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

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


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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetophenones / pharmacology
  • Aging / drug effects
  • Aging / physiology
  • Androstadienes / pharmacology
  • Animals
  • Antioxidants / pharmacology*
  • Aorta / metabolism
  • Aorta / physiopathology*
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Diabetic Angiopathies / drug therapy
  • Diabetic Angiopathies / physiopathology*
  • Inflammation / drug therapy
  • Inflammation / physiopathology*
  • Male
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Phosphatidylinositol 3-Kinases / physiology*
  • Proto-Oncogene Proteins c-akt / physiology*
  • Rats
  • Rats, Wistar
  • Thioctic Acid / antagonists & inhibitors
  • Thioctic Acid / pharmacology*
  • Vasodilation / drug effects
  • Vasodilation / physiology
  • Wortmannin


  • Acetophenones
  • Androstadienes
  • Antioxidants
  • Thioctic Acid
  • acetovanillone
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Wortmannin