Role of plasminogen activator inhibitor-1 in mediating age-related fibrosis

Summary

Principal Investigator: David Lu
Abstract: DESCRIPTION (provided by applicant): Cardiovascular aging results in cardiac fibrosis, diastolic dysfunction, and attenuated wound healing post-myocardial infarction (MI). While numerous studies have correlated increases in plasminogen activator inhibitor-1 (PAI-1) with aging, none have directly examined possible mechanisms of PAI-1-mediated inhibition of collagen turnover. The proposed study seeks to identify a role of PAI-1 in regulating age-related cardiac fibrosis. Age-dependent increases of PAI-1 correlate with decreased matrix metalloprotease (MMP) activity, increased collagen deposition, and blunted inflammatory response. As a consequence of impaired ECM degradation and fibroblast migration, the reduction in MMP activity may cause ventricular fibrosis by increasing collagen deposition and diminished inflammatory responses post-MI. Isolated rat cardiac fibroblasts (CFs) will be used to investigate the relationship between PAI-1 release and potential effects on collagen deposition and CF migration. The first aim of this study asks whether PAI-1 produced and released by CFs increases collagen deposition by inhibiting MMP activation. Total and active MMPs will be assayed in CFs by Western blotting, zymography, and ELISA. The second aim compares PAI-1 expression in CFs isolated from young and aged rats to examine whether expression increases with age and is responsible for increased collagen accumulation. The increase of PAI-1 with age is hypothesized to attenuate MMP activity. This in turn decreases collagen degradation and may also inhibit CF migration. Finally, the third aim of the study will use an ex vivo rat ischemia-reperfusion model. This provides a system to ascertain whether PAI-1 expression is increased basally in aged hearts and whether PAI-1 is up-regulated in physiologically relevant concentrations following ischemic stress. Acute inhibition of MMP activity by PAI-1 may explain the attenuated inflammatory and wound healing responses post-MI seen in aged individuals. Together, these findings may identify a novel PAI-1 dependent mechanism in which aged hearts are more prone to both fibrosis and attenuated wound healing following ischemic damage.
Funding Period: 2012-01-01 - 2013-06-30
more information: NIH RePORT

Top Publications

  1. pmc ATP released from cardiac fibroblasts via connexin hemichannels activates profibrotic P2Y2 receptors
    David Lu
    Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
    FASEB J 26:2580-91. 2012
  2. pmc Hydrolysis of extracellular ATP by ectonucleoside triphosphate diphosphohydrolase (ENTPD) establishes the set point for fibrotic activity of cardiac fibroblasts
    David Lu
    Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA
    J Biol Chem 288:19040-9. 2013
  3. pmc Increase in cellular cyclic AMP concentrations reverses the profibrogenic phenotype of cardiac myofibroblasts: a novel therapeutic approach for cardiac fibrosis
    David Lu
    Departments of Pharmacology D L, N A, U Y, P A I and Medicine P A I, University of California, San Diego, La Jolla, California Veterans Affairs San Diego Healthcare System, San Diego, California H H P Department of Anesthesiology, University of California, San Diego, La Jolla, California H H P and Cardiovascular Research Institute, Yokohama City University, Yokohama, Japan U Y
    Mol Pharmacol 84:787-93. 2013
  4. pmc Cellular mechanisms of tissue fibrosis. 6. Purinergic signaling and response in fibroblasts and tissue fibrosis
    David Lu
    Department of Pharmacology, University of California, San Diego, La Jolla, California and
    Am J Physiol Cell Physiol 306:C779-88. 2014

