Pitavastatin-attenuated cardiac dysfunction in mice with dilated cardiomyopathy via regulation of myocardial calcium handling proteins

Hu, Wei; Jiang, Wen-Bing

doi:10.2478/acph-2014-0004

Abstract

C57BL/6 mice with dilated cardiomyopathy (DCM) were randomly divided to receive placebo or pitavastatin at a dose of 1 or 3 mg kg^-1d^-1. After 8 weeks treatment, mice with dilated cardiomyopathy developed serious cardiac dysfunction characterized by significantly enhanced left ventricular end-diastolic diameter (LVIDd), decreased left ventricular ejection fraction (LVEF) as well as left ventricular short axis fractional shortening (LVFS), accompanied with enlarged cardiomyocytes, and increased plasma levels of N-terminal pro-B type natriuretic peptide (NT-proBNP) and plasma angiotensin II (AngII) concentration. Moreover, myocardium sarcoplasmic reticulum Ca²⁺ pump (SERCA-2) activity was decreased. The ratio of phosphorylated phospholamban (PLB) to total PLB decreased significantly with the down-regulation of SERCA- -2a and ryanodine receptor (RyR2) expression. Pitavastatin was found to ameliorate the cardiac dysfunction in mice with dilated cardiomyopathy by reversing the changes in the ratios of phosphorylated PLB to total PLB, SERCA-2a and RyR2 via reducing the plasma AngII concentration and the expressions of myocardium angiotensin II type 1 receptor (AT1R) and protein kinase C (PKC)b2. The possible underlying mechanism might be the regulation of myocardial AT₁R-PKCb2-Ca²⁺ handling proteins.

