Prevention of Vein Graft Failure

Summary

Principal Investigator: Colleen M Brophy
Affiliation: Vanderbilt University
Country: USA
Abstract: Approximately 1,000,000 aortocoronary and peripheral vascular revascularizations are performed using autologous conduits. The leading cause of graft failure is the subsequent development of intimal hyperplasia. Intimal hyperplasia represents a response to injury that involves smooth muscle proliferation, migration, phenotypic modulation, and extracellular matrix (ECM) deposition. This proposal will develop a cell permeant peptide therapeutic to enhance graft patency by preventing the events that lead to intimal hyperplasia. A small heat shock protein, HSP27, is phosphorylated by a kinase cascade involving p38 map kinase and MAPKAP kinase II (MK2). Phosphorylated HSP27 is associated with the formation of actin stress fibers (myofibroblast phenotype) and enhanced smooth muscle migration. We have developed a cell permeant peptide that inhibits MK2. This peptide also inhibits stress fiber formation and ECM production. The specific aims of this proposal are: Specific aim #1: Determine the effect of transducible peptides which inhibit the phosphorylation of HSP27 on smooth muscle physiology, morphology, and biochemistry: We will determine the effect of the novel MK2 inhibitor peptide on intact human vascular smooth muscle segments and cultured vascular smooth muscle cells. Specific aim #2: Determine the effect of optimized peptide mimetics on intimal hyperplasia. We will first determine the effect of the MK2 inhibitor on intimal hyperplasia in a human saphenous vein graft organ culture model. Subsequently, we will determine the effect of the mimetics in vivo in a rabbit carotid interposition model. Specific aim #3: Determine the molecular mechanisms by which phosphorylated HSP27 "stabilizes" the actin cytoskeleton: We will use quantitative, high throughput mass spectrometry techniques to analyze the molecular associations of phosphorylated and nonphosphorylated HSP27. The goal of this project is to engineer biomolecules that enhance graft patency using protein transduction domains to directly introduce peptides into smooth muscle cells. Autologous conduits represent an ideal target for this therapeutic approach in that the graft can be treated ex vivo, thus providing an optimal environment for the delivery of engineered protein/peptide therapeutics. The molecules designed in this proposal represent novel therapeutics in that the usual targets of drug development (cell surface receptors and signaling cascades) are "bypassed" and protein-protein interactions are stoichiometrically altered by changing the phosphorylation of downstream target effector proteins (HSP27).
Funding Period: ----------------2002 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. pmc Enhanced skin penetration of P20 phosphopeptide using protein transduction domains
    Luciana B Lopes
    Center for Metabolic Biology, Arizona State University, Tempe, AZ, USA
    Eur J Pharm Biopharm 68:441-5. 2008
  2. pmc Role of cyclic nucleotide-dependent actin cytoskeletal dynamics:Ca(2+)](i) and force suppression in forskolin-pretreated porcine coronary arteries
    Kyle M Hocking
    Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    PLoS ONE 8:e60986. 2013
  3. doi Cell-permeant peptide inhibitors of vasospasm and intimal hyperplasia
    Michael J Osgood
    Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
    Vascular 21:46-53. 2013
  4. pmc Intimal thickness associated with endothelial dysfunction in human vein grafts
    Fan dong Li
    Department of Surgery, Division of Vascular Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    J Surg Res 180:e55-62. 2013
  5. doi Role of the renin-angiotensin system in the pathogenesis of intimal hyperplasia: therapeutic potential for prevention of vein graft failure?
    Michael J Osgood
    Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 0011, USA
    Ann Vasc Surg 26:1130-44. 2012
  6. pmc Pressure control during preparation of saphenous veins
    Fan dong Li
    General Hospital of Jinan Military District, Jinan, China
    JAMA Surg 149:655-62. 2014
  7. pmc Surgical skin markers impair human saphenous vein graft smooth muscle and endothelial function
    Susan Eagle
    Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    Am Surg 77:922-8. 2011
  8. pmc Detrimental effects of mechanical stretch on smooth muscle function in saphenous veins
    Kyle M Hocking
    Department of Surgery, Vanderbilt University Medical Center, Nashville, Tenn 37232 2735, USA
    J Vasc Surg 53:454-60. 2011
  9. pmc A novel cell permeant peptide inhibitor of MAPKAP kinase II inhibits intimal hyperplasia in a human saphenous vein organ culture model
    Luciana B Lopes
    Center for Metabolic Biology, Arizona State University, Tempe, AZ, USA
    J Vasc Surg 52:1596-607. 2010
  10. pmc The small heat shock protein, HSPB6, in muscle function and disease
    Catherine M Dreiza
    Capstone Therapeutics, Tempe, AZ 85281, USA
    Cell Stress Chaperones 15:1-11. 2010

