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01-05-2009 | ORIGINAL CONTRIBUTION

Effects of atorvastatin on calcium-regulating proteins: a possible mechanism to repair cardiac dysfunction in spontaneously hypertensive rats

Authors: Lei Yao, Guo-Ping Chen, Xian Lu, Liang-Rong Zheng, Yun Mou, Shen-Jiang Hu

Published in: Basic Research in Cardiology | Issue 3/2009

Abstract

Previous clinical and experimental studies have demonstrated that statins, the inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, can improve left ventricular function in damaged hearts. Also, the normal expression of Ca²⁺ regulatory proteins is critical for efficient myocardial function. However, it is still unclear whether the beneficial effect of statins on cardiac function is associated with alterations of Ca²⁺ regulatory proteins. In this study, we investigated the effect of atorvastatin on cardiac function in spontaneously hypertensive rats (SHRs), focusing in particular on its impact on the expression of sarcoplasmic reticulum Ca²⁺-adenosine triphosphatase (SERCA2a), phospholamban (PLB) and its phosphorylated form (phosphorylated PLB), all of which are Ca²⁺ regulatory proteins in myocardium. SHRs showed decreases in gene expression of SERCA2a and phosphorylated PLB, and reduction in SERCA activity in the left ventricular myocardium, as well as reduced cardiac function, compared to age-matched Wistar Kyoto rats (WKYs). Furthermore, we showed that in SHRs atorvastatin preserved cardiac dysfunction accompanied by positive alterations in calcium regulatory proteins, with up-regulation in expression of SERCA2a and phosphorylated PLB, and with improvement of SERCA activity. Thus, atorvastatin has positive effects on calcium regulatory proteins, which may be one of the mechanisms of the beneficial effect of statins on cardiac function in spontaneously hypertensive rats.

Arai M, Alpert NR, MacLennan DH, Barton P, Periasamy M (1993) Alterations in sarcoplasmic reticulum gene expression in human failure: a possible mechanism for alterations in systolic and diastolic properties of the failing myocardium. Circ Res 72:463–469PubMed

Bauersachs J, Hiss K, Fraccarollo D, Laufs U, Ruetten H (2006) Simvastatin improves left ventricular function after myocardial infarction in hypercholesterolemic rabbits by anti-inflammatory effects. Cardiovasc Res 72:438–446PubMedCrossRef

Black AE, Sinz MW, Hayes RN, Woolf TF (1998) Metabolism and excretion studies in mouse after single and multiple oral doses of the 3-hydroxy-3-methylgutaryl-coa reductase inhibitor atorvastatin. Drug Metab Dispos 26:755–763PubMed

Boknik P, Heinroth-Hoffmann I, Kirchhefer U, Knapp J, Linck B, Luss H, Muller T, Schmitz W, Brodde O, Neumann J (2001) Enhanced protein phosphorylation in hypertensive hypertrophy. Cardiovasc Res 51:717–728PubMedCrossRef

Braz JC, Gregory K, Pathak A, Zhao W, Sahin B, Klevitsky R, Kimball TF, Lorenz JN, Nairn AC, Liggett SB, Bodi I, Wang S, Schwartz A, Lakatta EG, DePaoli-Roach AA, Robbins J, Hewett TE, Bibb JA, Westfall MV, Kranias EG, Molkentin JD (2004) PKC-α regulates cardiac contractility and propensity toward heart failure. Nat Med 10:248–254PubMedCrossRef

Carr AN, Schmidt AG, Suzuki Y, del Monte F, Sato Y, Lanner C, Breeden K, Jing SL, Allen PB, Greengard P, Yatani A, Hoit BD, Grupp IL, Hajjar RJ, DePaoli-Roach AA, Kranias EG (2002) Type 1 phosphatase, a negative regulator of cardiac function. Moll Cell Biol 22:4124–4135CrossRef

Collins HL, Loka AM, Dicarlo SE (2004) Daily exercise-induced cardioprotection is associated with changes in calcium regulatory proteins in hypertensive rats. Am J Physiol Heart Circ Physiol 288:532–540CrossRef

Del Monte F, Williams E, Lebeche D, Schmidt U, Rosenzweig A, Gwathmey JK, Lewandowski ED, Hajjar RJ (2001) Improvement in survival and cardiac metabolism after gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase in a rat model of heart failure. Circulation 104:1424–1429PubMedCrossRef

Gupta RC, Mishra S, Rastogi S, Imai M, Habib O, Sabbah HN (2003) Cardiac SR-coupled PP1 activity and expression are increased and inhibitor 1 protein expression is decreased in failing hearts. Am J Physiol Heart Circ Physiol 285:H2373–H2381PubMed

10.

