Abstract
Aim:
To investigate the effect of simvastatin on the cardiac contractile function and the alteration of gene and protein expression of the sarcoplasmic calcium regulatory proteins, including sarcoplasmic reticulum Ca2+-ATPase (SERCA), phospholamban (PLB), and ryanodine receptor 2 (RyR2) in rat hearts.
Methods:
Langendorff-perfused rat hearts were subjected to 60-min perfusion with different concentrations of simvastatin (1, 3, 10, 30, or 100 μmol/L), and the parameters of cardiac function such as left ventricular developed pressure (LVDP), +dp/dtmax, and -dp/dtmax were determined. The cultured neonatal rat ventricular cardiomyocytes were incubated with simvastatin (1, 3, 10, 30, and 100 μmol/L) for 1 h or 24 h. The levels of SERCA, PLB, and RyR2 expression were measured by reverse transcription-polymerase chain reaction and Western blot. Cytotoxic effect of simvastatin on ventricular cardiomyocytes was assessed by the MTT colorimetric assay.
Results:
LVDP, +dp/dtmax, and -dp/dtmax of hearts were increased significantly after treatment with simvastatin 3, 10, and 30 μmol/L. In simvastatin-treated isolated hearts, the levels of mRNA expression of SERCA and RyR2 were elevated compared with the control (P<0.05), while the mRNA expression of PLB did not change. After the cultured neonatal rat ventricular cardiomyocytes were incubated with 3, 10, 30, and 100 μmol/L simvastatin for 1 h, SERCA and RyR2 mRNA expressions of cardiomyocytes rose, but there was no alteration in protein expressions. However, with the elongation of simvastatin treatment to 24 h, the protein expression of SERCA and RyR2 were also elevated. Additionally, simvastatin (1-30 μmol/L) had no influence on cell viability of cultured cardiac myocytes, but simvastatin 100 μmol/L inhibited the cell viability.
Conclusion:
Simvastatin improved cardiac performance accompanied by the elevation of SERCA and RyR2 gene and protein expression.
Similar content being viewed by others
Article PDF
References
The Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–9.
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20, 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7–22.
Escobales N, Castro M, Altieri PI, Sanabria P . Simvastatin releases Ca2+ from a thapsigargin-sensitive pool and inhibits InsP3–dependent Ca2+ mobilization in vascular smooth muscle cells. J Cardiovasc Pharmacol 1996; 27: 383–91.
Alvarez de Sotomayor M, Andriantsitohaina R . Simvastatin and Ca2+ signaling in endothelial cells: involvement of Rho protein. Biochem Biophys Res Commun 2001; 280: 486–90.
Nakahara K, Yada T, Kuriyama M, Osame M . Cytosolic Ca2+ increase and cell damage in L6 rat myoblasts by HMG-CoA reductase inhibitors. Biochem Biophys Res Commun 1994; 202: 1579–8.
Bastiaanse EM, Atsma DE, Kuijpers MM, Van der Laarse A . Simvastatin-sodium delays cell death of anoxic cardiomyocytes by inhibition of the Na+/Ca2+ exchanger. FEBS Lett 1994; 343: 151–4.
Tesfamariam B, Frohlich BH, Gregg RE . Differential effects of pravastatin, simvastatin, and atorvastatin on Ca2+ release and vascular reactivity. J Cardiovasc Pharmacol 1999; 34: 95–101.
Alvarez de Sotomayor M, Perez-Guerrero C, Herrera MD, Marhuenda E . Effect of simvastatin on vascular smooth muscle responsiveness: involvement of Ca2+ homeostasis. Eur J Pharmacol 2001; 415: 217–24.
Yokoyama K, Ishibashi T, Ohkawara H, Kimura J, Matsuoka I, Sakamoto T . HMG-CoA reductase inhibitors suppress intracellular calcium mobilization and membrane current induced by lysophosphatidylcholine in endothelial cells. Circulation 2002; 105: 962–7.
Hill BJ, Dixon JL, Sturek M . Effect of atorvastatin on intracellular calcium uptake in coronary smooth muscle cells from diabetic pigs fed an atherogenic diet. Atherosclerosis 2001; 159: 117–24.
Llorente-Cortes V, Martinez-Gonzalez J, Badimon L . Differential cholesteryl ester accumulation in two human vascular smooth muscle cell subpopulations exposed to aggregated LDL: effect of PDGF-stimulation and HMG-CoA reductase inhibition. Atherosclerosis 1999; 144: 335–42.
