Cardiac mast cell-mediated activation of gelatinase and alteration of ventricular diastolic function

Abstract

Mast cells contain proteases capable of activating matrix metalloproteinases (MMPs). However, given the relatively low density of mast cells in the myocardium (i.e., 1.5-5.3 cells/mm(2)), it is unknown whether these enzymes are present in sufficient quantities in the normal heart to mediate MMP activation. Accordingly, this study sought to determine whether chemically induced degranulation of cardiac mast cells (with compound 48/80) would have an effect in isolated, blood-perfused, functioning rat hearts. Mast cell degranulation produced a 15% increase in histamine levels present in the coronary efflux, a significant increase in myocardial water (i.e., edema) relative to normal values (80.1 +/- 3.4% vs. 77.4 +/- 1.08%, P < or = 0.03), a substantial activation of MMP-2 (126% increase relative to controls, P < or = 0.02), and a marked decrease in myocardial collagen volume fraction (0.46 +/- 0.10% vs. 0.97 +/- 0.33%, P < or = 0.001). Furthermore, although an increase in ventricular stiffness was expected due to the extent of edema resulting from mast cell degranulation, modest ventricular dilatation was observed. These findings clearly demonstrate that the number of mast cells present in normal hearts is sufficient to mediate activation of MMPs and produce extracellular matrix degradation, thereby potentially causing subsequent ventricular dilatation.

Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

“…Previous work using the AV fistula model of chronic volume overload established a causal role for cardiac mast cells in the regulation of MMP activity (3,8). Mast cell-mediated MMP activation, leading to degradation of the extracellular matrix and ventricular dilatation, are well-documented features in this model of heart failure (3,6,8,9,20).…”

“…At the end of the experimental period, a transmural section of LV was taken from the midventricle and placed in buffered formalin for fixation. The tissue was then processed for routine histopathology, using sequential 5-m paraffin-embedded sections stained with either pinacyanol erthrosinate for the visualization of mast cell morphology or picrosirius red for quantification of myocardial interstitial collagen volume fraction (CVF) as previously described (8,31). Mast cell density was determined from the total number of mast cells per LV cross section normalized for the total myocardial area determined from the digitized image (ImageQuant, Molecular Dynamics).…”

“…MMP activity in cardiac tissue extracts was analyzed using gelatin zymography performed by standard procedures using a sodium dodecyl sulfate-polyacrylamide gel electrophoresis matrix containing gelatin (1 mg/ml) (8). The activity of the bands was quantified by densitometry (ImageQuant, Molecular Dynamics).…”

“…The ET B receptor subtype is responsible for systemic clearance of circulating ET-1 and nitric oxide (NO)-dependent vasodilatation (1). Previous studies from our laboratory using the aortocaval (AV) fistula model of volume overload established a causal role for cardiac mast cells in the activation of matrix metalloproteinases (MMPs) (3,8,22,31). The role of MMPs in mediating the degradation of the extracellular matrix leading to ventricular dilatation has been well documented (3,6,9,20,38).…”

The immune system and cardiac repair

“…Furthermore, mast cells are important sources of TGF-β [229], bFGF [230], and Vascular Endothelial Growth Factor (VEGF) [231], factors that can regulate fibroblast growth, modulate extracellular matrix metabolism and stimulate angiogenesis [232]. Mast cells may also influence healing and tissue remodeling by expressing gelatinases A and B [233][234][235] which are implicated in extracellular matrix metabolism. Finally, an important role for the chymase pathway in promoting angiotensin II generation and cardiac fibrosis has been suggested [236].…”