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Modulation of cardiac stem cell characteristics by metoprolol in hypertensive heart disease

Abstract

Cardiac stem cells (CSCs) play a vital role in cardiac remodeling. Uncontrolled hypertension leads to cardiac hypertrophy, followed by cardiac failure. Pathological remodeling is associated with enhanced oxidative stress. Decreased cardiac stem cell efficiency is speculated in heart diseases. Maintaining a healthy stem cell population is essential for preventing progressive cardiac remodeling. Some anti-hypertensive drugs are cardioprotective. However, the effect of these drugs on CSCs has not been investigated. Metoprolol is a cardioprotective anti-hypertensive agent. To examine whether metoprolol can prevent the deterioration of CSC efficiency, spontaneously hypertensive rats (SHRs) were treated with this drug, and the effects on stem cell function were evaluated. Six-month-old male SHRs were treated with metoprolol (50 mg × kg−1per day) for 2 months. The effectiveness of the treatment at reducing blood pressure and reducing hypertrophy was ensured, and the animals were killed. Cardiac stem cells were isolated from the atrial tissue, and the effect of metoprolol on stem cell migration, proliferation, differentiation, and survival was evaluated by comparing the treated SHRs with untreated SHRs and normotensive Wistar rats. Compared to the Wistar rats, the SHR rats presented with a decrease in stem cell migration and proliferation and an increase in intracellular oxidative stress and senescence. Treating SHRs with metoprolol increased CSC migration and proliferation potential and stemness retention. Cellular senescence and oxidative stress were reduced. The attributes of stem cells from the metoprolol-treated SHRs were comparable to those of the Wistar rats. The restoration of stem cell efficiency is expected to prevent hypertension-induced progressive cardiac remodeling.

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References

  1. 1.

    Cesselli D, Beltrami AP, D’Aurizio F, Marcon P, Bergamin N, Toffoletto B, Pandolfi M, Puppato E, Marino L, Signore S, Livi U, Verardo R, Piazza S, Marchionni L, Fiorini C, Schneider C, Hosoda T, Rota M, Kajstura J, Anversa P, Beltrami CA, Leri A. Effects of age and heart failure on human cardiac stem cell function. Am J Pathol. 2011;179:349–66.

  2. 2.

    Smits AM, van Vliet P, Hassink RJ, Goumans M-J, Doevendans PA. The role of stem cells in cardiac regeneration. J Cell Mol Med. 2005;9:25–36.

  3. 3.

    Serpi R, Tolonen A-M, Tenhunen O, Pieviläinen O, Kubin A-M, Vaskivuo T, Soini Y, Kerkelä R, Leskinen H, Ruskoaho H. Divergent effects of losartan and metoprolol on cardiac remodeling, c-kit+ cells, proliferation and apoptosis in the left ventricle after myocardial infarction. Clin Transl Sci. 2009;2:422–30.

  4. 4.

    Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000;86:494–501.

  5. 5.

    Fukai T, Folz RJ, Landmesser U, Harrison DG. Extracellular superoxide dismutase and cardiovascular disease. Cardiovasc Res. 2002;55:239–49.

  6. 6.

    Belch JJ, Bridges AB, Scott N, Chopra M. Oxygen free radicals and congestive heart failure. Br Heart J. 1991;65:245–8.

  7. 7.

    McMurray J, Chopra M, Abdullah I, Smith WE, Dargie HJ. Evidence of oxidative stress in chronic heart failure in humans. Eur Heart J. 1993;14:1493–8.

  8. 8.

    Kono Y, Nakamura K, Kimura H, Nishii N, Watanabe A, Banba K, Nishii N, Watanabe A, Banba K, Miura A, Nagase S, Sakuragi S, Kusano KF, Matsubara H, Ohe T. Elevated levels of oxidative DNA damage in serum and myocardium of patients with heart failure. Circ J Off J Jpn Circ Soc. 2006;70:1001–5.

  9. 9.

