Document Detail

Akt pathway is hypoactivated by synergistic actions of diabetes mellitus and hypercholesterolemia resulting in advanced coronary artery disease.
MedLine Citation:
PMID:  20601459     Owner:  NLM     Status:  MEDLINE    
Atherosclerosis is an inflammatory process leading to enhanced cellular proliferation, apoptosis, and vasa vasorum (VV) neovascularization. While both diabetes mellitus (DM) and hypercholesterolemia (HC) predispose to atherosclerosis, the precise interaction of these risk factors is unclear. Akt is a central node in signaling pathways important for inflammation, and we hypothesized that DM/HC would lead to aberrant Akt signaling and advanced, complex atherosclerosis. DM was induced in pigs by streptozotocin and HC by a high-fat diet. Animals were randomized to control (non-DM, non-HC), DM only, HC only, and DM/HC groups. Coronary artery homogenates were analyzed by immunoblotting for proteins involved in the Akt pathway, including phosphorylated (p)-Akt (Ser473), p-GSK-3beta (Ser9), activated NF-kappaB p65, and VEGF. Immunohistochemical staining for Ki67 (cell proliferation), terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) (apoptosis), and von Willebrand factor (vWF) (neovascularization) was performed. Neovascularization was visualized with micro-computerized tomography (CT). Only DM/HC animals developed advanced atherosclerosis and showed decreased p-Akt (Ser473) and p-GSK-3beta (Ser9) levels (P < 0.01 and P < 0.05, respectively). DM/HC arteries demonstrated increased cellular proliferation (P < 0.001), apoptosis (P < 0.01), and activation of NF-kappaB p65 (P < 0.05). Induction of DM/HC also resulted in significant VV neovascularization by enhanced VEGF expression (P < 0.05), increased vWF staining (P < 0.01), and increased density by micro-CT. In conclusion, DM and HC synergistically resulted in complex atherosclerosis associated with attenuated p-Akt (Ser473) levels. Aberrant Akt signaling correlated with increased inflammation, cellular proliferation, apoptosis, and VV neovascularization. Our results revealed a synergistic effect of DM and HC in triggering abnormal Akt signaling, resulting in advanced atherosclerosis.
Damir Hamamdzic; Robert S Fenning; Dhavalkumar Patel; Emile R Mohler; Ksenia A Orlova; Alexander C Wright; Raul Llano; Martin G Keane; Richard P Shannon; Morris J Birnbaum; Robert L Wilensky
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-07-02
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  299     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-08-31     Completed Date:  2010-09-22     Revised Date:  2014-01-10    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H699-706     Citation Subset:  IM    
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MeSH Terms
Analysis of Variance
Apoptosis / physiology
Blotting, Western
Cell Proliferation
Coronary Artery Disease / complications,  metabolism*
Coronary Vessels / drug effects,  metabolism
Diabetes Mellitus, Experimental / complications,  metabolism*
Dietary Fats / adverse effects
Hypercholesterolemia / complications,  metabolism*
Insulin / metabolism,  pharmacology
Neovascularization, Pathologic / complications,  metabolism
Phosphorylation / physiology
Proto-Oncogene Proteins c-akt / metabolism*
Random Allocation
Signal Transduction
Grant Support
Reg. No./Substance:
0/Dietary Fats; 0/Insulin; EC Proteins c-akt

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