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


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.


RESULTS
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.


CONCLUSIONS
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).
Bitar
Milad S
MS
Department of Pharmacology & Toxicology, School of Medicine, Kuwait University, Kuwait. milad.bitar@gmail.com <milad.bitar@gmail.com>
Ayed
Adel K
AK
Abdel-Halim
Samy M
SM
Isenovic
Esma R
ER
Al-Mulla
Fahd
F
D000098:Acetophenones / Q000494:pharmacology; D000375:Aging / Q000187:drug effects / Q000502:physiology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000503:physiopathology*; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D008063:Thioctic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D000077191:Wortmannin
D000098:Acetophenones; D000730:Androstadienes; D000975:Antioxidants; D008063:Thioctic Acid; C056165:acetovanillone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin