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Endothelin-1 mediates cardiac mast cell degranulation, matrix metalloproteinase activation, and myocardial remodeling in rats

Department of Anatomy, Physiology, and Pharmacology, Auburn University, Auburn, Alabama 36849

Submitted 21 January 2004 ; accepted in final form 30 June 2004

	ABSTRACT

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The objective of this study was to determine whether elevated circulating levels of endothelin (ET)-1 are capable of mediating left ventricular (LV) mast cell degranulation and thereby induce matrix metalloproteinase (MMP) activation. After the administration of 20 pg/ml ET-1 to blood-perfused isolated rat hearts, LV tissue was analyzed for signs of mast cell degranulation and MMP activation. Relative to control, ET-1 produced extensive mast cell degranulation as well as a significant increase in myocardial water content (78.8 ± 1.5% vs. 74.2 ± 2.2%, P < 0.01), a marked 107% increase in MMP-2 activity (P < 0.05), and a substantial decrease in collagen volume fraction (0.69 ± 0.09% vs. 0.99 ± 0.04%, P < 0.001). Although the myocardial edema would be expected to increase ventricular stiffness, compliance was not altered, and moderate ventricular dilatation was observed (end-diastolic volume at end-diastolic pressure of 0 mmHg of 330.2 ± 22.1 vs. 298.9 ± 17.4 µl in ET-1 treated vs. control, respectively, P = 0.07). Additionally, pretreatment with the mast cell stabilizer nedocromil prevented ET-1-induced changes in MMP-2 activity, myocardial water content, collagen volume fraction, and end-diastolic volume. These findings demonstrate that ET-1 is a potent cardiac mast cell secretogogue and further indicate that ET-1-mediated mast cell degranulation is a potential mechanism responsible for myocardial remodeling.

isolated heart; extracellular matrix; nedocromil; ventricular function

	MATERIALS AND METHODS

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All experiments were performed using adult male Sprague-Dawley rats housed under standard environmental conditions and maintained on commercial rat chow and tap water ad libitum. All studies conformed to the principles of the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by our institution's Animal Care and Use Committee. Anesthesia for the experimental procedure was affected by pentobarbital sodium (50 mg/kg ip).

Experimental design. The experimental groups included an untreated control group exposed to saline (n = 5), an untreated group perfused with ET-1 (n = 9), and a nedocromil sodium-treated group perfused with ET-1 (n = 6). Nedocromil sodium was administered via a 21-day time-release pellet (Innovative Research; Sarasota, FL) implanted subcutaneously 5 days before isolation of the heart to achieve a dosage of 30 mg·kg^–1·day^–1. Preliminary studies confirmed that administration of 30 mg·kg^–1·day^–1 nedocromil sodium effectively prevented both the increase in mast cell density and MMP activation at 24 h in the AV fistula model (data not shown). The experiments were performed using an isolated, blood-perfused heart preparation as previously described (5). Briefly, the ascending thoracic aorta in the anesthetized rat was cannulated for continuous retrograde perfusion of the heart via an apparatus consisting of a pressurized perfusion reservoir (100–105 mmHg) and a collection reservoir connected in circuit with a support rat. The extirpated heart was attached to the apparatus for perfusion with oxygenated blood obtained from the support rat via a carotid artery catheter. The coronary venous effluent was collected in a reservoir and returned to the support rat via a jugular vein catheter. The support rat and blood donors utilized for studying the nedocromil-treated group were also pretreated with nedocromil in an identical fashion to the experimental animals. After removal of the left atrium, a highly compliant latex balloon was inserted into the ventricular chamber to obtain LV pressure-volume (P-V) relationships. The proximal end of the balloon was connected via a short piece of tubing to a three-way stopcock that was used to adjust the balloon volume through one port while measuring LV pressure using a pressure transducer (Transpac IV, Abbott Critical Care Systems; North Chicago, IL) attached to the remaining port. Once the heart developed stable isovolumetric contractions, the balloon volume that produced an LV end-diastolic pressure (LVEDP) of 0 mmHg was used to determine baseline ventricular volume (V₀). The volume in the balloon was then increased in 5- to 10-µl increments until an LVEDP of 25 mmHg was attained. The end-diastolic and peak isovolumetric pressures were recorded after each increase in balloon volume, with three to four data sets collected to ensure that the preparation was stable.

