题名：Glucotoxic conditions induce endoplasmic reticulum stress to cause caspase 3 mediated lamin B degradation in pancreatic beta-cells: protection by nifedipine.
作者：SYEDA K; MOHAMMED AM; ARORA DK; KOWLURU A;
来源：Biochem Pharmacol. 2013 Nov 1;86(9):1338-46. doi: 10.1016/j.bcp.2013.08.023. Epub [ IF= 0.00 ] ]
摘要：Nuclear lamins form the lamina on the interior of the nuclear envelope, and are
involved in the regulation of various cellular processes, including DNA
replication and chromatin organization. Despite this evidence, little is known
about potential alterations in nuclear metabolism, specifically lamin structure
and integrity in isolated beta-cells subjected to stress conditions, including
chronic exposure to hyperglycemia (i.e., glucotoxicity). Herein, we investigated
effects of glucotoxic conditions on the catalytic activation of caspase 3 and the
associated degradation of one of its substrate proteins, namely lamin-B. We
report that incubation of insulin-secreting INS-1 832/13 cells, normal rat islets
or human islets under glucotoxic conditions (20 mM; 12-48 h) results in the
degradation of native lamin B leading to accumulation of the degraded products in
non-relevant cellular compartments, including cytosol. Moreover, the effects of
high glucose on caspase 3 activation and lamin B degradation were mimicked by
thapsigargin, a known inducer of endoplasmic reticulum stress (ER stress).
Nifedipine, a known blocker of calcium channel activation, inhibited high
glucose-induced caspase 3 activation and lamin B degradation in these cells.
4-Phenyl butyric acid, a known inhibitor of ER stress, markedly attenuated
glucose-induced CHOP expression (ER stress marker), caspase 3 activation and
lamin B degradation. We conclude that glucotoxic conditions promote caspase 3
activation and lamin B degradation, which may, in part, be due to increased ER
stress under these conditions. We also provide further evidence to support
beneficial effects of calcium channel blockers against metabolic dysfunction of
the islet beta-cell induced by hyperglycemic conditions.