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Effect of Eicosapentaenoic Acid on the Different Endothelin System Components in Endothelin-1–Induced Hypertrophied Cardiomyocytes

Nobutake Shimojo^*, Subrina Jesmin^*, Sohel Zaedi^*, Masaaki Soma^*, Tsutomu Kobayashi^*, Seiji Maeda^*, Iwao Yamaguchi^*, Katsutoshi Goto and Takashi Miyauchi^*,1

^* cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, and Department of Pharmacology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan

To whom requests for reprints should be addressed at ¹ Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. E-mail: t-miyauc{at}md.tsukuba.ac.jp

Abstract

The cardiovascular benefit of fish oil, including eicosapentaenoic acid (EPA), in humans and experimental animals has been reported. The role of endothelin-1 (ET-1) in cardiac hypertrophy is well known. Endothelin-1 stimulates prepro–ET-1 mRNA expression in cardiomyocytes, and the autocrine/paracrine system of ET-1 is important for cardiomyocyte hypertrophy. Although many studies link EPA to cardiac protection, the effect of EPA on cardiac hypertrophy has yet to be clarified. Recently, we demonstrated that ET-1–induced cardiomyocytic change could be prevented by pretreatment with EPA. The present study investigated the changes of different components of the ET system at the mRNA level in ET-1–administered cardiomyocytes, and examined the effect of EPA pretreatment. Ventricular cardiomyocytes were isolated from 2-day-old Sprague-Dawley rats, cultured in Dulbecco’s modified Eagle’s medium and Ham F12 supplemented with 0.1% fatty acid–free bovine serum albumin for 3 days. At Day 4 of culture, the cardiomyocytes were divided into 3 groups: control group, ET-1–treated (0.1 nM) group, and ET-1–treated group pretreated with EPA (10 µM). Twenty-four hours after treatment, the gene expressions of different components of the endothelin system in three experimental groups were evaluated by real-time polymerase chain reaction. Prepro–ET-1 mRNA expression was 53% upregulated in ET-1–induced hypertrophied cardiomyocytes and suppressed in the EPA-pretreated group. Endothelin-converting enzyme-1 (ECE-1) was also increased in ET-1–administered cardiomyocytes by 42% compared with the control group and was reversed in the EPA-pretreated group. The two receptors of ET system, ET_A and ET_B, tended to be increased in the ET-1–treated group, but no statistical significance was seen among study groups. Endothelin-1 increased prepro–ET-1 and ECE-1 mRNA expression in hypertrophied-neonatal cardiomyocytes, and this was reversed with EPA pretreatment. Thus, EPA may play a crucial role in the regression of ET-1–induced cardiomyocyte hypertrophy, partly through the suppression of ET-1 and ECE-1 expression.

Key Words: endothelin-1 • eicosapentaenoic acid (EPA) • neonatal cardiomyocytes • hypertrophy • endothelin system