Akt pathway is hypoactivated by synergistic actions of diabetes mellitus and hypercholesterolemia resulting in advanced coronary artery disease
Open Access
- 1 September 2010
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 299 (3), H699-H706
- https://doi.org/10.1152/ajpheart.00071.2010
Abstract
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-3β (Ser9), activated NF-κB 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-3β (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-κB 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.Keywords
This publication has 62 references indexed in Scilit:
- Prevention of vasa vasorum neovascularization attenuates early neointima formation in experimental hypercholesterolemiaBasic Research in Cardiology, 2009
- Maintenance of Constitutive IκB Kinase Activity by Glycogen Synthase Kinase-3α/β in Pancreatic CancerCancer Research, 2008
- Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque developmentNature Medicine, 2008
- Loss of Akt1 Leads to Severe Atherosclerosis and Occlusive Coronary Artery DiseaseCell Metabolism, 2007
- Glycogen Synthase Kinase 3α and 3β Mediate a Glucose-Sensitive Antiapoptotic Signaling Pathway To Stabilize Mcl-1Molecular and Cellular Biology, 2007
- AKT/PKB Signaling: Navigating DownstreamCell, 2007
- Only Akt1 Is Required for Proliferation, while Akt2 Promotes Cell Cycle Exit through p21 BindingMolecular and Cellular Biology, 2006
- S6K1 Regulates GSK3 under Conditions of mTOR-Dependent Feedback Inhibition of AktMolecular Cell, 2006
- The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolismNature Reviews Genetics, 2006
- Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR ComplexScience, 2005