Difluoromethylornithine attenuates isoproterenol‑induced cardiac hypertrophy by regulating apoptosis, autophagy and the mitochondria‑associated membranes pathway

Zhao,Yu; Jia,Wei-Wei; Ren,San; Xiao,Wei; Li,Guang-Wei; Jin,Li; Lin,Yan

doi:10.3892/etm.2021.10302

Difluoromethylornithine attenuates isoproterenol‑induced cardiac hypertrophy by regulating apoptosis, autophagy and the mitochondria‑associated membranes pathway

Authors:
- Yu Zhao
- Wei-Wei Jia
- San Ren
- Wei Xiao
- Guang-Wei Li
- Li Jin
- Yan Lin
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Affiliations: Department of Pathophysiology, Qiqihar Medical University, Qiqihar, Heilongjiang 161006, P.R. China
Published online on: June 13, 2021 https://doi.org/10.3892/etm.2021.10302
Article Number: 870
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Myocardial hypertrophy is an independent risk factor of cardiovascular diseases and is closely associated with the incidence of heart failure. In the present study, we hypothesized that difluoromethylornithine (DFMO) could attenuate cardiac hypertrophy through mitochondria‑associated membranes (MAM) and autophagy. Cardiac hypertrophy was induced in male rats by intravenous administration of isoproterenol (ISO; 5 mg/kg/day) for 1, 3,7 and 14 days. For DFMO treatment group, rats were given ISO (5 mg/kg/day) for 14 days and 2% DFMO in their water for 4 weeks. The expression of atrial natriuretic peptide (ANP) mRNA,heart parameters, apoptosis rate, fibrotic area and protein expressions of cleaved caspase3/9, GRP75, Mfn2, CypD and VDAC1 were measured to confirm the development of cardiac hypertrophy, apoptosis and autophagy induced by ISO. ANP mRNA and MAM protein expression levels were assessed by reverse transcription‑quantitative PCR and western blotting to evaluate hypertrophy and the effects of DFMO oral administration. The results demonstrated that heart parameters, ANP mRNA levels, fibrotic area and apoptosis rate were significantly increased in the heart tissue for ISO 7 and 14 day groups compared with the control group. Furthermore, treatment with DFMO significantly inhibited these indicators, and DFMO downregulated the MAM signaling pathway and upregulated the autophagy pathway in heart tissue compared with the ISO 14 day group. Overall, all ISO‑induced changes analyzed in the present study were attenuated following treatment with DFMO. The findings form this study suggested that DFMO treatment may be considered as a potential strategy for preventing ISO‑induced cardiac hypertrophy.

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1	Branco AF, Sampaio SF, Wieckowski MR, Sardão VA and Oliveira PJ: Mitochondrial disruption occurs downstream from - adrenergic overactivation by isoproterenol in differentiated, but not undifferentiated H9c2 cardiomyoblasts: Differential activation of stress and survival pathways. Int J Biochem Cell Biol. 45:2379–2391. 2013.PubMed/NCBI View Article : Google Scholar
2	Berenji K, Drazner MH, Rothermel BA and Hill JA: Does load-induced ventricular hypertrophy progress to systolic heart failure? Am J Physiol Heart Circ Physiol. 289:H8–H16. 2005.PubMed/NCBI View Article : Google Scholar
