"Phospholipids, Metabolic Syndrome and Response to Injury"

Summary

Principal Investigator: MARK GLYNN DAVIES
Affiliation: The Methodist Hospital
Country: USA
Abstract: DESCRIPTION (provided by applicant): Symptomatic cardiovascular disease in patients with metabolic syndrome (insulin resistance, dyslipidemia and hypertension) is an exploding public health concern and a significant clinical problem because these patients do not tolerate injury well. Metabolic syndrome results in a high glucose, free fatty rich environment in the body's tissues and understanding the influence of injury and metabolic syndrome on tissue responses will allow for focused changes in current therapeutic strategies. The phospholipid, Sphingosine-1 -phosphate (S-1-P) is released from platelets at sites of injury and is a potent mediator of cell migration, a hallmark of any remodeling process. Cell migration is a complex, but highly regulated process of cyclical attachment, detachment and contraction accompanied by alterations in metalloproteinase (MMP) and tissue inhibitors of MMP (TIMP) expression and activity that allow cells to move from the media through the extracellular matrix. Changes in MMPs, TIMPs, integrins and extracellular matrix constitute the proteolytic thermostat of a tissue. The goal of this program is to define the role of metabolic syndrome on the response to vascular injury with a particular focus on phospholipid signaling and define therapeutic options that will ameliorate its accelerant effects on the injury response. In the present proposal, we will test the hypothesis that S-1-P induced smooth muscle cell migration is enhanced in metabolic syndrome by redox-dependent regulation of the proteolytic thermostat. We will focus on the regulation of the MMP-2 pathway in a high glucose, free fatty acid rich environment in vitro and in vivo and plan: 1/ To examine the regulation of S-1-P mediated NAD(P)H oxidase activity;21 To determine the regulation the MMP-2 pathway by S-1-P;3/ To determine the role of the proteolytic thermostat in human vascular smooth muscle cells;4/ To evaluate the proteolytic thermostat in a vessel's response to injury and remodeling. This proposal examines two important components pf vessel remodeling, namely cell migration and the proteolytic thermostat. It is unique in that it addresses S-1-P signal transduction and protease activation in models of metabolic syndrome. By the end of this proposal, the role of smooth muscle cell migration in vitro and in vivo in metabolic syndrome will have been better defined. This will have direct clinical relevance to the biology of vascular injury after percutaneous intervention in patients with metabolic syndrome and will help guide therapy.
Funding Period: 2007-09-15 - 2012-06-30
more information: NIH RePORT

Top Publications

  1. doi Biology of metabolic syndrome in a vascular patient
    Daynene Vykoukal
    The Methodist Hospital Research Institute, Houston, TX 77030, USA
    Vascular 20:156-65. 2012
  2. pmc Gαq G proteins modulate MMP-9 gelatinase during remodeling of the murine femoral artery
    Yiping Zou
    Vascular Biology and Therapeutics Program, The Methodist Hospital Research Institute, Houston, Texas
    J Surg Res 181:32-40. 2013
  3. pmc Urokinase requires NAD(P)H oxidase to transactivate the epidermal growth factor receptor
    Enrico A Duru
    Department of Cardiovascular Surgery, Methodist DeBakey Heart and Vascular Center, Houston, TX, USA
    Surgery 152:879-85. 2012
  4. pmc Role for Gβγ G-proteins in protease regulation during remodeling of the murine femoral artery
    Yiping Zou
    Vascular Biology and Therapeutics Program, The Methodist Hospital Research Institute, and Department of Cardiovascular Surgery, Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, Texas 77030, USA
    J Surg Res 178:40-7. 2012
  5. pmc Vascular biology of metabolic syndrome
    Daynene Vykoukal
    Vascular Biology and Therapeutics Program, The Methodist Hospital Research Institute, The Methodist Hospital, Houston, TX77030, USA
    J Vasc Surg 54:819-31. 2011
  6. pmc Cell migration in response to the amino-terminal fragment of urokinase requires epidermal growth factor receptor activation through an ADAM-mediated mechanism
    Andrew M Bakken
    Vascular Biology and Therapeutics Program, Methodist DeBakey Heart and Vascular Center, Department of Cardiovascular Surgery, The Methodist Hospital, and The Methodist Hospital Research Institute, Houston, Tex 77030, USA
    J Vasc Surg 49:1296-303. 2009
  7. pmc Patterns of gelatinase activation induced by injury in the murine femoral artery
    Yiping Zou
    Vascular Biology and Therapeutics Program, Methodist DeBakey Heart and Vascular Center, Department of Cardiovascular Surgery, The Methodist Hospital, Houston, Texas 77030, USA
    J Surg Res 154:135-42. 2009
  8. pmc Mechanisms of sphingosine-1-phosphate-induced akt-dependent smooth muscle cell migration
    Elisa Roztocil
    Department of Cardiovascular Surgery, Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX 77030, USA
    Surgery 145:34-41. 2009
  9. pmc Insulin-induced epidermal growth factor activation in vascular smooth muscle cells is ADAM-dependent
    Elisa Roztocil
    Vascular Biology and Therapeutics Program, Methodist DeBakey Heart and Vascular Center, Department of Cardiovascular Surgery, The Methodist Hospital, Houston, TX 77030, USA
    Surgery 144:245-51. 2008
  10. pmc Sphingosine-1-phosphate-induced oxygen free radical generation in smooth muscle cell migration requires Galpha12/13 protein-mediated phospholipase C activation
    Eliza Roztocil
    Vascular Biology and Therapeutics Program, Department of Surgery, University of Rochester, Rochester, NY 14642, USA
    J Vasc Surg 46:1253-1259. 2007

