title: Role of caspase 2 in apoptotic signaling in primate and murine germ cells.
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 Te 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.
authors.affiliation: Division of Endocrinology, 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, USA.
authors.forename: Candace
authors.initials: C
authors.lastname: Johnson
authors.forename: Yue
authors.initials: Y
authors.lastname: Jia
authors.forename: Christina
authors.initials: C
authors.lastname: Wang
authors.forename: Yan-He
authors.initials: YH
authors.lastname: Lue
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Swerdloff
authors.forename: Xue-Shen
authors.initials: XS
authors.lastname: Zhang
authors.forename: Zhao-Yuan
authors.initials: ZY
authors.lastname: Hu
authors.forename: Yin-Chuan
authors.initials: YC
authors.lastname: Li
authors.forename: Yi-Xun
authors.initials: YX
authors.lastname: Liu
authors.forename: Amiya P Sinha
authors.initials: AP
authors.lastname: Hikim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053143:Caspase 2 / Q000378:metabolism*; D061945:Caspase Inhibitors; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D006062:Gonadotropins / Q000172:deficiency; D006358:Hot Temperature; D008252:Macaca fascicularis; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012708:Sertoli Cells / Q000378:metabolism; D015398:Signal Transduction; D013094:Spermatozoa / Q000201:enzymology*; D015854:Up-Regulation; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D061945:Caspase Inhibitors; D006062:Gonadotropins; D009842:Oligopeptides; D051636:X-Linked Inhibitor of Apoptosis Protein; C427308:benzoylcarbonyl-valyl-aspartyl-valyl-alanyl-aspartyl-fluoromethyl ketone; D045304:Cytochromes c; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D048308:Mitogen-Activated Protein Kinase 14; D053143:Caspase 2