3	Forte M, Schirone L, Ameri P, Basso C, Catalucci D, Modica J, Chimenti C, Crotti L, Frati G, Rubattu S, et al: The role of mitochondrial dynamics in cardiovascular diseases. Br J Pharmacol. 15:1–17. 2020.PubMed/NCBI View Article : Google Scholar
4	Wyss RK, Méndez-Carmona N, Sanz MN, Arnold M, Segiser A, Fiedler GM, Carrel TP, Djafarzadeh S, Tevaearai Stahel HT and Longnus SL: Mitochondrial integrity during early reperfusion in an isolated rat heart model of donation after circulatory death-consequences of ischemic duration. J Heart Lung Transplant. 38:647–657. 2019.PubMed/NCBI View Article : Google Scholar
5	Dudek J, Hartmann M and Rehling P: The role of mitochondrial cardiolipin in heart function and its implication in cardiac disease. Biochim Biophys Acta Mol Basis Dis. 1865:810–821. 2019.PubMed/NCBI View Article : Google Scholar
6	Raut GK, Manchineela S, Chakrabarti M, Bhukya CK, Naini R, Venkateshwari A, Reddy VD, Mendonza JJ, Suresh Y, Nallari P, et al: Imine stilbene analog ameliorate isoproterenol-induced cardiac hypertrophy and hydrogen peroxide-induced apoptosis. Free Radic Biol Med. 153:80–88. 2020.PubMed/NCBI View Article : Google Scholar
7	Wang S, Binder P, Fang Q, Wang Z, Xiao W, Liu W and Wang X: Endoplasmic reticulum stress in the heart: Insights into mechanisms and drug targets. Br J Pharmacol. 175:1293–1304. 2018.PubMed/NCBI View Article : Google Scholar
8	Rieusset J: Mitochondria and endoplasmic reticulum: Mitochondria-endoplasmic reticulum interplay in type 2 diabetes pathophysiology. Int J Biochem Cell Biol. 43:1257–1262. 2011.PubMed/NCBI View Article : Google Scholar
9	Monteiro JP, Oliveira PJ and Jurado AS: Mitochondrial membrane lipid remodeling in pathophysiology: A new target for diet and therapeutic interventions. Prog Lipid Res. 52:513–528. 2013.PubMed/NCBI View Article : Google Scholar
10	Tang LL, Wang JD, Xu TT, Zhao Z, Zheng JJ, Ge RS and Zhu DY: Mitochondrial toxicity of perfluorooctane sulfonate in mouse embryonic stem cell-derived cardiomyocytes. Toxicology. 382:108–116. 2017.PubMed/NCBI View Article : Google Scholar
11	Sironi L, Restelli LM, Tolnay M, Neutzner A and Frank S: Dysregulated interorganellar crosstalk of mitochondria in the pathogenesis of Parkinson's disease. Cells. 9(233)2020.PubMed/NCBI View Article : Google Scholar
12	Murata D, Arai K, Iijima M and Sesaki H: Mitochondrial division, fusion and degradation. J Biochem. 167:233–241. 2020.PubMed/NCBI View Article : Google Scholar
13	Ou Y, Wang SJ, Li D, Chu B and Gu W: Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc Natl Acad Sci USA. 113:E6806–E6812. 2016.PubMed/NCBI View Article : Google Scholar
14	Pegg AE: Functions of polyamines in mammals. J Biol Chem. 291:14904–14912. 2016.PubMed/NCBI View Article : Google Scholar
15	Murray Stewart T, Dunston TT, Woster PM and Casero RA Jr: Polyamine catabolism and oxidative damage. J Biol Chem. 293:18736–18745. 2018.PubMed/NCBI View Article : Google Scholar
16	Chen M, Xin J, Liu B, Luo L, Li J, Yin W and Li M: Mitogen-activated protein kinase and intracellular polyamine signaling is involved in TRPV1 activation-induced cardiac hypertrophy. J Am Heart Assoc. 5(e003718)2016.PubMed/NCBI View Article : Google Scholar