    Nakamura K, Kusano K, Nakamura Y, Kakishita M, Ohta K, Nagase S, Yamamoto M, Miyaji K, Saito H, Morita H, Emori T, Matsubara H, Toyokuni S, Ohe T. Carvedilol decreases elevated oxidative stress in human failing myocardium. Circulation. 2002;105:2867–71.

  10. 10.

    Yoo SM, Choi SH, Jung MDY, Lim SC, Baek SH. Short-term use of telmisartan attenuates oxidation and improves Prdx2 expression more than antioxidant β-blockers in the cardiovascular systems of spontaneously hypertensive rats. Hypertens Res Off J Jpn Soc Hypertens. 2015;38:106–15.

  11. 11.

    Watanabe H, Iwanaga Y, Miyaji Y, Yamamoto H, Miyazaki S. Renal denervation mitigates cardiac remodeling and renal damage in Dahl rats: a comparison with β-receptor blockade. Hypertens Res Off J Jpn Soc Hypertens. 2016;39:217–26.

  12. 12.

    Corea L, Bentivoglio M, Verdecchia P, Provvidenza M, Motolese M. Left ventricular hypertrophy regression in hypertensive patients treated with metoprolol. Int J Clin Pharmacol. 1984;22:365–70.

  13. 13.

    Weiss L, Lundgren Y, Folkow B. Effects of prolonged treatment with adrenergic β-receptor antagonists on blood pressure, cardiovascular design and reactivity in spontaneously hypertensive rats (SHR). Acta Physiol Scand. 1974;91:447–57.

  14. 14.

    Chan V, Fenning A, Hoey A, Brown L. Chronic β-adrenoceptor antagonist treatment controls cardiovascular remodeling in heart failure in the aging spontaneously hypertensive rat. J Cardiovasc Pharmacol. 2011;58:424–31.

  15. 15.

    Messina E, Angelis LD, Frati G, Morrone S, Chimenti S, Fiordaliso F, Salio M, Battaglia M, Latronico MV, Coletta M, Vivarelli E, Frati L, Cossu G, Giacomello A. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res. 2004;95:911–21.

  16. 16.

    Linke A, Müller P, Nurzynska D, Casarsa C, Torella D, Nascimbene A, Castaldo C, Cascapera S, Böhm M, Quaini F, Urbanek K, Leri A, Hintze TH, Kajstura J, Anversa P. Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci USA. 2005;102:8966–71.

  17. 17.

    Mallat Z, Philip I, Lebret M, Chatel D, Maclouf J, Tedgui A. Elevated levels of 8-iso-prostaglandin F2alpha in pericardial fluid of patients with heart failure: a potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure. Circulation. 1998;97:1536–9.

  18. 18.

    Dhalla AK, Hill MF, Singal PK. Role of oxidative stress in transition of hypertrophy to heart failure. J Am Coll Cardiol. 1996;28:506–14.

  19. 19.

    Miyamoto S, Kawaguchi N, Ellison GM, Matsuoka R, Shin’oka T, Kurosawa H. Characterization of long-term cultured c-kit+ cardiac stem cells derived from adult rat hearts. Stem Cells Dev. 2010;19:105–16.

  20. 20.

    Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, Kim J, Aryee MJ, Ji H, Ehrlich LI, Yabuuchi A, Takeuchi A, Cunniff KC, Hongguang H, McKinney-Freeman S, Naveiras O, Yoon TJ, Irizarry RA, Jung N, Seita J, Hanna J, Murakami P, Jaenisch R, Weissleder R, Orkin SH, Weissman IL, Feinberg AP, Daley GQ. Epigenetic memory in induced pluripotent stem cells. Nature. 2010;467:285–90.

  21. 21.

    Reinisch A, Etchart N, Thomas D, Hofmann NA, Fruehwirth M, Sinha S, Chan CK, Senarath-Yapa K, Seo EY, Wearda T, Hartwig UF, Beham-Schmid C, Trajanoski S, Lin Q, Wagner W, Dullin C, Alves F, Andreeff M, Weissman IL, Longaker MT, Schallmoser K, Majeti R, Strunk D. Epigenetic and in vivo comparison of diverse MSC sources reveals an endochondral signature for human hematopoietic niche formation. Blood. 2015;125:249–60.

