Mitochondrial dysfunction increases expression of endothelin-1 and inducesapoptosis through caspase-3 activation in rat cardiomyocytes in vitro

We have reported that the expression of endothelin-1 (ET-1) increases in th e failing heart. With the progress of heart failure, it has been reported t hat energy metabolism switches from mitochondrial b-oxidation to glycolysis . Furthermore, it has been reported that apoptosis is induced in the failin g heart. However, it is not known how the gene expression of preproendothel in-1 and cellular apoptosis are affected by the mitochondrial dysfunction. Therefore, in order to elucidate this problem, we developed an in vitro mod el of mitochondrial dysfunction using rotenone, a mitochondrial respiratory chain complex I inhibitor, and studied preproendothelin-1 gene expression and apoptosis. Rotenone greatly increased the gene expression of preproendo thelin-1 in cardiomyocytes. This result suggests that the gene expression o f preproendothelin-1 is induced by the mitochondrial dysfunction. Furthermo re, treatment of cardiomyocytes with rotenone induced an elevation of caspa se-3 activity, and caused a marked increase in DNA laddering, an indication of apoptosis. In conclusion, it is suggested that mitochondrial impairment in primary cultured cardiomyocytes induced by rotenone in vitro, mimics so me of the pathophysiological features of heart failure in vivo, and that ET -1 may have a role in myocardial dysfunction with impairment of mitochondri a in the failing heart.