Abstract 19867: Pai-1 Regulates Cardiac Tgf-β Expression And Fibrosis
Introduction: Cardiac fibrosis is the pathologic consequence of stress-induced myocardial remodeling and matrix accumulation. Our group and others have previously reported that genetic deficiency of the serine protease inhibitor, plasminogen activator inhibitor type I (PAI-1), leads to age-dependent spontaneous cardiac-selective fibrosis.
Hypothesis: We hypothesized that PAI-1 knockout mice (PAI-1 -/-) would exhibit accelerated fibrosis following myocardial stress, and that PAI-1 serves as a molecular switch that regulates TGF-β, extracellular matrix, and integrin expression following cardiac injury.
Results: Following infusion of Angiotensin II (AngII) via osmotic minipump (1000 ng/kg/min) PAI-1 -/- mice exhibit augmented cardiac fibrosis (16.4% vs 3.4% fibrotic area, p<0.005), and reduced systolic function (EF 40% vs 57%, p<0.005) compared to wild type mice (WT). Absence of PAI-1 did not mitigate cardiac hypertrophy, but attenuated AngII-mediated hypertension (SBP 134 mm Hg vs 167 mm Hg, p<0.05) compared to WT mice. Immunostaining of cardiac tissue reveals that laminin disorganization and cardiomyocyte β3-integrin expression occurs both during aging as well as AngII-induced interstitial fibrosis in PAI-1 -/- mice. Whole heart RNA sequencing analysis after only 1 week of AngII treatment reveals that PAI-1 -/- mice had marked elevation in transcripts for multiple forms of collagen, as well as other matrix components including matricellular proteins compared to WT mice. Cardiac integrin transcripts were also significantly altered, with the most pronounced elevation observed in integrin β3. Finally, absence of PAI-1 led to dramatic increases in cardiac TGF-β and TGF-β-receptor RNA in response to AngII. Interestingly, immunostaining also demonstrates that ventricular myocytes are a major source of TGF-β in the PAI-1 -/- heart.
Conclusions: PAI-1 is a key negative regulator of cardiomyocyte TGF-β expression and fibrosis in response to AngII. Together, these results define an upstream role of PAI-1 in matrix homeostasis and TGF-β-mediated fibrogenesis in multiple forms of cardiac stress.
Author Disclosures: P. Flevaris: None. M. Eren: None. A. Mackie: None. S. Khan: None. D. Vaughan: None.
- © 2016 by American Heart Association, Inc.