Original ArticleCardiac mast cell- and chymase-mediated matrix metalloproteinase activity and left ventricular remodeling in mitral regurgitation in the dog
Introduction
In hearts subjected to chronic volume overload, there is a complex sequence of compensatory events resulting in a continued state of myocardial remodeling characterized by changes in both cardiac morphology and the extracellular matrix (ECM). Current evidence suggests that matrix metalloproteinase (MMP) activation is responsible for the dissolution of interstitial collagen in the heart secondary to chronic volume overload [1], [2], [3], [4]. It is this ECM remodeling, which is thought to cause the progressive left ventricular (LV) chamber remodeling characterized by a disproportionate increase in LV diameter relative to wall thickness and the eventual development of congestive heart failure (CHF) [1], [5], [6].
There is mounting evidence supporting the hypothesis that a cause-and-effect relationship exists between increased mast cell density, MMP activation, and LV remodeling. Mast cell secretory products, such as trypsin, chymase, and stromelysin (MMP-3), have previously been shown to be potent in vitro activators of MMPs [7], [8], [9]. Increased numbers of cardiac mast cells have been reported in animal models of hypertension [10], myocardial infarction [11], and mitral regurgitation (MR) [12], as well as in human patients with end-stage cardiomyopathy [13], [14]. However, none of these studies identified whether this influx of mast cells in the heart was associated with the pathogenesis of these various conditions.
We recently reported increases in cardiac mast cell density in a rat model of chronic volume overload induced by an infrarenal aortocaval fistula [1]. In this model, the number of cardiac mast cells is significantly increased within hours of imposing the volume overload. A marked increase in myocardial MMP activity is seen concomitant with the increased cardiac mast cell density, followed by a significant reduction in the interstitial collagen density during the first 5 days post-fistula [1], [3], [15]. The strong correlation between increased cardiac mast cell density and MMP activity suggested the possibility that cardiac mast cells mediate MMP activation. Consistent with that hypothesis, we recently demonstrated that chemically induced mast cell degranulation produced an almost immediate, substantial activation of MMP-2 accompanied by a marked degradation of the interstitial fibrillar collagen in the isolated rat heart [16]. Taken together, these studies clearly demonstrate that cardiac mast cells are capable of mediating in vivo MMP activation and subsequent ECM degradation.
We also previously reported the observation that LV mast cell density as well as angiotensin-converting enzyme (ACE) and chymase activity was increased in dogs after 16 weeks of experimentally induced MR, and that this was associated with dissolution of the fine collagen weave and LV dilatation [12], [17]. Mast cells are the principal source of chymase in the heart as well as other proteases which are capable of activating MMPs [8], [18], [19], [20]. Accordingly, the objectives of the present study were: (1) to investigate whether a relationship exists between cardiac mast cell density, MMP activity and myocardial remodeling in the MR model of chronic volume overload; and (2) to determine the potential contribution of mast cell-derived chymase to renin–angiotensin system (RAS) activation and angiotensin II (ANG II) production in the heart during the subacute (2 and 4 weeks) and chronic (24 weeks) stages of experimental MR.
Section snippets
Experimental preparation
Chronic MR was induced in conditioned mongrel dogs of both sexes (18–26 kg) by chordal rupture using a fluoroscopic-guided catheterization method, previously described [12], [21]. Each dog was anesthetized with droperidol (2.0 mg, I.V.) and fentanyl (0.04 mg, I.V.), intubated and maintained in a surgical plane of anesthesia with isoflurane (0.75–1.5%). The right carotid artery and jugular vein were exposed by blunt dissection. A Swan–Ganz catheter was then introduced into the jugular vein and
MMP-2 activity, mast cell density, and interstitial collagen content
MMP-2 activity was significantly elevated above that of control by 106% at 2 weeks, 60% at 4 weeks, and 71% at 24 weeks (Fig. 1). Cardiac mast cell density was increased 4-fold at 2 weeks and 3-fold at 4 weeks versus control; however, mast cell density returned to baseline levels by 24 weeks (Fig. 2). The LV interstitial CVF was significantly decreased by 41–57% versus control throughout the entire study (Fig. 3). There was also a significant correlation between cardiac mast cell density and
Discussion
The current study supports the hypothesis that a temporal relationship exists between myocardial mast cell density, chymase expression, MMP activation, and the evolution of adverse LV remodeling induced by MR in the dog. At the early time points, 2- and 4 week post-MR, there was a marked increase in both the number of myocardial mast cells and chymase activity. This was associated with a concurrent marked increase in myocardial MMP-2 activity and a significant reduction in the interstitial
Acknowledgements
We are grateful to Lisa Henegar for preparing the histological material and Wei Luo for determining MMP activity. This work was partially supported by grants from the Morris Animal Foundation (J.S.J.), NIH R01-HL59981 (J.S.J.), NIH R01-HL62228 (J.S.J.), American Heart Association, Southern Research Consortium Grant-In-Aid 0051505B (G.L.B.), NIH R01-HL54816 (L.J.D.), VA Merit Review (L.J.D.), and American Heart Association, Southern Research Consortium postdoctoral fellowship (C.C.W.).
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