Haghighi K, Gregory KN, Kranias EG (2004) Sarcoplasmic reticulum Ca-ATPase-phospholamban interactions and dilated cardiomyopathy. Biochem Biophys Res Commun 322:1214–1222PubMedCrossRef

11.

Harris MB, Blackstone MA, Sood SG, Li C, Goolsby JM, Venema VJ, Kemp BE, Venema RC (2004) Acute activation and phosphorylation of endothelial nitric oxide synthase by HMG-CoA reductase inhibitors. Am J Physiol Heart Circ Physiol 287:H560–H566PubMedCrossRef

12.

Hasenfuss G, Pieske B (2002) Calcium cycling in congestive heart failure. J Mol Cell Cardiol 34:951–969PubMedCrossRef

13.

Hayashidani S, Tsutsui H, Shiomi T, Suematsu N, Kinugawa S, Ide T, Wen J, Takeshita A (2002) Fluvastatin, a 3-Hydroxy-3-Methylglutaryl coenzyme A reductase inhibitor, attenuate left ventricular remodeling and failure after experimental myocardial infarction. Circulation 105:868–873PubMedCrossRef

14.

Jones LR, Besch HR, Fleming JW, McConnaughey MM, Watanabe AM (1979) Separation of vesicles of cardiac sarcolemma from vesicles of cardiac sarcoplasmic reticulum. Comparative biochemical analysis of component activities. J Biol Chem 254:530–539PubMed

15.

Kokubo M, Uemura A, Matsubara T, Murohara T (2005) Noninvasive evaluation of the time course of change in cardiac function in spontaneously hypertensive rats by echocardiography. Hypertens Res 28:601–609PubMedCrossRef

16.

Kubo H, Margulies KB, Piacentino V, Gaughan JP, Houser SR (2001) Patients with end-stage congestive heart failure treated with β-adrenergic receptor antagonists have improved ventricular myocyte calcium regulatory protein abundance. Circulation 104:1012–1018PubMedCrossRef

17.

Kubota Y, Umegaki K, Kagota S, Tanaka N, Nakamura K, Kunitomo M, Shinozuka K (2006) Evaluation of blood pressure measured by tail-cuff methods (without heating) in spontaneously hypertensive rats. Biol Pharm Bull 29:1756–1758PubMedCrossRef

18.

Lamberts RR, Vaessen RJ, Westerhof N, Stienen GJ (2007) Right ventricular hypertrophy causes impairment of left ventricular diastolic function in the rat. Basic Res Cardiol 102(1):19–27PubMedCrossRef

19.

Landmesser U, Engberding N, Bahlmann FH, Schaefer A, Wiencke A, Heineke A, Spiekermann S, Hilfiker-Kleiner D, Templin C, Kotlarz D, Mueller M, Fuchs M, Hornig B, Haller H, Drexler H (2004) Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. Circulation 110:1933–1939PubMedCrossRef

20.

Maack C, O’Rourke B (2007) Excitation-contraction coupling and mitochondrial energetics. Basic Res Cardiol 102(5):369–392PubMedCrossRef

21.

Maier LS, Wahl-Schott C, Horn W, Weichert S, Pagel C, Wagner S, Dybkova N, Müller OJ, Nabauer M, Franz WM, Pieske B (2005) Increased SR Ca²⁺ cycling contributes to improved contractile performance in SERCA2a-overexpressing transgenic rats. Cardiovasc Res 67:636–646PubMedCrossRef

22.

Meyer M, Schillinger W, Pieske B, Holubarsch C, Heilmann C, Posival H, Kuwajima G, Mikoshiba K, Just H, Hasenfuss G (1995) Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation 92:778–784PubMed

23.

Minamisawa S, Hoshijima M, Chu G, Ward CA, Frank K, Gu Y, Martone ME, Wang Y, Ross J Jr, Kranias EG, Giles WR, Chien KR (1999). Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy. Cell 99:313–322PubMedCrossRef

24.

Mousa SA, Goncharuk O, Miller D (2007) Recent advances of TNF-alpha antagonists in rheumatoid arthritis and chronic heart failure. Expert Opin Biol Ther 7:617–625PubMedCrossRef

25.

Nef HM, Mollmann H, Skwara W, Bolck B, Schwinger RH, Hamm Ch, Kostin S, Schaper J, Elsasser A (2006) Reduced sarcoplasmic reticulum Ca²⁺-ATPase activity and dephosphorylated phospholamban contribute to contractile dysfunction in human hibernating myocardium. Mol Cell Biochem 282:53–63PubMedCrossRef

26.

Node K, Fujita M, Kitakaze M, Hori M, Liao JK (2003) Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation 108:839–843PubMedCrossRef

27.

