Mechanisms of coronary endothelial dysfunction in diabetes

Summary

Principal Investigator: Ayako Makino
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: ----------------2009 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. pmc Mitochondrial fragmentation and superoxide anion production in coronary endothelial cells from a mouse model of type 1 diabetes
    A Makino
    Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, MC0618, La Jolla, CA 92093 0618, USA
    Diabetologia 53:1783-94. 2010
  2. pmc Role of reactive oxygen species and redox in regulating the function of transient receptor potential channels
    Michael Y Song
    Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA
    Antioxid Redox Signal 15:1549-65. 2011
  3. pmc Regulation of mitochondrial morphology and function by O-GlcNAcylation in neonatal cardiac myocytes
    Ayako Makino
    Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, USA
    Am J Physiol Regul Integr Comp Physiol 300:R1296-302. 2011
  4. pmc Thyroid hormone receptor-α and vascular function
    Ayako Makino
    Section of Endocrinology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
    Am J Physiol Cell Physiol 302:C1346-52. 2012
  5. pmc Mitochondrial function in vascular endothelial cell in diabetes
    Meenal Pangare
    University of Illinois at Chicago, Chicago, IL 60612, USA
    J Smooth Muscle Res 48:1-26. 2012
  6. pmc STIM1 restores coronary endothelial function in type 1 diabetic mice
    Irene A Estrada
    Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
    Circ Res 111:1166-75. 2012
  7. pmc Apolipoprotein E enhances endothelial-NO production by modulating caveolin 1 interaction with endothelial NO synthase
    Lili Yue
    Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
    Hypertension 60:1040-6. 2012
  8. ncbi Endothelial and smooth muscle cell ion channels in pulmonary vasoconstriction and vascular remodeling
    Ayako Makino
    Department of Medicine, The University of Illinois at Chicago, Chicago, Illinois, USA
    Compr Physiol 1:1555-602. 2011

Detail Information

Publications9

  1. pmc Mitochondrial fragmentation and superoxide anion production in coronary endothelial cells from a mouse model of type 1 diabetes
    A Makino
    Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, MC0618, La Jolla, CA 92093 0618, USA
    Diabetologia 53:1783-94. 2010
    ....
  2. pmc Role of reactive oxygen species and redox in regulating the function of transient receptor potential channels
    Michael Y Song
    Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA
    Antioxid Redox Signal 15:1549-65. 2011
    ..This review aims at briefly describing (a) the role of TRP channels in receptor-operated and store-operated Ca(2+) entry, and (b) the role of ROS and redox status in regulating the function and structure of TRP channels...
  3. pmc Regulation of mitochondrial morphology and function by O-GlcNAcylation in neonatal cardiac myocytes
    Ayako Makino
    Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, USA
    Am J Physiol Regul Integr Comp Physiol 300:R1296-302. 2011
    ....
  4. pmc Thyroid hormone receptor-α and vascular function
    Ayako Makino
    Section of Endocrinology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
    Am J Physiol Cell Physiol 302:C1346-52. 2012
    ..These data suggest that TRα in SMCs has prominent effects on regulation of vascular tone and TH treatment helps decrease coronary vascular tone by increasing K(+) channel activity through TRα in SMCs...
  5. pmc Mitochondrial function in vascular endothelial cell in diabetes
    Meenal Pangare
    University of Illinois at Chicago, Chicago, IL 60612, USA
    J Smooth Muscle Res 48:1-26. 2012
    ..In this article, we review the physiological and pathophysiological role of mitochondria in endothelial function with special focus on diabetes...
  6. pmc STIM1 restores coronary endothelial function in type 1 diabetic mice
    Irene A Estrada
    Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
    Circ Res 111:1166-75. 2012
    ..Many proteins, including stromal interaction molecule 1/2 (STIM1/2), Orai1/2/3, and sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 3 (SERCA3), are involved in the ER Ca(2+) refilling after store depletion in ECs...
  7. pmc Apolipoprotein E enhances endothelial-NO production by modulating caveolin 1 interaction with endothelial NO synthase
    Lili Yue
    Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
    Hypertension 60:1040-6. 2012
    ..We conclude that macrophage-derived apoE enhances endothelial NO production by disrupting the inhibitory interaction of eNOS with cav-1. These results establish a novel mechanism by which apoE modulates endothelial cell function...
  8. ncbi Endothelial and smooth muscle cell ion channels in pulmonary vasoconstriction and vascular remodeling
    Ayako Makino
    Department of Medicine, The University of Illinois at Chicago, Chicago, Illinois, USA
    Compr Physiol 1:1555-602. 2011
    ....