References

1. A. Bielecka-Dabrowa, D. P. Mikhailidis, S. Hannam, W. S. Aronow, J. Rysz and M. Banach, Statins and dilated cardiomyopathy: do we have enough data, Expert Opin. Investig. Drugs 20 (2011) 315-323; DOI: 10.1517/13543784.2011.550570.10.1517/13543784.2011.55057021210757
Search in Google Scholar
2. M. Touvron, B. Escoubet, M. Mericskay, A. Angelini, L. Lamotte, M. P. Santini, N. Rosenthal, D. Daegelen, D. Tuil and J. F. Decaux, Locally expressed IGF1 propeptide improves mouse heart function in induced dilated cardiomyopathy by blocking myocardial fibrosis and SRF-dependent CTGF induction, Dis. Model. Mech. 5 (2012) 481-491; DOI: 10.1242/dmm.009456.10.1242/dmm.009456338071122563064
Search in Google Scholar
3. L. Werner, V. Deutsch, I. Barshack, H. Miller, G. Keren and J. George, Transfer of endothelial progenitor cells improves myocardial performance in rats with dilated cardiomyopathy induced following experimental myocarditis, J. Mol. Cell. Cardiol. 39 (2005) 691-697; DOI: 10.1016/ j.yjmcc.2005.06.015.10.1016/j.yjmcc.2005.06.01516125196
Search in Google Scholar
4. E. Hoshikawa, Y. Matsumura, T. Kubo, M. Okawa, N. Yamasaki, H. Kitaoka, T. Furuno, J. Takata and Y. L. Doi, Effect of left ventricular reverse remodeling on long-term prognosis after therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and beta blockers in patients with idiopathic dilated cardiomyopathy, Am. J. Cardiol. 107 (2011) 1065-1070; DOI: 10.1016/j.amjcard.2010.11.033.10.1016/j.amjcard.2010.11.03321296328
Search in Google Scholar
5. W. B. Zhang, Du QJ, H. Li, A. J. Sun, Z. H. Qiu, C. N.Wu, G. Zhao, H. Gong, K. Hu, Y. Z. Zou and J. B. Ge, The therapeutic effect of rosuvastatin on cardiac remodelling from hypertrophy to fibrosis during the end-stage hypertension in rats, J. Cell. Mol. Med. 16 (2012) 2227-2237; DOI: 10.1111/j.1582-4934.2012.01536.x.10.1111/j.1582-4934.2012.01536.x382299222288611
Search in Google Scholar
6. J. J. Goldberger, H. Subacius, A. Schaechter, A. Howard, R. Berger, A. Shalaby, J. Levine and A. H. Kadish, Effects of statin therapy on arrhythmic events and survival in patients with nonischemic dilated cardiomyopathy, J. Am. Coll. Cardiol. 48 (2006) 1228-1233; DOI: 10.1016/j.jacc. 2006.05.053.
Search in Google Scholar
7. F. Tehrani, R. Morrissey, A. Phan, C. Chien and E. R. Schwarz, Statin therapy in patients with diastolic heart failure, Clin. Cardiol. 33 (2010) E1-E5; DOI: 10.1002/clc.20615.10.1002/clc.20615665329520127896
Search in Google Scholar
8. S. K. Thambidorai, A. R. Deshmukh, R. W. Walters, P. D. Turner,M. S.Monaghan, A. N. Mooss, C. B. Hunter, D. J. Esterbrooks and S. M. Mohiuddin, Impact of statin use on heart failure mortality, Int. J. Cardiol. 147 (2011) 438-443; DOI: 10.1016/j.ijcard.2010.08.016.10.1016/j.ijcard.2010.08.01620971517
Search in Google Scholar
9. T. Sakamoto, S. Kojima, H. Ogawa, H. Shimomura, K. Kimura, Y. Ogata, N. Sakaino and A. Kitagawa, Effects of early statin treatment on symptomatic heart failure and ischemic events after acute myocardial infarction in Japanese, Am. J. Cardiol. 97 (2006) 1165-1171; DOI: 10.1016/ j.amjcard.2005.11.031.10.1016/j.amjcard.2005.11.03116616020
Search in Google Scholar
10. R. Jarai, C. Kaun, T. W. Weiss, W. S. Speidl, K. Rychli, G. Maurer, K. Huber and J. Wojta, Human cardiac fibroblasts express B-type natriuretic peptide: fluvastatin ameliorates its up-regulation by interleukin-1 alpha, tumour necrosis factor-alpha and transforming growth factor-beta, J. Cell. Mol. Med. 13 (2009) 4415-4421; DOI: 10.1111/j.1582-4934.2009.00704.x.10.1111/j.1582-4934.2009.00704.x451505719228263
Search in Google Scholar
