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

University Of California, San Diego, La Jolla CA

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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.