Porter MJ, Heidkamp MC, Scully BT, Patel N, Martin JL, Samarel AM (2003) Isoenzyme-selective regulation of SERCA2 gene expression by protein kinase C in neonatal rat ventricular myocytes. Am J Physiol Cell Physiol 285:C39–C47PubMed

28.

Rejane P, Christophe B, Olicier B et al (2006) Acute antiinflammatory properties of statins involve peroxisome proliferator-activated receptor-α via inhibition of the protein kinase C signaling pathway. Circ Res 98:361–369CrossRef

29.

Renna BF, Kubo H, MacDonnell SM, Crabbe DL, Reger PO, Houser SR, Libonati JR (2006) Enhanced acidotic myocardial Ca²⁺ responsiveness with training in hypertension. Med Sci Sport Exer 38:847–855CrossRef

30.

Sande JB, Sjaastad I, Hoen IB, Bøkenes J, Tønnessen T, Holt E, Lunde PK, Christensen G (2002) Reduced level of serine (16) phosphorylated phospholamban in the failing rat myocardium: a major contributor to reduced SERCA2 activity. Cardiovasc Res 53:382–391PubMedCrossRef

31.

Sevilla MA, Voces F, Carrón R, Guerrero EI, Ardanaz N, San Román L, Arévalo MA, Montero MJ (2004) Amlodipine decreases fibrosis and cardiac hypertrophy in spontaneously hypertensive rats: persistent effects after withdrawal. Life Sci 75:881–891PubMedCrossRef

32.

Simko F, Matuskova J, Luptak I, Krajcirovicova K, Kucharska J, Gvozdjakova A, Babal P, Pechanova O (2004) Effect of simvastatin on remodeling of the left ventricle and aorta in L-NAME-induced hypertension. Life Sci 74:1211–1214PubMedCrossRef

33.

Sola S, Mir MQ, Lerakis S, Tandon N, Khan BV (2006) Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure. J Am Coll Cardiol 47:332–337PubMedCrossRef

34.

Sun YL, Hu SJ, Wang LH, Hu Y, Zhou JY (2005) Effect of β-blockers on cardiac function and calcium handling protein in postinfarction heart failure rats. Chest 128:1812–1821PubMedCrossRef

35.

Tanaka K, Honda M, Takabatake T (2004) Anti-apoptotic effect of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, on cardiac myocytes through protein kinase C activation. Clin Exp Pharmacol Physiol 31:360–364PubMedCrossRef

36.

Weber T, Neumann J, Meissner A, Grosse Hartlage M, Van Aken H, Schmitz W, Boknik P (2006) Reduced serine-16 and threonine-17 phospholamban phosphorylation in stunning of conscious dogs: no evidenced for any involvement of protein kinase A or protein phosphatases. Basic Res Cardiol 101:253–260PubMedCrossRef

37.

Wojnicz R, Wilczek K, Nowalany-Kozielska E, Szygula-Jurkiewicz B, Nowak J, Poloński L, Dyrbus K, Badziński A, Mercik G, Zembala M, Wodniecki J, Rozek MM (2006) Usefulness of atorvastatin in patients with heart failure due to inflammatory dilated cardiomyopathy and elevated cholesterol levels. Am J Cardiol 97:899–904PubMedCrossRef

38.

Yasunari K, Maeda K, Minami M, Yoshikawa J (2001) HMG-CoA reductase inhibitors prevent migration of human coronary smooth muscle cells through suppression of increase in oxidative stress. Arterioscler Thromb Vasc Biol 21:937–942PubMed

39.

Yoshida J, Yamamoto K, Mano T, Sakata Y, Nishikawa N, Nishio M, Ohtani T, Miwa T, Hori M, Masuyama T (2004) AT1 receptor blocker added to ACE inhibitor provides benefits at advanced stage of hypertensive diastolic heart failure. Hypertension 43:686–691PubMedCrossRef

40.

Zheng X, Hu SJ (2005) Effects of simvastatin on cardiac performance and expression of sarcoplasmic reticular calcium regulatory proteins in rat heart. Acta Pharmacol Sin 26:696–704PubMedCrossRef

Title: Effects of atorvastatin on calcium-regulating proteins: a possible mechanism to repair cardiac dysfunction in spontaneously hypertensive rats
Authors: Lei Yao
Guo-Ping Chen
Xian Lu
Liang-Rong Zheng
Yun Mou
Shen-Jiang Hu
Publication date: 01-05-2009
Publisher: Steinkopff-Verlag
Published in: Basic Research in Cardiology / Issue 3/2009
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-008-0751-y

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Springer Medicine

Effects of atorvastatin on calcium-regulating proteins: a possible mechanism to repair cardiac dysfunction in spontaneously hypertensive rats

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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