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Role of Caspase 2 in Apoptotic Signaling in Primate and Murine Germ Cells¹

Division of Endocrinology,⁴ Department of Medicine, Harbor-University of California Los Angeles (UCLA) Medical Center, David Geffen School of Medicine at UCLA and Los Angeles Biomedical Research Institute, Torrance, California 90509 State Key Laboratory of Reproductive Biology,⁵ Institute of Zoology, Chinese Academy of Science, 100080 Beijing, China

ABSTRACT

This study investigates the role of caspase 2 in apoptotic signaling of nonhuman primate male germ cells triggered by mild testicular hyperthermia, testosterone (T_e) implants, or by combined interventions. Mean incidence of germ cell apoptosis increased significantly by Day 3 in the heat (H_e) alone group and by Day 8 in the T_e alone group but peaked at Day 3 in H_e + T_e group. We found activation of caspase 2 in both germ cells and Sertoli cells after induction of apoptosis. Most notably, active caspase 2 immunoreactivity was detected only in those germ cells susceptible to apoptosis compared with controls, where little or no such staining is detected. To further explore the role of caspase 2 in regulating male germ cell death, we next evaluated the efficacy of caspase 2 inhibition in preventing or attenuating heat-induced germ cell apoptosis in rats. Caspase 2 inhibition significantly (P < 0.05) prevented such heat-induced germ cell apoptosis. The protection offered by the caspase 2 inhibitor occurred upstream of mitochondria, involving suppression of mitogen-activated protein kinase (MAPK) 14 activation and inducible nitric oxide synthase (NOS2) induction and, in turn, suppression of cytochrome c-mediated death pathway. Together, our results show that caspase 2 is activated in male germ cells undergoing apoptosis in nonhuman primates after heat stress, hormonal deprivation, or after combined interventions. Blockade of caspase 2 activation prevents heat-induced germ cell apoptosis in rats by suppressing the MAPK14- and NO-mediated intrinsic pathway signaling..

apoptosis, caspase 2, male germ cells, MAPK14, monkey, NOS2, primate, rat, spermatogenesis

¹Supported by grants from the Mellon Reproductive Biology Center (R.S.S., C.W., Y.H.L., and A.P.S.H.), National Institutes of Health (RO1 HD39293 to A.P.S.H., R.S.S., and C.W.), Major Research Plan Project (2006 CBOF 1001), 973 project (2006 CB 504001), Chinese Academy of Sciences Chuangxi program (KSCA2-YW-R-55), and National Nature Science Foundation of China (30230190). C.J. is supported through the Initiative for Minority Student Development Program (IMSD) from the National Institutes of Health (R25 GM560902).

Correspondence: ²Amiya P. Sinha Hikim, Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Box 446, 1000 West Carson St., Torrance, CA 90509. FAX: 310 533 0627; e-mail: hikim{at}labiomed.org

³These authors contributed equally to this work.

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