Effects of simvastatin on cardiac performance and expression of sarcoplasmic reticular calcium regulatory proteins in rat heart.
OBJECTIVE
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 microml/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 micromol/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 micromol/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 mumol/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 micromol/L) had no influence on cell viability of cultured cardiac myocytes, but simvastatin 100 micromol/L inhibited the cell viability.


CONCLUSIONS
Simvastatin improved cardiac performance accompanied by the elevation of SERCA and RyR2 gene and protein expression.
Zheng
Xia
X
The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
Hu
Shen-jiang
SJ
D000818:Animals; D000831:Animals, Newborn; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000096:biosynthesis* / Q000235:genetics; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019821:Simvastatin / Q000494:pharmacology*; D017725:Ventricular Pressure / Q000187:drug effects*; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019821:Simvastatin; D000099211:Phospholamban