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THROMBOSPONDIN-1 AS A TARGET OF MICRONUTRIENT TRIVALENT CHROMIUM IN DIABETIC VASCULAR COMPLICATION

Ganguly, Rituparna

Abstract Details

2016, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
Atherosclerotic vascular disease is a major cause of morbidity and mortality in diabetic patients. Hyperglycemia, a hallmark of diabetes, is an independent risk-factor for accelerated development of atherosclerosis in diabetic individuals. Despite clinical correlations, the in-depth molecular mechanisms of hyperglycemia-induced atherosclerosis in diabetic patients remain unknown. Previous reports suggest proatherogenic protein Thrombospondin-1 (TSP-1) as a potential link between hyperglycemia and accelerated atherogenesis in diabetics. Trivalent chromium (Cr3+), a micronutrient with regulatory effects on glucose and lipid metabolism, is proposed to have beneficial glycemic and cardiovascular effects. However, precise mechanisms of Cr3+ action in diabetic macrovessels are not known. In Aim 1 of this dissertation we demonstrated that therapeutically relevant concentration of Cr3+ (100nM) resulted in a significant inhibition of high glucose-induced TSP-1 expression in human aortic smooth muscle cells (HASMC) and this regulation occurred via reduction in O-GlcNAcylated protein expression. Additionally, we validated these in vitro findings in an in vivo setting using STZ-induced hyperglycemic C57BL6/J mice, a mouse model of hyperglycemia. Using a plant virus-derived nanoparticle cowpea mosaic virus (CPMV) for site-directed delivery of Cr3+, we further demonstrated anti-atherogenic effects of Cr3+-loaded CPMV in primary HASMC cultures stimulated with high glucose in vitro. In aim 2 of the dissertation we demonstrated atheroprotective effect of Cr3+ in vivo in STZ-induced hyperglycemic atherosclerotic (ApoE-/-) mouse model accompanied with downregulation of TSP-1 expression in the aortic wall. Additionally, this study revealed a direct functional role of TSP-1 in hyperglycemia-induced atherogenesis. To the best of our knowledge, this dissertation provides the first evidence for TSP-1 as a 'therapeutic target' of the cost-effective nutritional supplement Cr3+ in diabetic atherosclerosis. Additionally, this project has advanced our overall understanding of hyperglycemia-induced development of atherosclerosis in diabetes.
Priya Raman (Advisor)

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Citations

  • Ganguly, R. (2016). THROMBOSPONDIN-1 AS A TARGET OF MICRONUTRIENT TRIVALENT CHROMIUM IN DIABETIC VASCULAR COMPLICATION [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1461323798

    APA Style (7th edition)

  • Ganguly, Rituparna. THROMBOSPONDIN-1 AS A TARGET OF MICRONUTRIENT TRIVALENT CHROMIUM IN DIABETIC VASCULAR COMPLICATION . 2016. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1461323798.

    MLA Style (8th edition)

  • Ganguly, Rituparna. "THROMBOSPONDIN-1 AS A TARGET OF MICRONUTRIENT TRIVALENT CHROMIUM IN DIABETIC VASCULAR COMPLICATION ." Doctoral dissertation, Kent State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=kent1461323798

    Chicago Manual of Style (17th edition)