© 2001 American Heart Association, Inc.
Cellular Biology |
Cyclin A/cdk2 Activation Is Involved in Hypoxia-Induced Apoptosis in Cardiomyocytes
From the Second Department of Internal Medicine (S.A., H.I., Y.O., T.N., S.A., F.M., M.H.), Department of Biochemical Genetics, Medical Research Institute (M.T.-A.), and Department of Developmental Biology, Graduate School of Dentistry (M.I.), Tokyo Medical and Dental University, Tokyo, Japan.
Correspondence to Michiaki Hiroe, MD, Second Department of Internal Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Abstract—Cardiomyocytes
are terminally differentiated cells characterized as withdrawal
cell-cycle machinery, but nonetheless they are known to express
cell-cycle regulators. Because many proteins related to the cell cycle
induce apoptosis in proliferating cells, we examined the involvement of
these proteins in the apoptosis pathway in cardiomyocytes. Primary rat
cardiomyocytes were exposed to a severe hypoxic condition to induce
apoptosis. The apoptosis rate of cardiomyocytes increased to 
40%
under 24 hours of hypoxia as evaluated by the TUNEL method. The cyclin
A protein level assessed by immunoblot analysis accumulated in a
time-dependent manner in cardiomyocytes, but there was no increase in
nonmyocytes. Hypoxia increased the activity of cyclin A–associated
kinase but not the activity of cyclin E–associated kinase, and the
apoptosis was inhibited by infection of dominant-negative cdk2
adenovirus, suggesting that cyclin A and its associated kinase play
significant roles in the apoptosis of cardiomyocytes. To investigate
the cyclin A–mediated apoptosis, we infected cultured cells with
cyclin A adenovirus. Apoptosis was induced in 63±12% of the infected
cardiomyocytes in contrast to only 12±3% of the LacZ-infected control
cells. In addition, the cells in the hypoxic condition showed an
increase in caspase-3 activity and a subsequent decrease in
p21cip1/waf1 protein, which is partly
cleaved by caspase-3. These findings confirm that cyclin A–associated
kinase mediates hypoxia-induced apoptosis in cardiomyocytes, and they
also suggest that additional elements of the cell-cycle–dependent
machinery participate in this
mechanism.
Key Words: apoptosis • hypoxia • cardiomyocytes • cell cycle
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