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Resveratrol and 1,25-dihydroxyvitamin D co-administration protects the heart against d-galactose-induced aging in rats: evaluation of serum and cardiac levels of klotho

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Abstract

The current study investigates the cooperative cardioprotective effect of calcitriol (active form of vitamin D) combined with resveratrol in a rat model of d-galactose (d.gal)-induced aging. Male Wistar rats received resveratrol (d.gal + Res), calcitriol (d.gal + Cal), or a combination of them (d.gal + Res + Cal). Intact animals served as control (Ctl). Blood pressure (BP) was recorded by cannulation of the left carotid artery. Fibrosis and cell size were assessed by Masson’s trichrome and hematoxylin–eosin staining, respectively. Cardiac and serum level of antiaging protein, klotho, was measured by ELISA assay method. Gene expression was evaluated by real-time RT-PCR. Biochemical tests were performed according to the standardized method. In d.gal + Res + Cal group, BP, heart weight-to-body weight ratio, and cardiomyocytes size decreased significantly compared with d-gal group. The cardiac transcription levels of catalase and superoxide dismutase 1 and 2 were upregulated in d.gal + Res + Cal compared to the d.gal group (P < 0.001, P < 0.05, P < 0.05, respectively). Increased level of malondialdehyde was observed in d.gal group (P < 0.01 vs. Ctl) which was normalized partially in d.gal + Res + Cal group (P < 0.05). Catalase and superoxide dismutase activity also increased in d.gal + Res + Cal group (P < 0.01 vs. d.gal). Cardiac Klotho, as the antiaging protein, remained unchanged at mRNA and protein levels among the experimental groups. The serum level of Klotho did not change significantly in d.gal group; however, in d.gal + Res + Cal group, serum klotho concentration was increased (P < 0.05 vs. d.gal). It could be concluded that co-administration of resveratrol and vitamin D protects the heart against aging-induced damage by the modulation of hemodynamic parameters and antioxidant status of the heart. Furthermore, increased serum level of klotho could be a novel mechanism for antiaging effects of resveratrol and vitamin D.

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References

  1. Steenman M, Lande G (2017) Cardiac aging and heart disease in humans. Biophys Rev 9:131–137. https://doi.org/10.1007/s12551-017-0255-9

    Article  PubMed  PubMed Central  Google Scholar 

  2. North BJ, Sinclair DA (2012) The intersection between aging and cardiovascular disease. Circ Res 110:1097–1108. https://doi.org/10.1161/CIRCRESAHA.111.246876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chang YM, Chang HH, Lin HJ et al (2017) Inhibition of cardiac hypertrophy effects in d-galactose-induced senescent hearts by alpinate oxyphyllae fructus treatment. Evid Based Complement Alternat Med 2017:2624384. https://doi.org/10.1155/2017/2624384

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wu W, Hou CL, Mu XP et al (2017) H2S donor NaHS changes the production of endogenous H2S and NO in d-galactose-induced accelerated ageing. Oxid Med Cell Longev 2017:5707830. https://doi.org/10.1155/2017/5707830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bo-Htay C, Palee S, Apaijai N et al (2018) Effects of d-galactose-induced ageing on the heart and its potential interventions. J Cell Mol Med 22:1392–1410. https://doi.org/10.1111/jcmm.13472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ding HY, Ma HX (2015) Significant roles of anti-aging protein klotho and fibroblast growth factor23 in cardiovascular disease. J Geriatr Cardiol 12:439–447. https://doi.org/10.11909/j.issn.1671-5411.2015.04.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dalton GD, Xie J, An SW et al (2017) New insights into the mechanism of action of soluble klotho. Front Endocrinol (Lausanne) 8:323. https://doi.org/10.3389/fendo.2017.00323

    Article  Google Scholar 

  8. Corsetti G, Pasini E, Scarabelli TM et al (2016) Decreased expression of Klotho in cardiac atria biopsy samples from patients at higher risk of atherosclerotic cardiovascular disease. J Geriatr Cardiol 13:701–711

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Xie J, Cha SK, An SW et al (2012) Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nat Commun 3:1238. https://doi.org/10.1038/ncomms2240

    Article  CAS  PubMed  Google Scholar 

  10. Navarro-González JF, Donate-Correa J, Muros de Fuentes M et al (2014) Reduced Klotho is associated with the presence and severity of coronary artery disease. Heart 100:34–40. https://doi.org/10.1136/heartjnl-2013-304746

    Article  PubMed  Google Scholar 

  11. Semba RD, Cappola AR, Sun K et al (2011) Plasma klotho and cardiovascular disease in adults. J Am Geriatr Soc 59:1596–1601. https://doi.org/10.1111/j.1532-5415.2011.03558.x

    Article  PubMed  PubMed Central  Google Scholar 

  12. Arking DE, Becker DM, Yanek LR et al (2003) KLOTHO allele status and the risk of early-onset occult coronary artery disease. Am J Hum Genet 72:1154–1161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nardin M, Verdoia M, Schaffer A et al (2016) Vitamin D status, diabetes mellitus and coronary artery disease in patients undergoing coronary angiography. Atherosclerosis 250:114–121. https://doi.org/10.1016/j.atherosclerosis.2016.05.019

    Article  CAS  PubMed  Google Scholar 

  14. Judd SE, Nanes MS, Ziegler TR et al (2008) Optimal vitamin D status attenuates the age-associated increase in systolic blood pressure in white Americans: results from the third National Health and Nutrition Examination Survey. Am J Clin Nutr 87:136–141

    Article  CAS  PubMed  Google Scholar 

  15. Liu LC, Voors AA, van Veldhuisen DJ et al (2011) Vitamin D status and outcomes in heart failure patients. Eur J Heart Fail 13:619–625. https://doi.org/10.1093/eurjhf/hfr032

    Article  CAS  PubMed  Google Scholar 

  16. Schleithoff SS, Zittermann A, Tenderich G et al (2006) Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 83:754–759

    Article  CAS  PubMed  Google Scholar 

  17. Witte KK, Byrom R, Gierula J et al (2016) Effects of vitamin D on cardiac function in patients with chronic HF: the VINDICATE study. J Am Coll Cardiol 67:2593–2603. https://doi.org/10.1016/j.jacc.2016.03.508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chekalina NI (2017) Resveratrol has a positive effect on parameters of central hemodynamics and myocardial ischemia in patients with stable coronary heart disease. Wiad Lek 70:286–291

    PubMed  Google Scholar 

  19. Gupta PK, DiPette DJ, Supowit SC (2014) Protective effect of resveratrol against pressure overload-induced heart failure. Food Sci Nutr 2:218–229. https://doi.org/10.1002/fsn3.92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Imamura H, Yamaguchi T, Nagayama D et al (2017) Resveratrol ameliorates arterial stiffness assessed by cardio-ankle vascular index in patients with type 2 diabetes mellitus. Int Heart J 58:577–583. https://doi.org/10.1536/ihj.16-373

    Article  CAS  PubMed  Google Scholar 

  21. Bhatt JK, Thomas S, Nanjan MJ (2012) Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr Res 32:537–541. https://doi.org/10.1016/j.nutres.2012.06.003

    Article  CAS  PubMed  Google Scholar 

  22. Magyar K, Halmosi R, Palfi A et al (2012) Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease. Clin Hemorheol Microcirc 50:179–187. https://doi.org/10.3233/CH-2011-1424

    Article  CAS  PubMed  Google Scholar 

  23. Militaru C, Donoiu I, Craciun A et al (2013) Oral resveratrol and calcium fructoborate supplementation in subjects with stable angina pectoris: effects on lipid profiles, inflammation markers, and quality of life. Nutrition 29:178–183. https://doi.org/10.1016/j.nut.2012.07.006

    Article  CAS  PubMed  Google Scholar 

  24. Hayes DP (2011) Resveratrol and vitamin D: significant potential interpretative problems arising from their mutual processes, interactions and effects. Med Hypotheses 77:765–772. https://doi.org/10.1016/j.mehy.2011.07.033

    Article  CAS  PubMed  Google Scholar 

  25. Dampf Stone A, Batie SF, Sabir MS et al (2015) Resveratrol potentiates vitamin D and nuclear receptor signaling. J Cell Biochem 116:1130–1143. https://doi.org/10.1002/jcb.25070

    Article  CAS  PubMed  Google Scholar 

  26. Uberti F, Morsanuto V, Aprile S et al (2017) Biological effects of combined resveratrol and vitamin D3 on ovarian tissue. J Ovarian Res 10:61. https://doi.org/10.1186/s13048-017-0357-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Safari F, Zarei F, Shekarforoush S et al (2015) Combined 1,25-dihydroxy-vitamin D and resveratrol: a novel therapeutic approach to ameliorate ischemia reperfusion-induced myocardial injury. Int J Vitam Nutr Res 85:174–184. https://doi.org/10.1024/0300-9831/a000236

    Article  CAS  PubMed  Google Scholar 

  28. Sharifi Klishadi M, Zarei F, Shekarforoush S et al (2014) Therapeutic effects of 1,25-dihydroxyvitamin D and losartan co-administration on myocardial ischemia-reperfusion injury in rats. Physiol Pharmacol 18:156–169

    Google Scholar 

  29. Beauchamp C, Fridovich I (1971) Superoxide dismutase: improved assays and an assay applicable to acrylamide gels. Anal Biochem 44:276–287

    Article  CAS  PubMed  Google Scholar 

  30. Cebe T, Yanar K, Atukeren P et al (2014) A comprehensive study of myocardial redox homeostasis in naturally and mimetically aged rats. Age (Dordr) 36:9728. https://doi.org/10.1007/s11357-014-9728-y

    Article  CAS  Google Scholar 

  31. Vaidya A, Forman JP (2012) Vitamin D and vascular disease: the current and future status of vitamin D therapy in hypertension and kidney disease. Curr Hypertens Rep 14:111–119. https://doi.org/10.1007/s11906-012-0248-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li YC, Kong J, Wei M et al (2002) 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 110:229–238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li X, Dai Y, Yan S et al (2016) Resveratrol lowers blood pressure in spontaneously hypertensive rats via calcium-dependent endothelial NO production. Clin Exp Hypertens 38:287–293. https://doi.org/10.3109/10641963.2015.1089882

    Article  CAS  PubMed  Google Scholar 

  34. Dolinsky VW, Soltys CL, Rogan KJ et al (2015) Resveratrol prevents pathological but not physiological cardiac hypertrophy. J Mol Med (Berl) 93:413–425. https://doi.org/10.1007/s00109-014-1220-8

    Article  CAS  Google Scholar 

  35. Chen S, Law CS, Grigsby CL et al (2011) Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy. Circulation 124:1838–1847. https://doi.org/10.1161/CIRCULATIONAHA.111.032680 (Epub 2011 Sep 26)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dorri Mashhadi F, Zavvar Reza J, Jamhiri M et al (2017) The effect of resveratrol on angiotensin II levels and the rate of transcription of its receptors in the rat cardiac hypertrophy model. J Physiol Sci 67:303–309. https://doi.org/10.1007/s12576-016-0465-0 (Epub 2016 Jun 21)

    Article  CAS  PubMed  Google Scholar 

  37. Farhangi MA, Nameni G, Hajiluian G et al (2017) Cardiac tissue oxidative stress and inflammation after vitamin D administrations in high fat- diet induced obese rats. BMC Cardiovasc Disord 17(1):161. https://doi.org/10.1186/s12872-017-0597-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mokni M, Hamlaoui S, Karkouch I et al (2013) Resveratrol provides cardioprotection after Ischemia/reperfusion injury via modulation of antioxidant enzyme activities. Iran J Pharm Res 12:867–875

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Yang B, Ma S, Wang YB et al (2016) Resveratrol exerts protective effects on anoxia/reoxygenation injury in cardiomyocytes via miR-34a/Sirt1 signaling pathway. Eur Rev Med Pharmacol Sci 20:2734–2741

    CAS  PubMed  Google Scholar 

  40. Gallagher JC (2013) Vitamin D and aging. Endocrinol Metab Clin N Am 42:319–332. https://doi.org/10.1016/j.ecl.2013.02.004

    Article  Google Scholar 

  41. Meehan M, Penckofer S (2014) The role of vitamin D in the aging adult. J Aging Gerontol 2:60–71

    Article  PubMed  PubMed Central  Google Scholar 

  42. Tanaka S, Fujita S, Kizawa S et al (2016) Association between FGF23, α-klotho, and cardiac abnormalities among patients with various chronic kidney disease stages. PLoS One 11:e0156860. https://doi.org/10.1371/journal.pone.0156860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Arking DE, Atzmon G, Arking A et al (2005) Association between a functional variant of the Klotho gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ Res 96:412–418

    Article  CAS  PubMed  Google Scholar 

  44. Wang Y, Kuro-o M, Sun Z (2012) Klotho gene delivery suppresses Nox2 expression and attenuates oxidative stress in rat aortic smooth muscle cells via the cAMP-PKA pathway. Aging Cell 11:410–417. https://doi.org/10.1111/j.1474-9726.2012.00796.x

    Article  CAS  PubMed  Google Scholar 

  45. Lau WL, Leaf EM, Hu MC et al (2012) Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. Kidney Int 82:1261–1270. https://doi.org/10.1038/ki.2012.322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tsujikawa H, Kurotaki Y, Fujimori T et al (2003) Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocrinol 17:2393–2403

    Article  CAS  PubMed  Google Scholar 

  47. Forster RE, Jurutka PW, Hsieh JC et al (2011) Vitamin D receptor controls expression of the anti-aging klotho gene in mouse and human renal cells. Biochem Biophys Res Commun 414:557–562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hsu SC, Huang SM, Chen A et al (2014) Resveratrol increases anti-aging Klotho gene expression via the activating transcription factor 3/c-Jun complex-mediated signaling pathway. Int J Biochem Cell Biol 53:361–371. https://doi.org/10.1016/j.biocel.2014.06.002

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This article was extracted from a Master’s thesis in Elderly health by the author Ali Dehghani, and was supported by Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

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Authors and Affiliations

  1. Department of Elderly Health, Faculty of Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Ali Dehghani

  2. Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Zeynab Hafizibarjin, Razieh Najjari & Fatemeh Safari

  3. Faculty of Paramedicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Fatemeh Kaseb

  4. Biotechnology Research Center, International Campus, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Fatemeh Safari

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  1. Ali Dehghani
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  2. Zeynab Hafizibarjin
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Correspondence to Fatemeh Safari.

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All of the experiments were performed according to Animal Ethics Committee of Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

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Dehghani, A., Hafizibarjin, Z., Najjari, R. et al. Resveratrol and 1,25-dihydroxyvitamin D co-administration protects the heart against d-galactose-induced aging in rats: evaluation of serum and cardiac levels of klotho. Aging Clin Exp Res 31, 1195–1205 (2019). https://doi.org/10.1007/s40520-018-1075-x

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