17	Lin Y, Zhang X, Wang L, Zhao Y, Li H, Xiao W, Xu C and Liu J: Polyamine depletion attenuates isoproterenol-induced hypertrophy and endoplasmic reticulum stress in cardiomyocytes. Cell Physiol Biochem. 34:1455–1465. 2014.PubMed/NCBI View Article : Google Scholar
18	Casero RA Jr, Murray Stewart T and Pegg AE: Polyamine metabolism and cancer: Treatments, challenges and opportunities. Nat Rev Cancer. 18:681–695. 2018.PubMed/NCBI View Article : Google Scholar
19	Lin Y, Liu JC, Zhang XJ, Li GW, Wang LN, Xi YH, Li HZ, Zhao YJ and Xu CQ: Downregulation of the ornithine decarboxylase/polyamine system inhibits angiotensin-induced hypertrophy of cardiomyocytes through the NO/cGMP-dependent protein kinase type-I pathway. Cell Physiol Biochem. 25:443–450. 2010.PubMed/NCBI View Article : Google Scholar
20	Pegg AE: Regulation of ornithine decarboxylase. J Biol Chem. 281:14529–14532. 2006.PubMed/NCBI View Article : Google Scholar
21	Lin Y, Zhang X, Xiao W, Li B, Wang J, Jin L, Lian J, Zhou L and Liu J: Endoplasmic reticulum stress is involved in DFMO attenuating isoproterenol-induced cardiac hypertrophy in rats. Cell Physiol Biochem. 38:1553–1562. 2016.PubMed/NCBI View Article : Google Scholar
22	Jiang G, Gong H, Niu Y, Yang C, Wang S, Chen Z, Ye Y, Zhou N, Zhang G, Ge J, et al: Identification of amino acid residues in angiotensin ii type 1 receptor sensing mechanical stretch and function in cardiomyocyte hypertrophy. Cell Physiol Biochem. 37:105–116. 2015.PubMed/NCBI View Article : Google Scholar
23	Wang W, Zhang H, Xue G, Zhang L, Zhang W, Wang L, Lu F, Li H, Bai S, Lin Y, et al: Exercise training preserves ischemic preconditioning in aged rat hearts by restoring the myocardial polyamine pool. Oxid Med Cell Longev. 2014(457429)2014.PubMed/NCBI View Article : Google Scholar
24	Braunwald E: Heart failure. JACC Heart Fail. 1:1–20. 2013.PubMed/NCBI View Article : Google Scholar
25	Perrone M, Caroccia N, Genovese I, Missiroli S, Modesti L, Pedriali G, Vezzani B, Vitto VAM, Antenori M, Lebiedzinska-Arciszewska M, et al: The role of mitochondria-associated membranes in cellular homeostasis and diseases. Int Rev Cell Mol Biol. 350:119–196. 2020.PubMed/NCBI View Article : Google Scholar
26	Imaeda A, Tanaka S, Tonegawa K, Fuchigami S, Obana M, Maeda M, Kihara M, Kiyonari H, Conway SJ, Fujio Y, et al: Myofibroblast β2 adrenergic signaling amplifies cardiac hypertrophy in mice. Biochem Biophys Res Commun. 510:149–155. 2019.PubMed/NCBI View Article : Google Scholar
27	de Lucia C, Eguchi A and Koch WJ: New insights in cardiac β-adrenergic signaling during heart failure and aging. Front Pharmacol. 9(904)2018.PubMed/NCBI View Article : Google Scholar
28	Ferrara N, Komici K, Corbi G, Pagano G, Furgi G, Rengo C, Femminella GD, Leosco D and Bonaduce D: β-adrenergic receptor responsiveness in aging heart and clinical implications. Front Physiol. 4(396)2014.PubMed/NCBI View Article : Google Scholar
29	Ramani D, De Bandt JP and Cynober L: Aliphatic polyamines in physiology and diseases. Clin Nutr. 33:14–22. 2014.PubMed/NCBI View Article : Google Scholar
30	Li Y and Liu X: The inhibitory role of Chinese materia medica in cardiomyocyte apoptosis and underlying molecular mechanism. Biomed Pharmacother. 118(109372)2019.PubMed/NCBI View Article : Google Scholar
