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Inhibition of Hypoxia-Induced Apoptosis by Modulation of Retinoblastoma Protein–Dependent Signaling in Cardiomyocytes

From the Department of Cardiology, Campus Virchow Clinic, Charité, Humboldt University, and the Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.

Correspondence to Rüdiger von Harsdorf, MD, Medizinische Klinik mit Schwerpunkt Kardiologie, Universitätsklinikum Charité, Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail rharsdo{at}mdc-berlin.de

Apoptotic cell death is an important mode of cell loss contributing to heart dysfunction. To analyze the importance of the E2F-dependent regulation of gene transcription in cardiomyocyte apoptosis, the function of cell cycle factors impinging on the retinoblastoma protein (pRb)/E2F pathway was investigated. In isolated neonatal ventricular myocytes, apoptotic cell death induced by hypoxia (deferoxamine, 100 µmol/L) specifically activated cyclin-dependent kinases (cdks) 2 and 3. Apoptotic cell death was inhibited by ectopic expression of cdk inhibitors p21^CIP and p27^KIP1 but not p16^INK4. In addition, apoptosis was also abrogated by forced expression of kinase dead mutant proteins of cdk2/3 but not of cdk4/6. Introduction of cdk inhibitors or dominant-negative cdk2/3 blocked pRb hyperphosphorylation and abrogated E2F-dependent gene transcription, including that of the E2F-responsive genes of proapoptotic caspase 3 and caspase 7. Moreover, introduction of constitutively active pRb and transcriptionally inert mutant E2F1/DP1 efficiently protected cardiomyocytes from apoptosis. In conclusion, these data demonstrate that cdk-specific inactivation of pRb and the subsequent activation of E2F-dependent gene transcription are required for cardiomyocyte apoptosis.

Key Words: apoptosis • hypoxia • cell cycle • signaling

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