To assess the effect of ET-1 on coronary flow and mast cell degranulation, 1 ml of blood containing ET-1 (Sigma; St. Louis, MO) was administered to the isolated heart of normal or nedocromil-treated rats by its introduction into the pressurized perfusion reservoir, allowing the solution to mix with the reservoir blood to achieve a final ET-1 concentration of 20 pg/ml. This pathophysiological dosage was selected based on 1) preliminary observations of tissue ET-1 levels in the infrarenal AV fistula model of chronic volume overload (data not shown), 2) baseline plasma ET-1 levels of 9.5 pg/ml reported in previously published studies using Sprague-Dawley rats, and 3) an expected two- to threefold increase in ET-1 characteristic of heart failure regardless of etiology (8, 18, 23). Coronary venous effluent was collected for 3 min immediately before and after ET-1 administration to determine coronary flow. The coronary venous blood containing ET-1 was not returned to the support rat. P-V relationships were obtained for each heart before and 30 min after infusion of ET-1. Control hearts underwent the same blood-perfused isolation procedure with saline introduced into the perfusion reservoir in place of ET-1.

After completion of the functional studies, the atria and great vessels were removed, and the LV (including septum) and right ventricle were separated. A complete transmural section of the LV at midventricle was placed in buffered formalin, and the remaining tissue was minced into 1-mm cubes, snap frozen in liquid nitrogen, and stored at –80°C. Wet-to-dry weight ratios expressed as percent myocardial water (%H₂O) were determined using 100 mg of the frozen LV tissue.

Histology: mast cells and collagen. The formalin-fixed section of the LV taken from the midventricle was processed for routine histopathology. Sequential 5-µm paraffin-embedded sections were stained with pinacyanol erthrosinate for the visualization of mast cell morphology (2) and picrosirius red for quantification of myocardial interstitial collagen. LV interstitial collagen volume fraction (CVF), reported as the percentage of collagen area relative to total myocardial area, was determined for the entire cross section of tissue in a blinded fashion from picrosirius red-stained sections using the ImagePro Plus Analysis System (Media Cybernetics; Silver Spring, MD) and established methods (4, 5, 9). Perivascular collagen was excluded from the analysis of CVF.

MMP activity. MMP activity in cardiac tissue extracts was analyzed by gelatin zymography using a SDS-PAGE matrix containing gelatin (1 mg/ml) as previously described (4, 5, 9). Briefly, samples (10–20 µg/lane) were electrophoresed on a 10% gel at 20°C. After electrophoresis, the gels were washed to remove the SDS and to permit enzyme renaturation, incubated in substrate buffer on a shaker for 18 h at 37°C, stained with 0.1% Coomassie brilliant blue, and destained in double distilled H₂O. Activity of the bands was quantified by densitometry (ImageQuant, Molecular Dynamics; Piscataway, NJ). All of the zymograms had four lytic bands corresponding to standards for the proenzyme (68 kDa) and activated (62 kDa) forms of gelatinase A (MMP-2) and the proenzyme (95 kDa) and activated (82 kDa) forms of gelatinase B (MMP-9; Chemicon International; Temecula, CA). Each gel was run in duplicate, and, to compare results from different gels, a single extract from the same control heart was used as a standard on all gels. The activities of the lytic bands in the other lanes of an individual gel were expressed as a percentage of this standard's activity. The MMP activity values for each sample were normalized for their protein concentration using a Bio-Rad protein assay. Once normalized in this fashion, the percentage of MMP-2 and MMP-9 activity from control and ET-1-perfused isolated heart groups were averaged.

Statistical analysis. Statistical analyses were performed with GraphPad Prism 4.0 (San Diego, CA). All grouped data are expressed as means ± SD except where noted. Grouped data comparisons were made by one-way ANOVA with intergroup comparisons analyzed using Bonferroni post hoc testing. Statistical significance was taken to be P < 0.05. For each heart, diastolic P-V relationships were fit to a third-order nonlinear regression (GraphPad Prism 4.0). The volumes corresponding to the pressure values at 2.5-mmHg increments between 0 and 25 mmHg were determined and corrected for the volume displaced by the balloon (i.e., mass of the balloon in the ventricle divided by the density of the latex). For each heart and for each EDP, the corresponding volumes were then averaged to obtain the final P-V relationship. P-V curves were analyzed using a two-factor repeated-measures ANOVA.

	RESULTS

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Evidence of extensive mast cell degranulation in isolated hearts treated with ET-1 was found on histological examination of all treated hearts (Fig. 1). Additionally, the percentage of mast cell degranulation was determined based on x400 microscopic examination of the entire LV section of four randomly selected hearts from control and treated groups. Degranulation was defined as the presence of disseminated granules external to the cell membrane and/or loss of membrane integrity. The number of mast cells that were degranulated was significantly higher in the ET-1-treated hearts compared with control and nedocromil-treated hearts (70 ± 3.5% vs. 25 ± 5.0% and 37 ± 8.5%, respectively, P < 0.05). Concomitant with cardiac mast cell degranulation, there was a significant increase in myocardial %H₂O in the ET-1-treated hearts relative to control hearts (78.8 ± 1.5% vs. 74.2 ± 2.2%, respectively, P < 0.01). Development of myocardial edema was prevented in the nedocromil-treated hearts. Average coronary flow was not significantly different in ET-1-treated isolated hearts as measured by timed collection of coronary effluent immediately before and after ET-1 administration (2.57 vs. 2.21 ml/min, respectively).

