Abstract
BackgroundTissue fibrosis and chamber remodeling is a hallmark of the failing heart and the final common pathway for heart failure of diverse etiologies. Sustained elevation of pro-fibrotic cytokine transforming growth factor-beta1 (TGFβ1) induces cardiac myofibroblast-mediated fibrosis and progressive structural tissue remodeling.ObjectivesWe examined the effects of low molecular weight fibroblast growth factor (LMW-FGF-2) on human cardiac myofibroblast-mediated extracellular matrix (ECM) dysregulation and remodeling.MethodsHuman cardiac biopsies were obtained during open-heart surgery and myofibroblasts were isolated, passaged, and seeded within type I collagen matrices. To induce myofibroblast activation and ECM remodeling, myofibroblast-seeded collagen gels were exposed to TGFβ1. The extent of ECM contraction, myofibroblast activation, ECM dysregulation, and cell apoptosis was determined in the presence of LMW-FGF-2 and compared to its absence. Using a novel floating nylon-grid supported thin collagen gel culture platform system, myofibroblast activation and local ECM remodeling around isolated single cells was imaged using confocal microscopy and quantified by image analysis.ResultsTGFβ1 induced significant myofibroblast activation and ECM dysregulation as evidenced by collagen gel contraction, structural ECM remodeling, collagen synthesis, ECM degradation, and altered TIMP expression. LMW-FGF-2 significantly attenuated TGFβ1 induced myofibroblast-mediated ECM remodeling. These observations were similar using either ventricular or atrial-derived cardiac myofibroblasts. In addition, for the first time using individual cells, LMW-FGF-2 was observed to attenuate cardiac myofibroblast activation and prevent local cell-mediated ECM perturbations.ConclusionsLMW-FGF-2 attenuates human cardiac myofibroblast-mediated ECM remodeling and may prevent progressive maladaptive chamber remodeling and tissue fibrosis for patients with diverse structural heart diseases.
Highlights
Tissue fibrosis and chamber remodeling is a hallmark of the failing heart and the final common pathway for heart failure of diverse etiologies
For the first time, we provide a novel assessment of the effects of LMW-fibroblast growth factor (FGF)-2 on human cardiac myofibroblast-mediated extracellular matrix (ECM) remodeling using an innovative 3-dimensional (3D) in vitro model
Transforming growth factor-beta1 (TGFβ1), a critical pro-fibrotic mediator of human diseases, stimulates cardiac fibroblasts to undergo phenotypic conversion into active myofibroblasts resulting in collagen ECM remodeling and fibrosis [4]
Summary
Tissue fibrosis and chamber remodeling is a hallmark of the failing heart and the final common pathway for heart failure of diverse etiologies. Specific bioactive proteins play an important role in maintaining ECM homeostasis by regulating the interaction between fibroblasts and their adjacent collagen matrix [12]. We believe that such bioactive proteins could be leveraged as effective therapeutic targets for patients at risk of cardiac remodeling and heart failure. We found FGF-2 to be an effective anti-remodeling therapy when used in a biosurgical approach with a lowmolecular weight FGF-2 (LMW-FGF-2) enhanced biomaterial surgically implanted on the epicardial surface of the heart after MI [11] These data and others suggest that LMW-FGF-2, through its bioactive effects on ECM homeostasis, may be a promising target as an antiremodeling strategy after MI
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