Identifying and intervening molecular pathways that directly contribute to vascular complications will have a significant clinical impact in preventing insulin dependent diabetes mellitus (IDDM)-associated vascular complications. We hypothesize that impaired physiological repair mechanisms due to altered endothelium- derived relaxation factor (nitric oxide) signaling pathway mediated by sustained high glucose is responsible for vascular complications. Under normal physiological condition, interaction of heat shock protein (Hsp-86) with endothelial nitric oxide synthase (NOS III) is responsible for nitric oxide-dependent endothelial functions. However, under high glucose condition, there is an enhanced inhibitor kB kinase activity (IKK-2), which competes out NOS lll from binding to Hsp-86. Further IKK-2 binding phosphorylates Hsp-86. This sequence of events lead to inadequate availability of Hsp-86 to NOS III, which decelerates NOS lll activity with a final outcome of integrin-focal adhesion disassembly, delayed endothelial migration and poor vascular repair. Blocking IKK-2 with genetic or pharmacological inhibitors in combination with agents, which are already in clinical practice, may open new avenues to improve nitric oxide production and reduce vascular damage in IDDM patients. The proposed study constitutes innovative approaches with the use of in vitro cell culture based assays using mammalian aortic endothelial cells. Use of genetically-induced diabetic animal model and optimized arterial injury procedures further complement the in vitro mechanistic approach.
The specific aims are:
Aim 1 will investigate the competitive cross talk between NOS III and IKK-2 with Hsp-86 under the influence of high glucose. The effect of sequentially altered nitric oxide signaling pathway on endothelial migration will be evaluated.
Aim 2 will determine in vivo, the contribution of Hsp-86 - IKK-2 cross talk in NOS lll dysregulation in Type-1 mouse model.
Aim 3 will evaluate the potentials of blocking IKK-2 independently or in combination with L-arginine in improving endothelial repair mechanism in response to arterial injury. The knowledge gained will help to identify new avenues that will improve the current treatment modalities aimed to prevent or minimize the severity of vascular complications of IDDM patients.

Public Health Relevance

Diabetes-associated vascular damage is responsible for the higher mortality of diabetic patients. Results of this study will identify effective therapeutic approaches to prevent or reduce vascular damage and improve their health and standard of living.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Jones, Teresa L Z
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University of Texas Health Science Center
Schools of Medicine
San Antonio
United States
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Natarajan, Mohan; Habib, Samy L; Reddick, Robert L et al. (2018) Endothelial cell-specific overexpression of endothelial nitric oxide synthase in Ins2Akita mice exacerbates diabetic nephropathy. J Diabetes Complications :
Natarajan, Mohan; Aravindan, Natarajan; Sprague, Eugene A et al. (2016) Hemodynamic Flow-Induced Mechanotransduction Signaling Influences the Radiation Response of the Vascular Endothelium. Radiat Res 186:175-88
Chandra, Saurav B; Mohan, Sumathy; Ford, Bridget M et al. (2016) Targeted overexpression of endothelial nitric oxide synthase in endothelial cells improves cerebrovascular reactivity in Ins2Akita-type-1 diabetic mice. J Cereb Blood Flow Metab 36:1135-42
Natarajan, Mohan; Konopinski, Ryszard; Krishnan, Manickam et al. (2015) Inhibitor-?B kinase attenuates Hsp90-dependent endothelial nitric oxide synthase function in vascular endothelial cells. Am J Physiol Cell Physiol 308:C673-83
Krishnan, Manickam; Janardhanan, Preethi; Roman, Linda et al. (2015) Enhancing eNOS activity with simultaneous inhibition of IKK? restores vascular function in Ins2(Akita+/-) type-1 diabetic mice. Lab Invest 95:1092-104