Our group has recently found that high glucose (HG) augmented the angiotensin (Ang II)_induce growth of vascular smooth muscle cells (VSMC) by increasing signal transduction through the JAK (janus kinase)/STAT (signal transducers and activation of transcription) pathway. Our general hypothesis is that the Ang II-induced JAK/STAT pathway plays a central role in increased VSMC growth and proliferation in type I diabetes mellitus. Therefore, the overall goal of this proposal is to define the molecular mechanisms by which HG enhances the Ang II-induce activation of the NAK/STAT pathway in an effort to elucidate the processes of increased VSMC growth and proliferation that occur during diabetes. We plan to use an integral approach using molecular and biochemical techniques in cultured VSMC along with in vivo studies in STZ-induced diabetic rats in order to address the following specific aims:
Specific Aim 1 : To test the hypothesis that high glucose augments the Ang II-induced JAK/STAT pathway in VSMC through reactive oxygen species generated via the polyol pathway activation of PKC-beta2.
Specific Aim 2 : To test the hypothesis that advanced glycation end products augment the AngII-induced JAK/STAT pathway in VSMC through reactive oxygen species generated via a non-polyol pathway activation of PKC-beta2.
Specific Aim 3 : Tp test the hypothesis that high glucose and advanced glycation end products augment the Ang II-induced growth responses in VSMC via the JAK/STAT pathway.
Specific Aim 4 : To test the hypothesis that the activation of JAK2, STAT1, STAT3 and STAT5 proteins in the aorta of STZ-induced diabetic rats is mediated by 1) AT1 receptor activation, 2) activation of PKC beta, 3) activation of the polyol pathway and the RAGE receptor, and 4) the over-production of reactive oxygen species.
Specific Aim 5 : To test the hypothesis that JAK2 plays a role in the expression of the early growth response genes c-fos and c-jun and collagen synthesis in the aorta of STZ-induced diabetic rats. We believe that it is important to characterize the molecular mechanisms responsible for abnormal cell growth in diabetes with the hope that prevention of such growth will delay the onset, retard the progression, or even prevent renal disease. This area of research will provide new strategies and the potential for new therapeutics agents in the flight against diabetic complications.
| Ketsawatsomkron, Pimonrat; Stepp, David W; Fulton, David J et al. (2010) Molecular mechanism of angiotensin II-induced insulin resistance in aortic vascular smooth muscle cells: roles of Protein Tyrosine Phosphatase-1B. Vascul Pharmacol 53:160-8 |
| Ali, M Irfan; Ketsawatsomkron, Pimonrat; Belin de Chantemele, Eric J et al. (2009) Deletion of protein tyrosine phosphatase 1b improves peripheral insulin resistance and vascular function in obese, leptin-resistant mice via reduced oxidant tone. Circ Res 105:1013-22 |
