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Inflammation and apoptosis in aortic tissues of aged type II diabetes: Amelioration with alpha-lipoic acid through phosphatidylinositol 3-kinase/Akt- dependent mechanism
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
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2010 (English)In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 86, no 23-24, 844-853 p.Article in journal (Refereed) Published
Abstract [en]

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 INF-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-kappa B dynamics in aged diabetic vessels revealed not only a marked increase in cytosolic phosphorylated levels of I kappa B-alpha, NIK, IRK but also an enhancement in nuclear localization of p65 concomitantly with augmented NF-kappa B-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-kappa B 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).

Place, publisher, year, edition, pages
2010. Vol. 86, no 23-24, 844-853 p.
Keyword [en]
Diabetes, Inflammation, Apoptosis, Oxidative stress, alpha-lipoic acid
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-136080DOI: 10.1016/j.lfs.2010.03.019ISI: 000278201900002PubMedID: 20388520OAI: oai:DiVA.org:uu-136080DiVA: diva2:376166
Available from: 2010-12-10 Created: 2010-12-09 Last updated: 2013-04-04Bibliographically approved

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