Abstract
Introduction: Preclinical data indicate that plasminogen activator inhibitor-1 (PAI-1) is cardioprotective by repressing fibrosis through TGF-β and plasminogen mediated pathways. Moreover, PAI-1 is suggested to be involved in the recruitment and polarization of M2 macrophages. Hypothesis: Elevated myocardial PAI-1 expression protects from fibrosis and acute inflammatory response. Methods: Endomyocardial biopsies (EMBs) of patients with dilated cardiomyopathy (DCM, n=27) and inflammatory dilated cardiomyopathy (DCMi, n=149) were retrospectively analyzed for PAI-1 expression, markers of fibrosis and M1/M2 macrophage polarization. Results: Patients with high-grade myocardial inflammation (DCMi-high, CD3 + lymphocytes > 30 cells/mm 2 ) had significantly increased PAI-1 levels compared to DCM and low-grade DCMi patients (DCMi-low, CD3 + lymphocytes = 14 - 30 cells/mm 2 ) (15.5 ± 0.4 % vs. 1.0 ± 0.1 % and 4.0 ± 0.1 %, p ≤ 0.001). Elevated PAI-1 expression in DCMi-high subjects was associated with a diminished degree of tissue fibrosis, accompanied by decreased levels of TGF-β and a reduced number of cardiac myofibroblasts. In addition, elevation of PAI-1 led to a shift from M1 to M2 macrophages. Conclusions: Our findings give evidence that increased expression of PAI-1 in DCMi patients suppresses cardiac fibrosis and promotes M2 macrophage polarization. Thus, PAI-1 could serve as a potential prognostic biomarker of cardiac fibrosis and inflammation, as well as possible therapeutic target in inflammatory cardiomyopathies.
Published Version
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