11. P. E. Lazzerini, P. L. Capecchi and F. Laghi-Pasini, Statins as a new therapeutic perspective in myocarditis and postmyocarditis dilated cardiomyopathy, Cardiovasc. Drugs Ther. 27 (2013) 365-369; DOI: 10.1007/s10557-013-6475-8.10.1007/s10557-013-6475-823832693
Search in Google Scholar
12. Y. Kameda, H. Hasegawa, A. Kubota, H. Tadokoro, Y. Kobayashi, I. Komuro and H. Takano, Effects of pitavastatin on pressure overload-induced heart failure in mice, Circ. J. 76 (2012) 1159-1168; DOI: 10.1253/circj.CJ-11-1114.10.1253/circj.CJ-11-1114
Search in Google Scholar
13. T. Aoyagi, F. Nakamura, T. Tomaru and T. Toyo-Oka, Beneficial effects of pitavastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, on cardiac function in ischemic and nonischemic heart failure, Int. Heart J. 49 (2008) 49-58; DOI: 10.1536/ihj.49.49.10.1536/ihj.49.4918360064
Search in Google Scholar
14. H. Takano, H. Mizuma, Y. Kuwabara, Y. Sato, S. Shindo, N. Kotooka, D. Fujimatsu, Y. Kobayashi, T. Inoue, K. Node and I. Komuro, Effects of pitavastatin in Japanese patients with chronic heart failure: the pitavastatin heart failure study (PEARL study), Circ. J. 77 (2013) 917-925; DOI: 10.1253/circj.CJ-12-1062.10.1253/circj.CJ-12-106223502990
Search in Google Scholar
15. J. Kjekshus, E. Apetrei, V. Barrios, M. Bohm, J. G. Cleland, J. H. Cornel, P. Dunselman, C. Fonseca, A. Goudev, P. Grande, L. Gullestad, A. Hjalmarson, J. Hradec, A. Janosi, G. Kamensky, M. Komajda, J. Korewicki, T. Kuusi, F. Mach, V. Mareev, J. J. McMurray, N. Ranjith, M. Schaufelberger, J. Vanhaecke, D. J. van Veldhuisen, F. Waagstein, H. Wedel and J. Wikstrand, Rosuvastatin in older patients with systolic heart failure, N. Engl. J. Med. 357 (2007) 2248-2261; DOI: 10.1056/NEJMoa0706201.10.1056/NEJMoa070620117984166
Search in Google Scholar
16. S. A. Chang, Y. J. Kim, H. W. Lee, D. H. Kim, H. K. Kim, H. J. Chang, D. W. Sohn, B. H. Oh and Y. B. Park, Effect of rosuvastatin on cardiac remodeling, function, and progression to heart failure in hypertensive heart with established left ventricular hypertrophy, Hypertension 54 (2009) 591-597; DOI: 10.1161/HYPERTENSIONAHA.109.131243.10.1161/HYPERTENSIONAHA.109.13124319564547
Search in Google Scholar
17. K. Krishnamurthy, R. Kanagasabai, L. J. Druhan and G. Ilangovan, Heat shock protein 25-enriched plasma transfusion preconditions the heart against doxorubicin-induced dilated cardiomyopathy in mice, J. Pharmacol. Exp. Ther. 341 (2012) 829-839; DOI: 10.1124/jpet.112.192245.10.1124/jpet.112.192245336288022438470
Search in Google Scholar
18. F.N.Gava, E. Zacche, E.M.Ortiz, T. Champion,M. B. Bandarra, R. O. Vasconcelos, J. C. Barbosa and A. A. Camacho, Doxorubicin induced dilated cardiomyopathy in a rabbit model: an update, Res. Vet. Sci. 94 (2013) 115-121; DOI: 10.1016/j.rvsc.2012.07.027.10.1016/j.rvsc.2012.07.02722902286
Search in Google Scholar
19. K. Suzuki, B. Murtuza, N. Suzuki, R. T. Smolenski andM. H. Yacoub, Intracoronary infusion of skeletal myoblasts improves cardiac function in doxorubicin-induced heart failure, Circulation 104 (2001) 1213-1217; DOI: 10.1161/hc37t1.094929.10.1161/hc37t1.09492911568058
Search in Google Scholar
20. M. Sano, T. Minamino, H. Toko, H. Miyauchi, M. Orimo, Y. Qin, H. Akazawa, K. Tateno, Y. Kayama, M. Harada, I. Shimizu, T. Asahara, H. Hamada, S. Tomita, J. D. Molkentin, Y. Zou and I. Komuro, p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload, Nature 446 (2007) 444-448; DOI: 10.1038/nature05602.10.1038/nature0560217334357
Search in Google Scholar
21. Y. C. Liao, Y. C. Hsieh, C. Y. Hung, J. L. Huang, C. H. Lin, K. Y.Wang and T. J. Wu, Statin therapy reduces the risk of ventricular arrhythmias, sudden cardiac death, and mortality in heart failure patients: A nationwide population-based cohort study, Int. J. Cardiol. 2013, in press; DOI: 10.1016/j.ijcard.2013.07.036.10.1016/j.ijcard.2013.07.03623890884
