TY - JOUR
T1 - Inflammation and apoptosis in aortic tissues of aged type II diabetes
T2 - Amelioration with α-lipoic acid through phosphatidylinositol 3-kinase/Akt- dependent mechanism
AU - Sami Bitar, Milad
AU - Ayed, Adel K.
AU - Abdel-Halim, Samy M.
AU - Isenovic, Esma R.
AU - Al-Mulla, Fahd
PY - 2010/6/1
Y1 - 2010/6/1
N2 - 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: α-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-α, 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-κB dynamics in aged diabetic vessels revealed not only a marked increase in cytosolic phosphorylated levels of IκB-α, NIK, IKK but also an enhancement in nuclear localization of p65 concomitantly with augmented NF-κB-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-κB 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).
AB - 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: α-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-α, 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-κB dynamics in aged diabetic vessels revealed not only a marked increase in cytosolic phosphorylated levels of IκB-α, NIK, IKK but also an enhancement in nuclear localization of p65 concomitantly with augmented NF-κB-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-κB 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).
KW - α-lipoic acid
KW - Apoptosis
KW - Diabetes
KW - Inflammation
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=77953022783&partnerID=8YFLogxK
U2 - 10.1016/j.lfs.2010.03.019
DO - 10.1016/j.lfs.2010.03.019
M3 - Article
C2 - 20388520
AN - SCOPUS:77953022783
VL - 86
SP - 844
EP - 853
JO - Life Sciences
JF - Life Sciences
SN - 0024-3205
IS - 23-24
ER -