The role of smooth muscle PPAR gamma in neointima formation

Summary

Principal Investigator: SETH BERNAT FURGESON
Abstract: DESCRIPTION (provided by applicant): PROJECT SUMMARY The goal of this project is to define the role of peroxisome proliferator-activated receptor (PPAR)3 activation in neointima formation. Neointima formation occurs frequently after angioplasty and causes significant morbidity;vascular smooth muscle cells (SMCs) are key cells during neointima formation. We will study the effects of two clinically available agents on SMC biology and neointima formation. PPAR3 is a ligand-activated nuclear receptor that has been shown to have beneficial effects on vascular disorders. We will compare the effects of two agents: pioglitazone (activates PPAR3 only) and bexarotene (an RXR agonist which activates PPAR3, PPAR1, PPAR4, LXR, and FXR). Our hypothesis is that PPAR3 activation specifically in smooth muscle cells (SMC) will reduce neointima formation by decreasing resident SMC migration and proliferation as well as SMC-derived chemokine production and subsequent recruitment of bone marrow-derived cells. We believe both pioglitazone and bexarotene will be effective but bexarotene may be more effective due to activation of other nuclear receptors. In Aim One, we will compare the effects of pioglitazone to bexarotene on SMCs. We will measure changes in proliferation, cytokine production, and smooth muscle gene expression. In Aim Two, we will determine if the agents affect levels of microRNAs crucial to maintaining SMC phenotype, such as miR- 143, miR-145, and miR-221. In Aim Three, we will examine the effects of the agents in vivo during femoral artery wire injury. To track recruitment of bone-marrow derived cells to the site of arterial injury, all mice will receive bone marrow transplants from a GFP positive donor. After wire injury, mice will be analyzed at multiple time points. Along with neointima size, we will measure production of chemokines (IL-6, MCP-1, SDF-11, and KC), recruitment of bone marrow-derived cells and macrophages, and cellular proliferation. We also plan to study the role of PPAR3 activation specifically in smooth muscle cells during neointima formation. Using an inducible tissue-specific knockout model, we will deplete PPAR3 in smooth muscle cells after mice have received bone marrow transplants from GFP positive donors. Inducible PPAR3 knockout mice and control mice will receive therapy with either pioglitazone, bexarotene or control and be subjected to femoral artery wire injury. At multiple time points, neointima size will again be measured. All mice used in Aim 3B will have the R26R reporter allele in which smooth muscle cells are labeled with 2-galactosidase. Since we can measure both bone marrow derived and resident SMCs, we will determine the relative contribution each cell type makes to the neointima. We will also be able to determine if PPAR3 specifically in smooth muscle cells mediates the effects of bexarotene or pioglitazone. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Bexarotene and pioglitazone are two clinically used drugs that activate PPAR3. In Aim One, we will test whether both agents can affect smooth muscle cell biology equally and, in Aim Two, we will determine whether the agents can change microRNA levels. In Aim Three, we will determine which agent can reduce neointima size the greatest after wire injury.
Funding Period: 2011-04-18 - 2016-03-31
more information: NIH RePORT

Top Publications

  1. pmc SDF-1α induction in mature smooth muscle cells by inactivation of PTEN is a critical mediator of exacerbated injury-induced neointima formation
    Raphael A Nemenoff
    Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA
    Arterioscler Thromb Vasc Biol 31:1300-8. 2011
  2. pmc Serum response factor regulates expression of phosphatase and tensin homolog through a microRNA network in vascular smooth muscle cells
    Henrick N Horita
    Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
    Arterioscler Thromb Vasc Biol 31:2909-19. 2011

Detail Information

Publications2

  1. pmc SDF-1α induction in mature smooth muscle cells by inactivation of PTEN is a critical mediator of exacerbated injury-induced neointima formation
    Raphael A Nemenoff
    Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA
    Arterioscler Thromb Vasc Biol 31:1300-8. 2011
    ..We investigated the effects of SDF-1α on resident SMC and bone marrow-derived cells and in mediating neointima formation...
  2. pmc Serum response factor regulates expression of phosphatase and tensin homolog through a microRNA network in vascular smooth muscle cells
    Henrick N Horita
    Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
    Arterioscler Thromb Vasc Biol 31:2909-19. 2011
    ..Our goal was to determine the effect of SRF depletion on PTEN levels and define mechanisms mediating this effect...

Research Grants30

  1. KLF4-Dependent Regulation of SMC Differentiation and Phenotypic Switching
    Gary K Owens; Fiscal Year: 2013
    ..abstract_text> ..
  2. Role of Hippo-YAP Pathway in Smooth Muscle Phenotypic Modulation
    Jiliang Zhou; Fiscal Year: 2013
    ..abstract_text> ..
  3. Improved Therapeutics for Drug Eluting Stents
    Alyssa Panitch; Fiscal Year: 2013
    ..This proposal focuses on new DESs that promote endothelialization while preventing intimal hyperplasia and thrombosis. ..
  4. NFATs and Vascular Injury
    Gadiparthi N Rao; Fiscal Year: 2013
    ....
  5. The Role of PPARgamma in Lung Cancer Progression and Metastasis
    Howard Li; Fiscal Year: 2013
    ..Such an environment maximizes the potential for the applicant to establish a scientific niche from which an academic career can be constructed. ..
  6. GPCR Signaling &Vascular Wall Remodeling
    Gadiparthi N Rao; Fiscal Year: 2013
    ....
  7. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  8. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  9. TGF-Beta in Intimal Hyperplasia after Vascular Bypass
    K Craig Kent; Fiscal Year: 2013
    ..The long-term goal is to develop specific therapies that prevent or halt the progression of arterial restenosis, thus reducing morbidity and mortality for thousands of individuals each year. ..
  10. CALCIUM/CALMODULIN ACTIVATED KINASES IN SMOOTH MUSCLE
    Harold A Singer; Fiscal Year: 2013
    ..abstract_text> ..
  11. Connection of Mineral and Energy Metabolism by the Nuclear Receptor PPAR-gamma
    Yihong Wan; Fiscal Year: 2013
    ..Therefore, this investigation will significantly impact the broader scientific, clinical, and patient community. ..