31	Huang P, Fu J, Chen L, Ju C, Wu K, Liu H, Liu Y, Qi B, Qi B and Liu L: Redd1 protects against post infarction cardiac dysfunction by targeting apoptosis and autophagy. Int J Mol Med. 44:2065–2076. 2019.PubMed/NCBI View Article : Google Scholar
32	Takeshima H, Venturi E and Sitsapesan R: Takeshima1 H, Venturi E and Sitsapesan R: New and notable ion-channels in the sarcoplasmic/endoplasmic reticulum: Do they support the process of intracellular Ca²⁺ release? J Physiol. 593:3241–3251. 2015.PubMed/NCBI View Article : Google Scholar
33	Sun D, Chen X, Gu G, Wang J and Zhang J: Potential roles of mitochondria-associated ER membranes (MAMs) in traumatic brain injury. Cell Mol Neurobiol. 37:1349–1357. 2017.PubMed/NCBI View Article : Google Scholar
34	Dingreville F, Panthu B, Thivolet C, Ducreux S, Gouriou Y, Pesenti S, Chauvin MA, Chikh K, Errazuriz-Cerda E, Van Coppenolle F, et al: Differential effect of glucose on ER-mitochondria Ca²⁺ exchange participates in insulin secretion and glucotoxicity-mediated dysfunction of β-cells. Diabetes. 68:1778–1794. 2019.PubMed/NCBI View Article : Google Scholar
35	Betz C, Stracka D, Prescianotto-Baschong C, Frieden M, Demaurex N and Hall MN: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology. Proc Natl Acad Sci USA. 110:12526–12534. 2013.PubMed/NCBI View Article : Google Scholar
36	Roman B, Kaur P, Ashok D, Kohr M, Biswas R, O'Rourke B, Steenbergen C and Das sS: Nuclear-mitochondrial communication involving miR-181c plays an important role in cardiac dysfunction during obesity. J Mol Cell Cardiol. 144:87–96. 2020.PubMed/NCBI View Article : Google Scholar
37	Szabadkai G, Bianchi K, Várnai P, De Stefani D, Wieckowski MR, Cavagna D, Nagy AI, Balla T and Rizzuto R: Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca²⁺ channels. J Cell Biol. 175:901–911. 2006.PubMed/NCBI View Article : Google Scholar
38	Mitra A, Basak T, Datta K, Naskar S, Sengupta S and Sarkar S: Role of α-crystallin B as a regulatory switch in modulating cardiomyocyte apoptosis by mitochondria or endoplasmic reticulum during cardiac hypertrophy and myocardial infarction. Cell Death Dis. 4(e582)2013.PubMed/NCBI View Article : Google Scholar
39	Javadov S, Rajapurohitam V, Kilić A, Zeidan A, Choi A and Karmazyn M: Anti-hypertrophic effect of NHE-1 inhibition involves GSK-3beta-dependent attenuation of mitochondrial dysfunction. J Mol Cell Cardiol. 46:998–1007. 2009.PubMed/NCBI View Article : Google Scholar
40	Li X, Lu J, Xu Y, Wang J, Qiu X, Fan L, Li B, Liu W, Mao F, Zhu J, et al: Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease. Acta Pharm Sin B. 10:646–666. 2020.PubMed/NCBI View Article : Google Scholar
41	Cheon SY, Kim H, Rubinsztein DC and Lee JE: Autophagy, cellular aging and age-related human diseases. Exp Neurobiol. 28:643–657. 2019.PubMed/NCBI View Article : Google Scholar
42	Mizushima N, Yoshimori T and Ohsumi Y: The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol. 27:107–132. 2011.PubMed/NCBI View Article : Google Scholar
43	Gelmetti V, De Rosa P, Torosantucci L, Marini ES, Romagnoli A, Di Rienzo M, Arena G, Vignone D, Fimia GM and Valente EM: PINK1 and BECN1 relocalize at mitochondria-associated membranes during mitophagy and promote ER-mitochondria tethering and autophagosome formation. Autophagy. 13:654–669. 2017.PubMed/NCBI View Article : Google Scholar