Kurosaki K, Ikeda U, Maeda Y, Shimpo M, Ueno S, Shimada K . Effects of vesnarinone on nitric oxide synthesis in rat cardiac myocytes. Cardiovasc Res 1998; 38: 192–7.
Zhong Y, Ahmed S, Grupp IL, Matlib MA . Altered SR protein expression associated with contractile dysfunction in diabetic rat hearts. Am J Physiol Heart Circ Physiol 2001; 281: H1137–47.
Kwak BR, van Kempen MJ, Theveniau-Ruissy M, Gros DB, Jongsma HJ . Connexin expression in cultured neonatal rat myocytes reflects the pattern of the intact ventricle. Cardiovasc Res 1999; 44: 370–80.
Huang YT, Chueh SC, Teng CM, Guh JH . Investigation of ouabain-induced anticancer effect in human androgen-independent prostate cancer PC-3 cells. Biochem Pharmacol 2004; 67: 727–33.
Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA . Stroke protection by 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci USA 1998; 95: 8880–5.
Lefer AM, Campbell B, Shin YK, Scalia R, Hayward R, Lefer DJ . Simvastatin preserves the ischemic-reperfused myocardium in normocholesterolemic rat hearts. Circulation 1999; 100: 178–84.
Wagner AH, Kohler T, Ruckschloss U, Just I, Hecker M . Improvement of nitric oxide-dependent vasodilation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol 2000; 20: 61–9.
Bourcier T, Libby P . HMG-CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells. Arterioscler Thromb Vasc Biol 2000; 20: 556–62.
Di Napoli P, Antonio Taccardi A, Grilli A, Spina R, Felaco M, Barsotti A . Simvastatin reduces reperfusion injury by modulating nitric oxide synthase expression: an ex vivo study in isolated working rat hearts. Cardiovasc Res 2001; 51: 283–93.
Jones SP, Trocha SD, Lefer DJ . Pretreatment with Simvastatin attenuates myocardial dysfunction after ischemia and chronic reperfusion. Arterioscler Thromb Vasc Biol 2001; 21: 2059–64.
Wassmann S, Laufs U, Baumer AT, Muller K, Ahlbory K, Linz W . HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species. Hypertension 2001; 37: 1450–7.
Satoh K, Ichihara K . Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischemic rat hearts. Eur J Pharmacol 1995; 292: 271–5.
Arai M, Otsu K, MacLennan DH, Alpert NR, Periasamy M . Effect of thyroid hormone on the expression of mRNA encoding sarcoplasmic reticulum proteins. Circ Res 1991; 69: 266–76.
Kong JY, Rabkin SW . Mitochondrial effects with ceramide-induced cardiac apoptosis are different from those of palmitate. Arch Biochem Biophys 2003; 412: 196–206.
Balligand JL, Ungureanu-Longrois D, Simmons WW, Pimental D, Malinski TA, Kapturczak M . Cytokine-inducible nitric oxide synthase (iNOS) expression in cardiac myocytes. Characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. J Biol Chem 1994; 269: 27580–8.
Author information
Authors and Affiliations
Corresponding author
Additional information
Project supported by grants from Health Bureau of Zhejiang Province, China (No 2004A035).
Rights and permissions
About this article
Cite this article
Zheng, X., Hu, Sj. Effects of simvastatin on cardiac performance and expression of sarco-plasmic reticular calcium regulatory proteins in rat heart. Acta Pharmacol Sin 26, 696–704 (2005). https://doi.org/10.1111/j.1745-7254.2005.00105.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2005.00105.x
Keywords
This article is cited by
-
Interrelated In Vitro Mechanisms of Sibutramine-Induced Cardiotoxicity
Cardiovascular Toxicology (2021)
-
Rosuvastatin Reduces L-Type Ca2+ Current and Alters Contractile Function in Cardiac Myocytes via Modulation of β-Adrenergic Receptor Signaling
Cardiovascular Toxicology (2021)
-
Statin therapy improves survival in patients with severe pulmonary hypertension: a propensity score matching study
Heart and Vessels (2017)
-
Long-term administration of rosuvastatin prevents contractile and electrical remodelling of diabetic rat heart
Journal of Bioenergetics and Biomembranes (2013)
-
Effects of atorvastatin on calcium-regulating proteins: a possible mechanism to repair cardiac dysfunction in spontaneously hypertensive rats
Basic Research in Cardiology (2009)