View larger version (97K): [in this window] [in a new window]   Fig. 1. Representative histological sections demonstrating the appearance of mast cells in normal hearts (A) and hearts after degranulation by endothelin (ET)-1 treatment (B).

View larger version (27K): [in this window] [in a new window]   Fig. 2. A: representative zymogram depicting matrix metalloproteinase (MMP)-2 activity in control (C) and ET-1-treated isolated hearts as well as normal tissue extract (NormTissue) and tissue extract incubated with ET-1 (NormTissue+ET-1). B: comparison of average active MMP-2 levels in control (expressed as 100%) and ET-1-treated isolated hearts and ET-1 plus nedocromil sodium (Nedoc)-treated and ET-1-treated tissue extracts from normal hearts. Values are means ± SD. *P < 0.01 vs. control.

The average LVEDP and LV end-diastolic volume (LVEDV) relationships before and after ET-1 administration are depicted in Fig. 3. In ET-1-treated hearts, LVEDV at an LVEDP pressure of 0 mmHg (V₀) was increased from 298.9 ± 17.4 to 330.2 ± 22.1 µl (P = 0.07) after ET-1 administration, reflecting a strong trend approaching significance for development of ventricular dilatation. However, myocardial compliance as assessed by the volume required to increase LVEDP from 0 to 25 mmHg (V₂₅) was not different after ET-1 administration (77.3 ± 13.8 vs. 82.4 ± 17.1 µl, P > 0.6). These data reflect a parallel shift to the right, consistent with moderate ventricular dilatation, despite the presence of significant myocardial edema after exposure to ET-1. This rightward shift after ET-1 administration was observed in seven of nine hearts. The two hearts that did not develop this rightward shift despite extensive mast cell degranulation and elevated MMP-2 activity had the highest (81.7%) and third highest (79.2%) %H₂O values. Similarly, the V₀ shift for the heart with the second highest value (79.7%) %H₂O was minimal (6 µl). Furthermore, linear regression analysis of %H₂O versus the change in V₀ pre- and post-ET-1 administration from all nine ET-1-treated hearts was inversely correlated (r² = 0.76), indicating that the greater the degree of edema present, the less extensive the degree of ventricular dilatation. Administration of nedocromil initiated 5 days before the isolated heart study completely abrogated the ET-1-induced increase in V₀.

View larger version (14K): [in this window] [in a new window]   Fig. 3. Average left ventricular end-diastolic pressure-end-diastolic volume relationships for hearts before and after ET-1 perfusion. Values are means ± SE.

	DISCUSSION

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Although increased MMP activity has been observed in several models of heart failure (i.e., secondary to rapid pacing, myocardial infarction, and chronic volume overload) (6, 15, 29, 31, 32), very little is known with regard to the factor(s) responsible for MMP activation. Our recent findings implicate cardiac mast cell degranulation as an in vivo mechanism responsible for activating MMPs and the subsequent ECM degradation (4, 6, 9, 10, 32); however, the stimulus initiating these cardiac mast cell-mediated effects has not been elucidated. Specifically, the intrinsic events and/or hormonal agents that initiate cardiac mast cell degranulation are not known. In this study, we focused on the neurohormone ET-1 because the elevation in plasma and ventricular tissue levels of ET-1 corresponds to the severity of heart failure in both human patients and animal models (20, 21, 23, 28).

Several studies have established MMP activation as causing the ventricular dilatation characteristic of the failing heart (4, 10, 31). Typically, increased MMP activity causes a rapid disruption of the ECM as measured by a reduction in CVF or hydroxyproline (19, 22, 26, 27, 31). Other studies have shown that treatment with ET receptor antagonists significantly attenuates ventricular remodeling during the progression of congestive heart failure in rats (13, 14, 22, 25, 27); however, the potential mechanisms mediating these phenomena were thought to lie in the reduction of afterload, thereby lessening LV wall stress and limiting the stimulus for progressive ventricular remodeling. Accordingly, this is the first study to establish a specific mechanism mediating the structural remodeling induced by pathophysiological elevations in ET-1.