Detail Information

Publications11

  1. doi Biology of metabolic syndrome in a vascular patient
    Daynene Vykoukal
    The Methodist Hospital Research Institute, Houston, TX 77030, USA
    Vascular 20:156-65. 2012
    ..This review focuses on the complex biology of metabolic syndrome and its relevance to management of vascular patients, including outcomes and implications for the coronary, cerebrovascular and lower-extremity vascular beds...
  2. pmc Gαq G proteins modulate MMP-9 gelatinase during remodeling of the murine femoral artery
    Yiping Zou
    Vascular Biology and Therapeutics Program, The Methodist Hospital Research Institute, Houston, Texas
    J Surg Res 181:32-40. 2013
    ..This study now examines the role of Gαq in the developing intimal hyperplasia in a murine model and the impact of disruption of Gαq signaling on intimal hyperplasia development...
  3. pmc Urokinase requires NAD(P)H oxidase to transactivate the epidermal growth factor receptor
    Enrico A Duru
    Department of Cardiovascular Surgery, Methodist DeBakey Heart and Vascular Center, Houston, TX, USA
    Surgery 152:879-85. 2012
    ..This study examines the role of NAD(P)H oxidase during epidermal growth factor receptor (EGFR) transactivation by ATF in human vascular smooth muscle cells (VSMC)...
  4. pmc Role for Gβγ G-proteins in protease regulation during remodeling of the murine femoral artery
    Yiping Zou
    Vascular Biology and Therapeutics Program, The Methodist Hospital Research Institute, and Department of Cardiovascular Surgery, Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, Texas 77030, USA
    J Surg Res 178:40-7. 2012
    ..The aim of this study is to characterize the expression of Gβγ G-proteins in the developing intimal hyperplasia in a murine model and the impact of disruption of Gβγ signaling on intimal hyperplasia development...
  5. pmc Vascular biology of metabolic syndrome
    Daynene Vykoukal
    Vascular Biology and Therapeutics Program, The Methodist Hospital Research Institute, The Methodist Hospital, Houston, TX77030, USA
    J Vasc Surg 54:819-31. 2011
    ....
  6. pmc Cell migration in response to the amino-terminal fragment of urokinase requires epidermal growth factor receptor activation through an ADAM-mediated mechanism
    Andrew M Bakken
    Vascular Biology and Therapeutics Program, Methodist DeBakey Heart and Vascular Center, Department of Cardiovascular Surgery, The Methodist Hospital, and The Methodist Hospital Research Institute, Houston, Tex 77030, USA
    J Vasc Surg 49:1296-303. 2009
    ..We hypothesize that A Disintegrin and Metalloproteinase Domains (ADAM) allows the transactivation of EGFR by ATF...
  7. pmc Patterns of gelatinase activation induced by injury in the murine femoral artery
    Yiping Zou
    Vascular Biology and Therapeutics Program, Methodist DeBakey Heart and Vascular Center, Department of Cardiovascular Surgery, The Methodist Hospital, Houston, Texas 77030, USA
    J Surg Res 154:135-42. 2009
    ..Modulation of the extracellular matrix by proteases is a pivotal component of the response to injury. The aim of this study is to characterize the changes in gelatinase (MMP-2/TIMP-2 and MMP-9/TIMP-1) systems in a murine model...
  8. pmc Mechanisms of sphingosine-1-phosphate-induced akt-dependent smooth muscle cell migration
    Elisa Roztocil
    Department of Cardiovascular Surgery, Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX 77030, USA
    Surgery 145:34-41. 2009
    ..The objective of this study was to examine the regulation of akt signaling during smooth muscle cell (SMC) migration in response to S-1-P...
  9. pmc Insulin-induced epidermal growth factor activation in vascular smooth muscle cells is ADAM-dependent
    Elisa Roztocil
    Vascular Biology and Therapeutics Program, Methodist DeBakey Heart and Vascular Center, Department of Cardiovascular Surgery, The Methodist Hospital, Houston, TX 77030, USA
    Surgery 144:245-51. 2008
    ..EGFR is transactivated by both G-protein-coupled receptors and receptor-linked tyrosine kinases and is key to many of their responses...
  10. pmc Sphingosine-1-phosphate-induced oxygen free radical generation in smooth muscle cell migration requires Galpha12/13 protein-mediated phospholipase C activation
    Eliza Roztocil
    Vascular Biology and Therapeutics Program, Department of Surgery, University of Rochester, Rochester, NY 14642, USA
    J Vasc Surg 46:1253-1259. 2007
    ..The role of phospholipase C (PLC) in oxygen free radical generation, and the regulation of VSMC migration in response to S-1-P, are poorly understood...
  11. pmc Patterns of kinase activation induced by injury in the murine femoral artery
    Yiping Zou
    Vascular Biology and Therapeutics Program, Department of Surgery, University of Rochester, Rochester, New York, USA
    J Surg Res 142:332-40. 2007
    ..The aim of this study was to define a baseline pattern of histological changes and kinase activation in a murine model...