Cardiovascular complications account for significant morbidity and mortality in diabetic patients. Diabetic coronary vascular disease has been recognized as a risk factor that may lead to heart failure. Endothelial cells play a major role in the maintenance of vascular tone and revascularization, while an endothelial dysfunction is commonly observed in diabetes. Gap junctions, formed by connexins (Cxs), provide important pathways for the cell-cell communication and Cx40 is known to be specially important in pathogenesis of hypertension and hyperlipidemia. It is, however, unclear whether Cx40 contributes to the development of coronary vascular complication in diabetes. The object of this application is to investigate the role of Cx40 in coronary endothelial dysfunction using diabetic mice. The hypothesis of this study is that chronic exposure of endothelial cells to hyperglycemia results in downregulated Cx40 protein expression, which increases coronary vascular resistance, decreases cardiac blood supply and increases mortality in diabetes.
Three specific aims are proposed to test the hypothesis: 1) To examine whether exposure of coronary endothelial cells to hyperglycemia decreases capillary density and inhibits vascular function through downregulation of Cx40 protein expression; 2) To test whether overexpression of Cx40 gene in endothelial cells serves as a therapeutic approach for coronary endothelial dysfunction in diabetic mice; and 3) To determine whether Cx40 function in diabetes is controlled by enzymatic 0-linked glycosylation of Cx40's transcription factors and Cx40 itself. My long-term goal is to identify the mechanisms for diabetic coronary vascular dysfunction and to develop endothelial cell-based therapeutic strategies to reduce or prevent the progression of coronary vascular disease. To work under a mentorship of Dr. Wolfgang Dillmann provides a great opportunity to learn how to generate endothelial cell-based transgenic mouse model to investigate Cx40 function at the molecular level in diabetes. The purpose of this award is to obtain support for my independent research project and to facilitate my transition to become a fully independent investigator conducting basic and translational research in the field of cardiovascular pathophysiology.

Public Health Relevance

Completion of this study will provide important insights into developing new therapeutic interventions for coronary vascular decease in diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Scientist Development Award - Research & Training (K01)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Hyde, James F
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University of Illinois at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Estrada, Irene A; Donthamsetty, Reshma; Debski, Patryk et al. (2012) STIM1 restores coronary endothelial function in type 1 diabetic mice. Circ Res 111:1166-75
Pangare, Meenal; Makino, Ayako (2012) Mitochondrial function in vascular endothelial cell in diabetes. J Smooth Muscle Res 48:1-26
Yue, Lili; Bian, Jing-Tan; Grizelj, Ivana et al. (2012) Apolipoprotein E enhances endothelial-NO production by modulating caveolin 1 interaction with endothelial NO synthase. Hypertension 60:1040-6
Makino, Ayako; Wang, Hong; Scott, Brian T et al. (2012) Thyroid hormone receptor-? and vascular function. Am J Physiol Cell Physiol 302:C1346-52
Song, Michael Y; Makino, Ayako; Yuan, Jason X-J (2011) STIM2 Contributes to Enhanced Store-operated Ca Entry in Pulmonary Artery Smooth Muscle Cells from Patients with Idiopathic Pulmonary Arterial Hypertension. Pulm Circ 1:84-94
Song, Michael Y; Makino, Ayako; Yuan, Jason X-J (2011) Role of reactive oxygen species and redox in regulating the function of transient receptor potential channels. Antioxid Redox Signal 15:1549-65
Makino, Ayako; Firth, Amy L; Yuan, Jason X-J (2011) Endothelial and smooth muscle cell ion channels in pulmonary vasoconstriction and vascular remodeling. Compr Physiol 1:1555-602
Makino, Ayako; Suarez, Jorge; Gawlowski, Thomas et al. (2011) Regulation of mitochondrial morphology and function by O-GlcNAcylation in neonatal cardiac myocytes. Am J Physiol Regul Integr Comp Physiol 300:R1296-302
Ko, Eun A; Song, Michael Y; Donthamsetty, Reshma et al. (2010) Tension Measurement in Isolated Rat and Mouse Pulmonary Artery. Drug Discov Today Dis Models 7:123-130
Makino, A; Scott, B T; Dillmann, W H (2010) Mitochondrial fragmentation and superoxide anion production in coronary endothelial cells from a mouse model of type 1 diabetes. Diabetologia 53:1783-94

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