This study demonstrated that ET-1-induced mast cell degranulation produced a marked increase in the levels of active MMP-2. Conversely, incubation of normal myocardial tissue extracts with ET-1 at the same dose and for the same duration as that used in the isolated heart preparation did not produce an increase in MMP activity. Moreover, prevention of MMP-2 activation by treatment with the mast cell stabilizer nedocromil sodium firmly establishes that ET-1-induced MMP-2 activation in the heart is mediated via degranulation of resident cardiac mast cells. This novel finding that ET-1 increases MMP activity indirectly through the activation of cardiac mast cells suggests that ET-1 receptor antagonism might be effective in preventing myocardial remodeling. Indeed, that hypothesis is supported by other studies that have shown that ET-1 receptor antagonism attenuates the myocardial remodeling process by inhibiting MMP activation (3, 13, 14, 30). Specifically, Podesser et al. (30) reported that ET_A receptor subtype blockade by sitaxsentan prevented MMP activation after myocardial infarction in rats. Although others have found that noncardiac mast cells are responsive to ET-1 (3, 34, 35), the findings in this study are the first to demonstrate that ET-1 is capable of causing cardiac mast cell degranulation, thereby activating MMPs, which in turn produce ECM degradation. Thus the findings of others combined with the results herein indicate that ET receptor-mediated stimulation of mast cell degranulation is responsible for ET-1-induced MMP activation.

Significant myocardial edema was observed as a result of ET-1-induced mast cell degranulation. Although histamine release was not measured in these hearts after ET-1 administration, Chancey et al. (9) found comparable increases in myocardial edema largely due to increased vasopermeability produced by documented histamine release from cardiac mast cells exposed to compound 48/80. It should also be noted that several previous studies have demonstrated that comparable increases in %H₂O typically resulted in a nonparallel leftward shift in the LV diastolic P-V relationship. For example, Cross et al. (11) found that decreased distensibility in canine hearts was proportional to the extent of myocardial interstitial fluid accumulation. Similarly, Amirhamezeh et al. (1) found that a 4.5% increase in myocardial water content resulted in a nonparallel leftward shift in the P-V relationship in rat hearts. Accordingly, the parallel rightward shift in the P-V relationship obtained herein indicates that the significant MMP activation and subsequent interstitial collagen degradation produced ventricular dilatation and increased compliance, which offset the expected edema-related increase in myocardial stiffness. An alternative possibility of compromised coronary perfusion contributing to or enhancing the rightward shift in the P-V relationship of these hearts is refuted by the observation that coronary flow was unchanged and systolic function was preserved.

Previous findings from our laboratory have demonstrated that a 30-min perfusion of compound 48/80 induced 1) mast cell degranulation; 2) significant activation of myocardial MMPs; 3) a moderate rightward shift in the P-V relationship (i.e., an increase of 32 µl in EDV at an EDP of 0 mmHg), the extent of which was lessened by significant myocardial edema; and 4) a 52% reduction in CVF (9). In that study, it was concluded that degradation of the interstitial collagen matrix was sufficient to counteract the expected decrease in diastolic compliance due to the significant increase in myocardial water content. Similar observations were made by MacKenna et al. (19) utilizing bacterial collagenase-perfused rat hearts. That is, they observed a significant increase in V₀ of 55 µl that was associated with a 36% decrease in CVF. Although the rightward shift during the 60-min collagenase perfusion was progressive, the largest shift occurred within the first 30 min. However, in that study, the collagenase infusion did not result in an increase in myocardial %H₂O above that in the control group. Consequently, although there was a trend for the noncollagenase-perfused P-V curves to rotate to the left (i.e., become stiffer) over the 1-h study period, the ECM degradation produced a rightward shift in the P-V relationship of the collagenase-perfused hearts that was essentially parallel. In the present study, we observed analogous results with ET-1-mediated mast cell degranulation producing marked MMP activation and extensive interstitial collagen degradation, both of which were prevented by pretreatment with nedocromil sodium.

In summary, this is the first study to demonstrate ET-1-induced degranulation of cardiac mast cells. This is also the first study to conclusively demonstrate that MMP activation is not a direct effect of ET-1 but rather involves ET-1 dependent degranulation of cardiac mast cells. Consequently, we conclude that ET-1 is capable of inducing cardiac mast cell degranulation, thereby producing the subsequent increase in MMP activity, ECM degradation, and ventricular dilatation.

	GRANTS

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This study was supported by National Heart, Lung, and Blood Institute Grant RO1-HL-62228 (to J. S. Janicki) and by American Heart Association Southern Research Consortium Postdoctoral Fellowship 0325228B (to D. B. Murray).

	ACKNOWLEDGMENTS

 
We are grateful to Bruce Abrahams for assisting in the determination of matrix metalloproteinase activity.

	FOOTNOTES

 

Address for reprint requests and other correspondence: D. B. Murray, 240A Greene Hall, Auburn Univ., Auburn, AL 36849-5518 (E-mail: murradb{at}auburn.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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This Article Abstract Full Text (PDF) All Versions of this Article: 287/5/H2295    most recent 00048.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (16) Citing Articles via Google Scholar Google Scholar Articles by Murray, D. B. Articles by Janicki, J. S. Search for Related Content PubMed PubMed Citation Articles by Murray, D. B. Articles by Janicki, J. S.