  22. 22.

    Ganesh SK, Tragante V, Guo W, Guo Y, Lanktree MB, Smith EN, Johnson T, Castillo BA, Barnard J, Baumert J, Chang YP, Elbers CC, Farrall M, Fischer ME, Franceschini N, Gaunt TR, Gho JM, Gieger C, Gong Y, Isaacs A, Kleber ME, Mateo Leach I, McDonough CW, Meijs MF, Mellander O, Molony CM, Nolte IM, Padmanabhan S, Price TS, Rajagopalan R, Shaffer J, Shah S, Shen H, Soranzo N, van der Most PJ, Van Iperen EP, Van Setten J, Vonk JM, Zhang L, Beitelshees AL, Berenson GS, Bhatt DL, Boer JM, Boerwinkle E, Burkley B, Burt A, Chakravarti A, Chen W, Cooper-Dehoff RM, Curtis SP, Dreisbach A, Duggan D, Ehret GB, Fabsitz RR, Fornage M, Fox E, Furlong CE, Gansevoort RT, Hofker MH, Hovingh GK, Kirkland SA, Kottke-Marchant K, Kutlar A, Lacroix AZ, Langaee TY, Li YR, Lin H, Liu K, Maiwald S, Malik R, Murugesan G, Newton-Cheh C, O’Connell JR, Onland-Moret NC, Ouwehand WH, Palmas W, Penninx BW, Pepine CJ, Pettinger M, Polak JF, Ramachandran VS, Ranchalis J, Redline S, Ridker PM, Rose LM, Scharnag H, Schork NJ, Shimbo D, Shuldiner AR, Srinivasan SR, Stolk RP, Taylor HA, Thorand B, Trip MD, van Duijn CM, Verschuren WM, Wijmenga C, Winkelmann BR, Wyatt S, Young JH, Boehm BO, Caulfield MJ, Chasman DI, Davidson KW, Doevendans PA, Fitzgerald GA, Gums JG, Hakonarson H, Hillege HL, Illig T, Jarvik GP, Johnson JA, Kastelein JJ, Koenig W, LifeLines Cohort Study, März W, Mitchell BD, Murray SS, Oldehinkel AJ, Rader DJ, Reilly MP, Reiner AP, Schadt EE, Silverstein RL, Snieder H, Stanton AV, Uitterlinden AG, van der Harst P, van der Schouw YT, Samani NJ, Johnson AD, Munroe PB, de Bakker PI, Zhu X, Levy D, Keating BJ, Asselbergs FW. Loci influencing blood pressure identified using a cardiovascular gene-centric array. Hum Mol Genet. 2013;22:1663–78.

  23. 23.

    Collis LP, Srivastava S, Coetzee WA, Artman M. beta2-Adrenergic receptor agonists stimulate L-type calcium current independent of PKA in newborn rabbit ventricular myocytes. Am J Physiol Heart Circ Physiol. 2007;293:H2826–35.

  24. 24.

    Khan M, Mohsin S, Avitabile D, Siddiqi S, Nguyen J, Wallach K, Quijada P, McGregor M, Gude N, Alvarez R, Tilley DG, Koch WJ, Sussman MA. β-Adrenergic regulation of cardiac progenitor cell death versus survival and proliferation. Circ Res. 2013;112:476–86.

  25. 25.

    Cruickshank JM. The beta 1 hyperselectivity in beta-blocker treatment. J Cardiovasc Pharmacol. 1995;25:S35–46.

  26. 26.

    Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, Kiedrowski M, Rovner A, Ellis SG, Thomas JD, DiCorleto PE, Topol EJ, Penn MS. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet Lond Engl. 2003;362:697–703.

  27. 27.

