Cyclosporine Effect on the Expression Pattern of the Myosin Heavy Chain Gene and the Morphologic Changes of Myocardium in Overloaded Left Ventricle of Rats.

Korean J Leg Med. 2000 Oct;24(2):1-14. Korean.

Department of Forensic Medicine, Chonnam National University Medical School, Kwangju, Korea.

BACKGROUND: In response to numerous pathologic stimuli, the myocardium undergoes a hypertrophic response characterized by increased myocardial cell size and activation of fetal cardiac genes. Recently, the calcineurin inhibitor, cyclosporine has been reported to prevent the development of cardiac hypertrophy, however, others reported data which are disagreed to the cyclosporine effect on the prevention of cardiac hypertrophy. METHOD: To clarify whether the calcineurin signaling pathway is a critical for overloaded hypertrophy in vivo and to characterize the cyclosporine effect on the develpment of cardiac hypertrophy, I examined the effects of cyclosporine on the left ventricular overload in the experimental model of clipping of abdominal aorta between the diaphragm and renal artery for three weeks in rats. RESULTS: Left ventricular mass was larger in the group of clipping of abdominal aorta than in the group of cyclosporine injection after clipping of abdominal aorta, however, which had larger ventricular mass rather than control group. It means that cyclosporine suppress hypertrophic growth. Both treated and untreated animals showed increased nuclear polymorphism and euchromatin pattern, and also, ultrastructurally, showed degenerative changes in the cardiac myocytes such as swelling of subsarcolemmal cytoplasm with indistinct sarcoplasmic reticulum and "T" tubules, loosening of myofibril bundles with decreased electron density, and electron dense mitochondria with decreased number. Characteristically, the group of cyclosporine injection after clipping of abdominal aorta showed polymorphic electron dense unswollen giant mitochondria which was not characteristic in other groups. alpha-MyHC mRNA including non-spliced mRNA of the group of abdominal aortic clipping was downregulated in the both groups of clipping of abdominal aorta. beta-MyHC mRNA was upregulated in the group of clipping of abdominal aorta and downregulated in the group of cyclosporine injection after clipping of abdominal aorta. From the above results, initial response to overload is a degenerative changes of cardiac myocytes and cyclosporine may suppress hypertrophic response and the fetal gene reactivation such as beta-MyHC mRNA in this experiment.

Key words: Overloaded heart, Cyclosporine, Ultrastructure, Myosin heavy chain