"Phospholipids, Metabolic Syndrome and Response to Injury"
Principal Investigator: MARK GLYNN DAVIES
Affiliation: The Methodist Hospital
Abstract: 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
- Patterns of kinase activation induced by injury in the murine femoral arteryYiping 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...
- Sphingosine-1-phosphate-induced oxygen free radical generation in smooth muscle cell migration requires Galpha12/13 protein-mediated phospholipase C activationEliza 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...
- Insulin-induced epidermal growth factor activation in vascular smooth muscle cells is ADAM-dependentElisa 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...
- Mechanisms of sphingosine-1-phosphate-induced akt-dependent smooth muscle cell migrationElisa 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...
- Patterns of gelatinase activation induced by injury in the murine femoral arteryYiping 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...
- Cell migration in response to the amino-terminal fragment of urokinase requires epidermal growth factor receptor activation through an ADAM-mediated mechanismAndrew 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...