Mitochondrial dysfunction increases expression of endothelin-1 and induces apoptosis through caspase-3 activation in rat cardiomyocytes in vitro.
We have reported that the expression of endothelin-1 (ET-1) increases in the failing heart. With the progress of heart failure, it has been reported that energy metabolism switches from mitochondrial b-oxidation to glycolysis. Furthermore, it has been reported that apoptosis is induced in the failing heart. However, it is not known how the gene expression of preproendothelin-1 and cellular apoptosis are affected by the mitochondrial dysfunction. Therefore, in order to elucidate this problem, we developed an in vitro model 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 pre-proendothelin-1 in cardiomyocytes. This result suggests that the gene expression of preproendothelin-1 is induced by the mitochondrial dysfunction. Furthermore, treatment of cardiomyocytes with rotenone induced an elevation of caspase-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 some of the pathophysiological features of heart failure in vivo, and that ET-1 may have a role in myocardial dysfunction with impairment of mitochondria in the failing heart.
Yuki
K
K
Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.
Miyauchi
T
T
Kakinuma
Y
Y
Murakoshi
N
N
Suzuki
T
T
Hayashi
J
J
Goto
K
K
Yamaguchi
I
I
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000502:physiology*; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000235:genetics*; D004789:Enzyme Activation; D008929:Mitochondria, Heart / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000494:pharmacology
D019332:Endothelin-1; D012402:Rotenone; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases