Evidence for the involvement of cGMP and protein kinase G in nitric oxide-induced apoptosis in the pancreatic B-cell line, HIT-T15

FEBS Lett. 1997 Jan 6;400(3):285-8. doi: 10.1016/s0014-5793(96)01392-0.


Intracellular production of nitric oxide (NO) is thought to mediate the pancreatic B-cell-directed cytotoxicity of cytokines in insulin-dependent diabetes mellitus, and recent evidence has indicated that this may involve induction of apoptosis. A primary effect of NO is to activate soluble guanylyl cyclase leading to increased cGMP levels and this effect has been demonstrated in pancreatic B-cells, although no intracellular function has been defined for islet cGMP. Here we demonstrate that the NO donor, GSNO, induces apoptosis in the pancreatic B-cell line HIT-T15 in a dose- and time-dependent manner. This response was significantly attenuated by micromolar concentrations of a specific inhibitor of soluble guanylyl cyclase, ODQ, and both 8-bromo cGMP (100 microM) and dibutyryl cGMP (300 microM) were able to fully relieve this inhibition. In addition, incubation of HIT-T15 cells with each cGMP analogue directly promoted cell death in the absence of ODQ. KT5823, a potent and highly selective inhibitor of cGMP-dependent protein kinase (PKG), abolished the induction of cell death in HIT cells in response to either GSNO or cGMP analogues. This effect was dose-dependent over the concentration range of 10-250 nM. Overall, these data provide evidence that the activation of apoptosis in HIT-T15 cells by NO donors is secondary to a rise in cGMP and suggest that the pathway controlling cell death involves activation of PKG.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / pharmacology
  • Animals
  • Apoptosis* / drug effects
  • Carbazoles*
  • Cell Line
  • Cyclic GMP / analogs & derivatives
  • Cyclic GMP / metabolism*
  • Cyclic GMP / pharmacology
  • Cyclic GMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic GMP-Dependent Protein Kinases / metabolism*
  • Dibutyryl Cyclic GMP / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Glutathione / analogs & derivatives
  • Glutathione / pharmacology
  • Indoles*
  • Islets of Langerhans / cytology*
  • Nitroso Compounds / pharmacology
  • Oxadiazoles / pharmacology
  • Quinoxalines / pharmacology
  • S-Nitrosoglutathione


  • 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
  • Alkaloids
  • Carbazoles
  • Enzyme Inhibitors
  • Indoles
  • Nitroso Compounds
  • Oxadiazoles
  • Quinoxalines
  • KT 5823
  • 8-bromocyclic GMP
  • Dibutyryl Cyclic GMP
  • S-Nitrosoglutathione
  • Cyclic GMP-Dependent Protein Kinases
  • Glutathione
  • Cyclic GMP