Scientific Experts

  • Padmini Komalavilas
  • Colleen M Brophy
  • Kyle M Hocking
  • Joyce Cheung-Flynn
  • Michael J Osgood
  • Susan Eagle
  • Luciana B Lopes
  • Fan dong Li
  • Colleen Brophy
  • Charles R Flynn
  • Alyssa Panitch
  • Michael Osgood
  • Kevin W Sexton
  • Gowthami Putumbaka
  • Akihito Muto
  • Marzia Leacche
  • Catherine M Dreiza
  • Sneha Venkatraman
  • Franz J Baudenbacher
  • David G Harrison
  • Igor V Voskresensky
  • Raul J Guzman
  • Kinam Park
  • Namho Kim
  • Alan Dardik
  • Kyle Hocking
  • Jorge M Balaguer
  • Syed Z Rizvi
  • Kevin Sexton
  • Michael R Sheller
  • Brandon Seal
  • Christopher Smoke
  • Elizabeth J Furnish
  • ZhengPing Yi
  • Benjamin P Bowen
  • Christopher C Smoke
  • Brandon L Seal
  • Elizabeth Furnish
  • M Vitoria L B Bentley

Detail Information

Publications11

  1. pmc Enhanced skin penetration of P20 phosphopeptide using protein transduction domains
    Luciana B Lopes
    Center for Metabolic Biology, Arizona State University, Tempe, AZ, USA
    Eur J Pharm Biopharm 68:441-5. 2008
    ..It was concluded that selected non-covalently linked PTDs can be used as a penetration enhancer, but greater skin penetration efficiency can be achieved by covalently binding the PTD to the therapeutic agent...
  2. pmc Role of cyclic nucleotide-dependent actin cytoskeletal dynamics:Ca(2+)](i) and force suppression in forskolin-pretreated porcine coronary arteries
    Kyle M Hocking
    Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    PLoS ONE 8:e60986. 2013
    ..This model of complete force suppression can be employed to further elucidate the mechanisms responsible for smooth muscle tone, and may offer cues to pathological situations, such as hypertension and vasospasm...
  3. doi Cell-permeant peptide inhibitors of vasospasm and intimal hyperplasia
    Michael J Osgood
    Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
    Vascular 21:46-53. 2013
    ....
  4. pmc Intimal thickness associated with endothelial dysfunction in human vein grafts
    Fan dong Li
    Department of Surgery, Division of Vascular Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    J Surg Res 180:e55-62. 2013
    ..In the present investigation, we hypothesized that the basal intimal thickness in the human saphenous vein is a predictor of endothelial dysfunction and, potentially, intimal hyperplasia...
  5. doi Role of the renin-angiotensin system in the pathogenesis of intimal hyperplasia: therapeutic potential for prevention of vein graft failure?
    Michael J Osgood
    Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 0011, USA
    Ann Vasc Surg 26:1130-44. 2012
    ....
  6. pmc Pressure control during preparation of saphenous veins
    Fan dong Li
    General Hospital of Jinan Military District, Jinan, China
    JAMA Surg 149:655-62. 2014
    ..Preparation of HSVs before implantation leads to conduit injury, which may promote VGF...
  7. pmc Surgical skin markers impair human saphenous vein graft smooth muscle and endothelial function
    Susan Eagle
    Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    Am Surg 77:922-8. 2011
    ..Our data demonstrated that marking HSV with surgical skin markers reduces smooth muscle and endothelial functional viability...
  8. pmc Detrimental effects of mechanical stretch on smooth muscle function in saphenous veins
    Kyle M Hocking
    Department of Surgery, Vanderbilt University Medical Center, Nashville, Tenn 37232 2735, USA
    J Vasc Surg 53:454-60. 2011
    ..This study evaluated the smooth muscle functional response and viability of human saphenous vein (HSV) grafts after harvest and explored the effect of mechanical stretch on contractile responses of porcine saphenous vein (PSV)...
  9. pmc A novel cell permeant peptide inhibitor of MAPKAP kinase II inhibits intimal hyperplasia in a human saphenous vein organ culture model
    Luciana B Lopes
    Center for Metabolic Biology, Arizona State University, Tempe, AZ, USA
    J Vasc Surg 52:1596-607. 2010
    ....
  10. pmc The small heat shock protein, HSPB6, in muscle function and disease
    Catherine M Dreiza
    Capstone Therapeutics, Tempe, AZ 85281, USA
    Cell Stress Chaperones 15:1-11. 2010
    ..This review will focus on the physiologic and biochemical properties of HSPB6 in smooth, cardiac, and skeletal muscle; the putative mechanisms of action; and therapeutic implications...
  11. pmc Inhibition of Mitogen Activated Protein Kinase Activated Protein Kinase II with MMI-0100 reduces intimal hyperplasia ex vivo and in vivo
    Akihito Muto
    Department of Surgery, Yale University School of Medicine, New Haven, CT, USA
    Vascul Pharmacol 56:47-55. 2012
    ..MMI-0100 prevents vein graft intimal thickening ex vivo and in vivo. These results suggest that inhibition of MK2 with the cell-permeant peptide MMI-0100 may be a novel strategy to suppress fibrotic processes such as vein graft disease...