Research Grants

  1. Mental Stress Ischemia: Prognosis and Genetic Influences
    Arshed A Quyyumi; Fiscal Year: 2013
  2. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
  3. FIBROBLAST GROWTH FACTOR SIGNALING IN HEART INJURY AND REPAIR
    David M Ornitz; Fiscal Year: 2013
  4. Cardioprotective Effect of Growth Hormone Releasing Hormone
    Joshua M Hare; Fiscal Year: 2013
  5. Extracellular matrix remodeling and fibrosis
    JANE M SOTTILE; Fiscal Year: 2013
  6. Restoring Mycocardial Healing
    MARK ALAN SUSSMAN; Fiscal Year: 2013
  7. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
  8. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
  9. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
  10. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013

Detail Information

Publications4

  1. pmc ATP released from cardiac fibroblasts via connexin hemichannels activates profibrotic P2Y2 receptors
    David Lu
    Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
    FASEB J 26:2580-91. 2012
    ..Thus, ATP release activates P2Y(2) receptors to mediate profibrotic responses in CFs, implying that nucleotide release under both basal and activated states is likely an important mechanism for fibroblast homeostasis...
  2. pmc Hydrolysis of extracellular ATP by ectonucleoside triphosphate diphosphohydrolase (ENTPD) establishes the set point for fibrotic activity of cardiac fibroblasts
    David Lu
    Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA
    J Biol Chem 288:19040-9. 2013
    ..These findings also imply that cellular homeostasis and fibrotic response involve the integration of signaling that is pro-fibrotic by ATP and anti-fibrotic by adenosine and that is regulated by ENTPDs. ..
  3. pmc Increase in cellular cyclic AMP concentrations reverses the profibrogenic phenotype of cardiac myofibroblasts: a novel therapeutic approach for cardiac fibrosis
    David Lu
    Departments of Pharmacology D L, N A, U Y, P A I and Medicine P A I, University of California, San Diego, La Jolla, California Veterans Affairs San Diego Healthcare System, San Diego, California H H P Department of Anesthesiology, University of California, San Diego, La Jolla, California H H P and Cardiovascular Research Institute, Yokohama City University, Yokohama, Japan U Y
    Mol Pharmacol 84:787-93. 2013
    ..We conclude that therapeutic strategies designed to enhance cellular cAMP concentrations in CFs may provide a means to reverse excessive scar formation following injury and to treat cardiac fibrosis. ..
  4. pmc Cellular mechanisms of tissue fibrosis. 6. Purinergic signaling and response in fibroblasts and tissue fibrosis
    David Lu
    Department of Pharmacology, University of California, San Diego, La Jolla, California and
    Am J Physiol Cell Physiol 306:C779-88. 2014
    ..This review summarizes recent findings related to purinergic signaling in the regulation of fibroblasts and the development of tissue fibrosis in the heart, lungs, liver, and kidney...

Research Grants30

  1. Mental Stress Ischemia: Prognosis and Genetic Influences
    Arshed A Quyyumi; Fiscal Year: 2013
    ....
  2. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  3. FIBROBLAST GROWTH FACTOR SIGNALING IN HEART INJURY AND REPAIR
    David M Ornitz; Fiscal Year: 2013
    ..This knowledge will be essential to effectively design and implement FGF-based therapies for the treatment of human CVD. ..
  4. Cardioprotective Effect of Growth Hormone Releasing Hormone
    Joshua M Hare; Fiscal Year: 2013
    ..This proposal has major implications for developing a promising new treatment strategy for the prevention and reversal of remodeling following MI. ..
  5. Extracellular matrix remodeling and fibrosis
    JANE M SOTTILE; Fiscal Year: 2013
    ..These studies may lead to the development a new therapeutic approach for limiting fibrosis, for which there are few effective treatments. ..
  6. Restoring Mycocardial Healing
    MARK ALAN SUSSMAN; Fiscal Year: 2013
    ..The goal of this program will be to delineate these deleterious signaling mechanisms and determine how they can be overcome to restore endogenous cellular repair processes that heal the damaged heart. ..
  7. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  8. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
    ..The long-term objective of this PPG is to advance basic understanding of vector-cell-animal model interactions for safe gene delivery. ..
  9. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  10. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  11. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..