    Somanna NK, Valente AJ, Krenz M, McDonald KS, Higashi Y, Noda M, Chandrasekar B. Histone deacetyltransferase inhibitors trichostatin A and mocetinostat differentially regulate MMP9, IL-18 and RECK expression, and attenuate angiotensin II-induced cardiac fibroblast migration and proliferation. Hypertens Res Off J Jpn Soc Hypertens. 2016;39:709–16.

  28. 28.

    Murray TVA, Smyrnias I, Shah AM, Brewer AC. NADPH oxidase 4 regulates cardiomyocyte differentiation via redox activation of c-Jun protein and the cis-regulation of GATA-4 gene transcription. J Biol Chem. 2013;288:15745–59.

  29. 29.

    Schmelter M, Ateghang B, Helmig S, Wartenberg M, Sauer H. Embryonic stem cells utilize reactive oxygen species as transducers of mechanical strain-induced cardiovascular differentiation. FASEB J Off Publ Fed Am Soc Exp Biol. 2006;20:1182–4.

  30. 30.

    Li J, Stouffs M, Serrander L, Banfi B, Bettiol E, Charnay Y, Steger K, Krause KH, Jaconi ME. The NADPH oxidase NOX4 drives cardiac differentiation: role in regulating cardiac transcription factors and MAP kinase activation. Mol Biol Cell. 2006;17:3978–88.

  31. 31.

    Sauer H, Rahimi G, Hescheler J, Wartenberg M. Role of reactive oxygen species and phosphatidylinositol 3-kinase in cardiomyocyte differentiation of embryonic stem cells. FEBS Lett. 2000;476:218–23.

  32. 32.

    Puceat M. Role of Rac-GTPase and reactive oxygen species in cardiac differentiation of stem cells. Antioxid Redox Signal. 2005;7:1435–9.

  33. 33.

    Takimoto E, Kass DA. Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension. 2007;49:241–8.

  34. 34.

    Purushothaman S, Renuka Nair R, Harikrishnan VS, Fernandez AC. Temporal relation of cardiac hypertrophy, oxidative stress, and fatty acid metabolism in spontaneously hypertensive rat. Mol Cell Biochem. 2011;351:59–64.

  35. 35.

    Nakamura K, Murakami M, Miura D, Yunoki K, Enko K, Tanaka M, Saito Y, Nishii N, Miyoshi T, Yoshida M, Oe H, Toh N, Nagase S, Kohno K, Morita H, Matsubara H, Kusano KF, Ohe T, Ito H. Beta-blockers and oxidative stress in patients with heart failure. Pharmaceuticals. 2011;4:1088–100.

  36. 36.

    Yao EH, Yu Y, Fukuda N. Oxidative stress on progenitor and stem cells in cardiovascular diseases. 2017. http://www.eurekaselect.com/55726/article.

  37. 37.

    Teng L, Bennett E, Cai C. Preconditioning c-Kit positive human cardiac stem cells with a nitric oxide donor enhances cell survival through activation of survival signaling pathways. J Biol Chem. 2016;291:9733–47.

  38. 38.

    Chen J-H, Ozanne SE, Hales CN. Methods of cellular senescence induction using oxidative stress. Methods Mol Biol. 2007;371:179–89.

  39. 39.

    Su Q, Li L, Liu Y-C, Zhou Y, Lu Y-G, Wen W-M. Effect of metoprolol on myocardial apoptosis and caspase-9 activation after coronary microembolization in rats. Exp Clin Cardiol. 2013;18:161–5.

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Acknowledgements

The study was supported by the Board of Research in Nuclear Sciences, Govt. of India. Ms. Sherin Saheera received an INSPIRE Fellowship from the Department of Science and Technology, Govt. of India. We are grateful to the director of the Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, for the facilities and permission to publish the findings.

Author contributions

Sherin Saheera: designed the study, performed the experiments, analyzed the data, and prepared the manuscript; Ajay Godwin Potnuri: designed and performed the animal experiments; Renuka Nair: conceived the study and edited the manuscript.

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Conflict of interest

The authors declare that they have no conflict of interest.

Correspondence to Renuka R Nair.

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