[http://dx.doi.org/10.1042/BJ20081056] [PMID: 18842113]
[15]
Crackower, M.A.; Oudit, G.Y.; Kozieradzki, I. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell, 2002, 110(6), 737-749.
[http://dx.doi.org/10.1016/S0092-8674(02)00969-8] [PMID: 12297047]
[16]
Hua, Y.; Zhang, Y.; Ceylan-Isik, A.F.; Wold, L.E.; Nunn, J.M.; Ren, J. Chronic Akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: Role of autophagy. Basic Res. Cardiol., 2011, 106(6), 1173-1191.
[http://dx.doi.org/10.1007/s00395-011-0222-8] [PMID: 21901288]
[17]
Takimoto, E.; Kass, D.A. Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension, 2007, 49(2), 241-248.
[http://dx.doi.org/10.1161/01.HYP.0000254415.31362.a7] [PMID: 17190878]
[18]
Vanden Hoek, T.L.; Becker, L.B.; Shao, Z.; Li, C.; Schumacker, P.T. Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes. J. Biol. Chem., 1998, 273(29), 18092-18098.
[http://dx.doi.org/10.1074/jbc.273.29.18092] [PMID: 9660766]
[19]
Brand, M.D. The sites and topology of mitochondrial superoxide production. Exp. Gerontol., 2010, 45(7-8), 466-472.
[http://dx.doi.org/10.1016/j.exger.2010.01.003] [PMID: 20064600]
[20]
Kroemer, G.; Galluzzi, L.; Brenner, C. Mitochondrial membrane permeabilization in cell death. Physiol. Rev., 2007, 87(1), 99-163.
[http://dx.doi.org/10.1152/physrev.00013.2006] [PMID: 17237344]
[21]
Sanderson, T.H.; Reynolds, C.A.; Kumar, R.; Przyklenk, K.; Hüttemann, M. Molecular mechanisms of ischemia-reperfusion injury in brain: Pivotal role of the mitochondrial membrane potential in reactive oxygen species generation. Mol. Neurobiol., 2013, 47(1), 9-23.
[http://dx.doi.org/10.1007/s12035-012-8344-z] [PMID: 23011809]
[22]
Sato, H. Tako-tsubo-like left ventricular dysfunction due to multivessel coronary spasm. In: Kodama K, Haze K, Hon M, Eds. Clinical aspects of myocardial injury: From ischemia to heart failure. Tokyo, Japan: Kagakuhyouronsya Publishing Co. 1990; 56-64
[23]
Yamanaka, O.; Yasumasa, F.; Nakamura, T. “Myocardial stunning”-like phenomenon during a crisis of pheochromocytoma. Jpn. Circ. J., 1994, 58(9), 737-742.
[http://dx.doi.org/10.1253/jcj.58.737] [PMID: 7967019]
[24]
Movahed, A.; Reeves, W.C.; Mehta, P.M.; Gilliland, M.G.; Mozingo, S.L.; Jolly, S.R. Norepinephrine-induced left ventricular dysfunction in anesthetized and conscious, sedated dogs. Int. J. Cardiol., 1994, 45(1), 23-33.
[http://dx.doi.org/10.1016/0167-5273(94)90051-5] [PMID: 7995660]
[25]
Paur, H.; Wright, P.T.; Sikkel, M.B. High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenoceptor/Gi-dependent manner: A new model of takotsubo cardiomyopathy. Circulation, 2012, 112 111591https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890655/
[PMID: 22732314]
[26]
Eitel, I.; von Knobelsdorff-Brenkenhoff, F.; Bernhardt, P. Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA, 2011, 306(3), 277-286.
[http://dx.doi.org/10.1001/jama.2011.992] [PMID: 21771988]
[27]
Fineschi, V.; Michalodimitrakis, M.; D’Errico, S. Insight into stress-induced cardiomyopathy and sudden cardiac death due to stress. A forensic cardio-pathologist point of view. Forensic Sci. Int., 2010, 194(1-3), 1-8.
[http://dx.doi.org/10.1016/j.forsciint.2009.10.025] [PMID: 19939595]
[28]
Shao, Y.; Redfors, B.; Scharin Täng, M. Novel rat model reveals important roles of β-adrenoreceptors in stress-induced cardiomyopathy. Int. J. Cardiol., 2013, 168(3), 1943-1950.
[http://dx.doi.org/10.1016/j.ijcard.2012.12.092] [PMID: 23357048]
[29]
Fujio, Y.; Nguyen, T.; Wencker, D.; Kitsis, R.N.; Walsh, K. Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. Circulation, 2000, 101(6), 660-667.
[http://dx.doi.org/10.1161/01.CIR.101.6.660] [PMID: 10673259]
[30]
Matsui, T.; Rosenzweig, A. Convergent signal transduction pathways controlling cardiomyocyte survival and function: The role of PI 3-kinase and Akt. J. Mol. Cell. Cardiol., 2005, 38(1), 63-71.
[http://dx.doi.org/10.1016/j.yjmcc.2004.11.005] [PMID: 15623422]
[31]
Lai, K-M.V.; Gonzalez, M.; Poueymirou, W.T. Conditional activation of akt in adult skeletal muscle induces rapid hypertrophy. Mol. Cell. Biol., 2004, 24(21), 9295-9304.
[http://dx.doi.org/10.1128/MCB.24.21.9295-9304.2004] [PMID: 15485899]
[32]
Shiojima, I.; Sato, K.; Izumiya, Y. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J. Clin. Invest., 2005, 115(8), 2108-2118.
[http://dx.doi.org/10.1172/JCI24682] [PMID: 16075055]


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VOLUME: 17
ISSUE: 1
Year: 2020
Page: [35 - 43]
Pages: 9
DOI: 10.2174/1567202617666191223144715
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