Control of Vascular Smooth Muscle Function by Insulin

Summary

Principal Investigator: Louis Ragolia
Abstract: [unreadable] DESCRIPTION (provided by applicant): Diabetes is associated with increased risk of cardiovascular diseases, which arise in part due to abnormalities in vascular smooth muscle (VSM) contraction resulting from an abnormal vascular tone. The overall goal of this project is to examine how insulin regulates the intracellular signal transduction pathways, which mediate relaxation in normal VSM and to identify potential pathway defects in diabetes. Contraction and relaxation of VSM is mediated primarily by phosphorylation and dephosphorylation of the regulatory myosin light chain (MLC20) by myosin light chain kinase and myosin bound phosphatase (MBP) respectively. The proposed studies will test the hypotheses that 1) insulin-induced vasorelaxation is mediated by MBP activation, and 2) cellular sensitivity and responsiveness to insulin and other vasoactive hormones are controlled by the factors which regulate the site-specific phosphorylation status of the myosin-bound subunit (MBS) of the phosphatase, MBP. Using aortic tissue, the proposed studies will examine 1) the role of MBP in insulin-mediated relaxation of VSM and to identify the mechanism whereby MBS regulates the MBP enzymatic activity. 2) Define the roles of PI3-kinase/Akt and RhoA/Rho kinase in insulin-mediated MBP activation and identify potential defects in these pathways in diabetes, and 3) Investigate potential interactions between angiotensin II, endothelin I and interleukin-1 [3/IL-6 and insulin signaling system and its impact on Rho signaling, MBS phosphorylation and MBP enzymatic activity. The functions of the key regulatory components on myosin dephosphorylation/relaxation will be elucidated by transfecting the gene of interest (activated MBS, PI3-kinase, iNOS, Akt, etc) into aortic tissue using adenovirus mediated gene transfer technique. Cumulatively, this work will lead to define the role of MBS in insulin activation of MBP, and the molecular basis of MBP regulation by insulin and potential cross-talk between insulin signaling pathways, cytokines and other vasoactive hormones. Thus, in a therapeutic context, the activation of MBP could be of value in preventing excessive contractility of VSM and thereby will have an important effect on reducing and/or preventing stroke, cardiovascular disease and renal failure in diabetes.
Funding Period: 2003-04-03 - 2008-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Accelerated glucose intolerance, nephropathy, and atherosclerosis in prostaglandin D2 synthase knock-out mice
    Louis Ragolia
    Vascular Biology Laboratory, Winthrop University Hospital, Mineola, New York 11501, USA
    J Biol Chem 280:29946-55. 2005
  2. pmc AKT phosphorylation is essential for insulin-induced relaxation of rat vascular smooth muscle cells
    Jin Hee Lee
    Vascular Biology Institute, Winthrop University Hospital, Mineola, NY 11501, USA
    Am J Physiol Cell Physiol 291:C1355-65. 2006
  3. pmc Effect of cyclooxygenase inhibition on cholesterol efflux proteins and atheromatous foam cell transformation in THP-1 human macrophages: a possible mechanism for increased cardiovascular risk
    Edwin S L Chan
    Division of Clinical Pharmacology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA
    Arthritis Res Ther 9:R4. 2007
  4. pmc Post-translational modification regulates prostaglandin D2 synthase apoptotic activity: characterization by site-directed mutagenesis
    Louis Ragolia
    Vascular Biology Laboratory, Winthrop University Hospital, Mineola, NY 11501, USA
    Prostaglandins Other Lipid Mediat 83:25-32. 2007
  5. pmc Upregulation of AT2 receptor and iNOS impairs angiotensin II-induced contraction without endothelium influence in young normotensive diabetic rats
    Jin Hee Lee
    Winthrop Univ Hospital, Vascular Biology Institute, Mineola, NY, USA
    Am J Physiol Regul Integr Comp Physiol 295:R144-54. 2008
  6. pmc Impaired insulin-mediated vasorelaxation in diabetic Goto-Kakizaki rats is caused by impaired Akt phosphorylation
    Jin Hee Lee
    Vascular Biology Institute, Winthrop Univ Hospital, 222 Station Plaza North, Rm 505B, Mineola, NY 11501, USA
    Am J Physiol Cell Physiol 296:C327-38. 2009

Scientific Experts

Detail Information

Publications6

  1. ncbi Accelerated glucose intolerance, nephropathy, and atherosclerosis in prostaglandin D2 synthase knock-out mice
    Louis Ragolia
    Vascular Biology Laboratory, Winthrop University Hospital, Mineola, New York 11501, USA
    J Biol Chem 280:29946-55. 2005
    ..We conclude that L-PGDS plays an important role regulating insulin sensitivity and atherosclerosis in type 2 diabetes and may represent a novel model of insulin resistance, atherosclerosis, and diabetic nephropathy...
  2. pmc AKT phosphorylation is essential for insulin-induced relaxation of rat vascular smooth muscle cells
    Jin Hee Lee
    Vascular Biology Institute, Winthrop University Hospital, Mineola, NY 11501, USA
    Am J Physiol Cell Physiol 291:C1355-65. 2006
    ....
  3. pmc Effect of cyclooxygenase inhibition on cholesterol efflux proteins and atheromatous foam cell transformation in THP-1 human macrophages: a possible mechanism for increased cardiovascular risk
    Edwin S L Chan
    Division of Clinical Pharmacology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA
    Arthritis Res Ther 9:R4. 2007
    ..NS398-treated THP-1 macrophages show greater vulnerability to form foam cells. Increased cardiovascular risk with COX inhibition may be ascribed at least in part to altered cholesterol metabolism...
  4. pmc Post-translational modification regulates prostaglandin D2 synthase apoptotic activity: characterization by site-directed mutagenesis
    Louis Ragolia
    Vascular Biology Laboratory, Winthrop University Hospital, Mineola, NY 11501, USA
    Prostaglandins Other Lipid Mediat 83:25-32. 2007
    ..We conclude that post-translational modification of L-PGDS, by either glycosylation or phosphorylation, enhances its apoptotic activity and inhibits VSMC hyperproliferation and postulate that this process is altered in type 2 diabetes...
  5. pmc Upregulation of AT2 receptor and iNOS impairs angiotensin II-induced contraction without endothelium influence in young normotensive diabetic rats
    Jin Hee Lee
    Winthrop Univ Hospital, Vascular Biology Institute, Mineola, NY, USA
    Am J Physiol Regul Integr Comp Physiol 295:R144-54. 2008
    ..In conclusion, these results clearly demonstrate that enhanced AT2R and iNOS-induced, NO-mediated vasodilation impair ANG II-induced contraction in an endothelium-independent manner at the early stage of type 2 diabetes...
  6. pmc Impaired insulin-mediated vasorelaxation in diabetic Goto-Kakizaki rats is caused by impaired Akt phosphorylation
    Jin Hee Lee
    Vascular Biology Institute, Winthrop Univ Hospital, 222 Station Plaza North, Rm 505B, Mineola, NY 11501, USA
    Am J Physiol Cell Physiol 296:C327-38. 2009
    ....