Search in Google Scholar
22. A. Tidholm, J. Haggstrom and K. Hansson, Effects of dilated cardiomyopathy on the renin- -angiotensin-aldosterone system, atrial natriuretic peptide activity, and thyroid hormone concentrations in dogs, Am. J. Vet. Res. 62 (2001) 961-967; DOI: 10.2460/ajvr.2001.62.961.10.2460/ajvr.2001.62.96111400857
Search in Google Scholar
23. X. Y. Tian, W. T. Wong, A. Xu, Z. Y. Chen, Y. Lu, L. M. Liu, V. W. Lee, C.W. Lau, X. Yao and Y. Huang, Rosuvastatin improves endothelial function in db/db mice: role of angiotensin II type 1 receptors and oxidative stress, Br. J. Pharmacol. 164 (2011) 598-606; DOI: 10.1111/j.1476-5381. 2011.01416.x.
Search in Google Scholar
24. H. Toba, T. Mitani, T. Takahashi, N. Imai, R. Serizawa, J. Wang, M. Kobara and T. Nakata, Inhibition of the renal renin-angiotensin system and renoprotection by pitavastatin in type1 diabetes, Clin. Exp. Pharmacol. Physiol. 37 (2010) 1064-1070; DOI: 10.1111/j.1440-1681.2010.05436.x.10.1111/j.1440-1681.2010.05436.x20678154
Search in Google Scholar
25. G. Nickenig and D. G. Harrison, The AT(1)-type angiotensin receptor in oxidative stress and atherogenesis: part I: oxidative stress and atherogenesis, Circulation 105 (2002) 393-396; DOI: 10.1161/hc0302.102618.10.1161/hc0302.10261811804998
Search in Google Scholar
26. S. L. Belmonte, B. C. Blaxall, PKC-ing is believing: targeting protein kinase C in heart failure, Circ. Res. 109 (2011) 1320-1322; DOI: 10.1161/CIRCRESAHA.111.259358.10.1161/CIRCRESAHA.111.25935822158646
Search in Google Scholar
27. A. L. Beck, M. E. Otto, L. B. D’Avila, F. M. Netto, M. K. Armendaris and A. C. Sposito, Diastolic function parameters are improved by the addition of simvastatin to enalapril-based treatment in hypertensive individuals, Atherosclerosis 222 (2012) 444-448; DOI: 10.1016/j.atherosclerosis. 2012.03.030.
Search in Google Scholar
28. X. Zhou, D. Shang, T. Zhang, L. Li, T. Zhou and W. Lu, Modeling of angiotensin II-angiotensin-( 1 ) counterbalance in disease progression in spontaneously hypertensive rats treated with/ without perindopril, Pharmacol. Res. 66 (2012) 177-184; DOI: 10.1016/j.phrs.2012.04.001.10.1016/j.phrs.2012.04.00122513176
Search in Google Scholar
29. M. J. Crespo, N. Cruz, P. I. Altieri and N. Escobales, Enalapril and losartan are more effective than carvedilol in preventing dilated cardiomyopathy in the Syrian cardiomyopathic hamster, J. Cardiovasc. Pharmacol. Ther. 13 (2008) 199-206; DOI: 10.1177/1074248408320006.10.1177/107424840832000618593848
Search in Google Scholar
30. M. R. O’Grady, M. L. O’Sullivan, S. L. Minors and R. Horne, Efficacy of benazepril hydrochloride to delay the progression of occult dilated cardiomyopathy in Doberman Pinschers, J. Vet. Intern. Med. 23 (2009) 977-983; DOI: 10.1111/j.1939-1676.2009.0346.x.10.1111/j.1939-1676.2009.0346.x19572914
Search in Google Scholar
31. G. Pela, P. Pattoneri, M. Passera, G. Tirabassi, C. Reverberi, A. Montanari and T. Gherli, Long- -term effects of perindopril on left ventricular structure and function in patients with stable coronary artery disease: a conventional and Doppler tissue echocardiographic pilot study, J. Cardiovasc. Med. (Hagerstown) 10 (2009) 781-786; DOI: 10.2459/JCM.0b013e32832dbfe9. 10.2459/JCM.0b013e32832dbfe919525856
Search in Google Scholar

Pitavastatin-attenuated cardiac dysfunction in mice with dilated cardiomyopathy via regulation of myocardial calcium handling proteins

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