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Life Sci. 2010 Jun 5;86(23-24):844-53. doi: 10.1016/j.lfs.2010.03.019. Epub 2010 Apr 11.

Inflammation and apoptosis in aortic tissues of aged type II diabetes: amelioration with alpha-lipoic acid through phosphatidylinositol 3-kinase/Akt- dependent mechanism.

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1
Department of Pharmacology & Toxicology, School of Medicine, Kuwait University, Kuwait. milad.bitar@gmail.com <milad.bitar@gmail.com>

Abstract

AIMS:

Endothelial dysfunction is a key triggering event in the development of cardiovascular diseases and the current study explored this phenomenon in the context of inflammation, apoptosis, reactive oxygen species (ROS) and the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway during chronic diabetes.

MAIN METHODS:

alpha-Lipoic acid (ALA) and wortmannin (WM) were chronically administered to aged Goto Kakizaki (GK) rats, a genetic model of non-obese type II diabetes. Key indices of inflammation, apoptosis and oxidative stress were assessed using western blotting, real-time PCR and immunofluoresence-based techniques.

KEY FINDINGS:

A chronic inflammation (e.g., increased mRNA/protein levels of TNF-alpha, ICAM, fractalkine, CD-68, myeloperoxidase) in connection with increased caspase-based apoptotic cell death and heightened state of oxidative stress (HSOS)- appear to exist in diabetic cardiovascular tissues. An assessment of NF-kappaB dynamics in aged diabetic vessels revealed not only a marked increase in cytosolic phosphorylated levels of IkappaB-alpha, NIK, IKK but also an enhancement in nuclear localization of p65 concomitantly with augmented NF-kappaB-DNA binding activity. Most of the aforementioned cardiovascular-based diabetic abnormalities including reduced activities of PI3K and Akt kinase were ameliorated following chronic ALA therapy. WM, given to GK rats negated the anti-inflammatory and anti-apoptotic actions of ALA.

SIGNIFICANCE:

Our data highlight a unifying mechanism whereby HSOS through an induction of NF-kappaB activity together with an impairment in PI3K/Akt pathway favors pro-inflammatory/pro-apoptotic diabetic vascular milieu that culminate in the onset of endothelial dysfunction, a phenomenon which appears to be amenable to treatment with antioxidants and/or PI3/Akt mimetics (e.g., ALA).

PMID:
20388520
DOI:
10.1016/j.lfs.2010.03.019
[Indexed for MEDLINE]
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