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Publication
Regulation of Macrophage Apoptosis and Atherosclerosis by Lipid-Induced PKCd
Isoform Activation.
Authors Li Q, Park K, Xia Y, Matsumoto M, Qi W, Fu J, Yokomizo H, Khamaisi M, Wang X,
Rask-Madsen C, King GL
Submitted By Submitted Externally on 11/5/2018
Status Published
Journal Circulation research
Year 2017
Date Published 10/1/2017
Volume : Pages 121 : 1153 - 1167
PubMed Reference 28855204
Abstract Activation of monocytes/macrophages by hyperlipidemia associated with diabetes
mellitus and obesity contributes to the development of atherosclerosis. PKCd
(protein kinase C d) expression and activity in monocytes were increased by
hyperlipidemia and diabetes mellitus with unknown consequences to
atherosclerosis., To investigate the effect of PKCd activation in macrophages on
the severity of atherosclerosis., PKCd expression and activity were increased in
Zucker diabetic rats. Mice with selective deletion of PKCd in macrophages were
generated by breeding PKCd flox/flox mice with LyzM-Cre and ApoE-/- mice
(MPKCdKO/ApoE-/- mice) and studied in atherogenic (AD) and high-fat diet (HFD).
Mice fed AD and HFD exhibited hyperlipidemia, but only HFD-fed mice had insulin
resistance and mild diabetes mellitus. Surprisingly, MPKCdKO/ApoE-/- mice
exhibited accelerated aortic atherosclerotic lesions by 2-fold versus ApoE-/-
mice on AD or HFD. Splenomegaly was observed in MPKCdKO/ApoE-/- mice on AD and
HFD but not on regular chow. Both the AD or HFD increased macrophage number in
aortic plaques and spleen by 1.7- and 2-fold, respectively, in MPKCdKO/ApoE-/-
versus ApoE-/- mice because of decreased apoptosis (62%) and increased
proliferation (1.9-fold), and not because of uptake, with parallel increased
expressions of inflammatory cytokines. Mechanisms for the increased macrophages
in MPKCdKO/ApoE-/- were associated with elevated phosphorylation levels of
prosurvival cell-signaling proteins, Akt and FoxO3a, with reduction of
proapoptotic protein Bim associated with PKCd induced inhibition of P85/PI3K.,
Accelerated development of atherosclerosis induced by insulin resistance and
hyperlipidemia may be partially limited by PKCd isoform activation in the
monocytes, which decreased its number and inflammatory responses in the arterial
wall.




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