Role of caspase 2 in apoptotic signaling in primate and murine germ cells

Biol Reprod. 2008 Nov;79(5):806-14. doi: 10.1095/biolreprod.108.068833. Epub 2008 Jul 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Caspase 2 / metabolism*
  • Caspase Inhibitors
  • Cytochromes c / metabolism
  • Down-Regulation
  • Enzyme Activation
  • Gonadotropins / deficiency
  • Hot Temperature
  • Macaca fascicularis
  • Male
  • Mitochondria / metabolism
  • Mitogen-Activated Protein Kinase 14 / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Oligopeptides / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Sertoli Cells / metabolism
  • Signal Transduction*
  • Spermatozoa / enzymology*
  • Up-Regulation
  • X-Linked Inhibitor of Apoptosis Protein / metabolism


  • Caspase Inhibitors
  • Gonadotropins
  • Oligopeptides
  • X-Linked Inhibitor of Apoptosis Protein
  • benzoylcarbonyl-valyl-aspartyl-valyl-alanyl-aspartyl-fluoromethyl ketone
  • Cytochromes c
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Mitogen-Activated Protein Kinase 14
  • Caspase 2