Submitted on June 6, 2003
Accepted on October 11, 2004
Effect of Simvastatin on Left Ventricular Mass in Hypercholesterolemic Rabbits
Tsung-Ming Lee1*, Mei-Shu Lin2, Tsai-Fwu Chou3, and Nen-Chung Chang4
1 Department of Internal Medicine, Taipei Medical University and Chi-Mei Medical Center, Tainan, Taiwan, Taiwan
2 Department of Pharmacy, National Taiwan University, Taipei, Taiwan, Taiwan
3 Department of Surgery, Municipal Jen-Ai Hospital, Taipei, Taiwan, Taiwan
4 Department of Medicine, Taipei Medical University, Taipei, Taiwan, Taiwan
* To whom correspondence should be addressed. E-mail: tsungm.lee{at}msa.hinet.net.
Epidemiological studies showed that hypercholesterolemia was associated with a higher left ventricular mass. Endothelin signaling is activated in hyperlipidemic animals, and may contribute to progressive ventricular hypertrophy. Simvastatin has been shown to inhibit endothelin-1. However, the behavior of simvastatin on ventricular hypertrophy in hyperlipidemic animals is not well understood. In this study, we evaluated the hemodynamic, biochemical, and morphological responses to simvastatin in cholesterol-fed (1%) rabbits. The left ventricular weight increased 8 weeks after cholesterol-feeding in comparison to that in normocholesterolemic rabbits. Simvastatin at clinical therapeutic dose (1.2 mg/kg per day) significantly decreased the left ventricular weight by 14% and left ventricular myocyte sizes by 14% isolated by enzymatic dissociation. Hypercholesterolemia upregulated ventricular preproendothelin-1 mRNA assessed by real-time quantitative RT-PCR and elevated production of cardiac endothelin-1 concentration. The increased endothelin-1 responses can be inhibited after simvastatin administration. Left ventricular mass indexed by body weight positively correlated with tissue endothelin-1 levels (P = 0.0003). In Langendorff-perfused rabbit hearts, hyperlipidemia led to significant QT prolongation compared with normocholesterolemia, which can be reversed by administering simvastatin. In contrast, simvastatin-induced beneficial effects were reversed by the addition of mevalonate. Addition of bosentan, a nonspecific endothelin receptor blocker, improved the response in hypercholesterolemic rabbits and did not have additional beneficial effects on simvastatin-treated rabbits. The results of the present study suggest that the antihypertropic and electrocardiographic effects of simvastatin at clinical therapeutic dose are mediated through inhibition of tissue endothelin-1 expression, which is linked to mevalonate metabolism, and result in an amelioration of cardiomyocyte hypertrophy development by an atherogenic diet.
