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Cardiovascular Research 2006 69(3):657-665; doi:10.1016/j.cardiores.2005.10.020
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Copyright © 2005, European Society of Cardiology

Cardiac mast cell regulation of matrix metalloproteinase-related ventricular remodeling in chronic pressure or volume overload

Joseph S. Janicki*, Gregory L. Brower, Jason D. Gardner, Mary F. Forman, James A. Stewart, Jr., David B. Murray and Amanda L. Chancey

Department of Cell and Developmental Biology & Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29208, United States

* Corresponding author. Tel.: +1 803 733 1536; fax: +1 803 733 1533. Email address: jjanicki{at}gw.med.sc.edu

Received 14 June 2005; revised 19 October 2005; accepted 27 October 2005


   Abstract
Top
 Abstract
1. The extracellular matrix...
 2. MMP activity in...
 3. MMP activity in...
 4. MMP activity in...
 5. Role of cardiac...
 6. Summary
 References
 
The chronic elevation in ventricular wall stress secondary to ventricular volume or pressure overload leads to structural remodeling of the muscular, vascular and extracellular matrix components of the myocardium. While initially a compensatory response, the progressive hypertrophy and ventricular dilatation induced by this condition ultimately have a detrimental effect on ventricular function, resulting in heart failure. Fibrillar collagen provides the skeletal framework which interconnects the cardiomyocytes, thereby maintaining ventricular shape and size and contributing to tissue stiffness. Accordingly, these myocardial collagen fibers must be disrupted for ventricular dilatation, sphericalization and wall thinning to occur. The presence of an abundant, latent matrix metalloproteinase (MMP) population which coexists with myocardial fibrillar collagen has been documented. Thus, the potential for collagen degradation to exceed synthesis exists should there be significant activation of this latent MMP system. Mast cells are known to store and release a variety of biologically active mediators including TNF-{alpha} and proteases such as tryptase and chymase, which can induce MMP activation. Increased cardiac mast cell density has been implicated in the pathophysiology of human end-stage cardiomyopathy and experimental myocardial infarction, hypertension and chronic volume overload secondary to mitral regurgitation and aorto-caval fistula. The potential role of cardiac mast cells in activating MMPs, which then results in fibrillar collagen degradation and adverse myocardial remodeling secondary to chronic volume and pressure overload will be the subject of this review.

KEYWORDS Extracellular matrix; Remodeling; Matrix metalloproteinase; Cytokines; Proteases

An increase in myocardial stress secondary to cardiac injury and/or persistent elevations in ventricular volume or developed pressure induces a compensatory structural remodeling of the muscular, vascular and extracellular matrix (ECM) components in the myocardium. This remodeling process consists of progressive changes in the relative composition of the myocardial components and also in the ventricular wall and chamber dimensions. Depending on the magnitude and duration of the elevated stress, surviving myocytes are enlarging through parallel and/or in-series addition of sarcomeres and the extracellular matrix is undergoing alterations in its fibrillar collagen concentration, types and cross-linking. As a result of this process, the stressed ventricle initially exhibits adequate function, normal shape and an above normal ventricular mass-to-volume ratio. However, a point is reached where the compensatory ability of the heart is exhausted and the heart begins to fail. At this stage, ventricular wall thickness is disproportionately reduced relative to an increased chamber volume, and ventricular shape tends to become spherical. Because the ECM is in intimate contact with all other components of the myocardium, it plays a crucial role in the maintenance of ventricular shape, size and function. Closely associated with the matrix fibrillar collagen network is an abundant amount of latent matrix metalloproteinases (MMP). Thus, there exists the potential for collagen degradation to exceed synthesis should there be a significant MMP activation. Indeed evidence is accumulating to indicate that MMP activation and consequent fibrillar collagen breakdown are responsible for adverse ventricular remodeling and that the cardiac mast cell plays an important role in the initiation of this process. The purpose of this article is to review the current understanding regarding the role of cardiac mast cells in regulating MMP activation and the consequent MMP-related ventricular remodeling process in chronic pressure or volume overload.


   1. The extracellular matrix and matrix metalloproteinase systems in the heart
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 Abstract
 1. The extracellular matrix...
2. MMP activity in...
 3. MMP activity in...
 4. MMP activity in...
 5. Role of cardiac...
 6. Summary
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The interstitium of the heart consists of connective tissue, ground substance, nerves, and blood vessels. Its connective tissue is predominantly collagen with relatively small amounts of fibronectin, laminin and elastin. The organization of the fibrillar collagen matrix has been described as forming intricate networks of fibers that surround, group and interconnect individual myocytes, myofibrils, muscle fibers and muscle bundles [1–4]. The collagen types found in myocardial fibrillar collagen are I, III, and V. While their relative proportions appear to be species dependent [5], the typical composition is as follows: greater than 80%, type I; between 10% and 15%, type III; and less than 5%, type V [4]. Being in intimate contact with the contractile units of the heart, the ECM is clearly capable of influencing diastolic and systolic function in addition to maintaining ventricular size and shape [6,7].

There are over 20 known endogenous MMPs with each having a particular specificity for one or more matrix components. While there is redundancy or overlap in the ability of the MMPs to degrade the various matrix proteins, they nevertheless appear to act in a coordinated fashion. Typically, the collagenases (MMP-1, MMP-8 and MMP-13) will initiate the degradation process by cleaving all three alpha chains of native types I, II and III collagens at a single, specific locus into 3/4 and 1/4 fragments. At physiological temperatures the cleaved fragments spontaneously denature into nonhelical gelatin derivatives. Gelatinases (MMP-2 and MMP-9) digest these products into smaller peptides that are further cleaved by nonspecific proteases. As will be seen below, most studies dealing with myocardial MMP activation secondary to pressure or volume overload have measured only one or more of the following: MMP-1, MMP-2, MMP-9 and MMP-13. Accordingly, these will be the focus of this review.

The presence of an abundant collagenase system that is closely associated with the interstitial collagen matrix in the heart was first described by Montfort and Pérez-Tamayo [8]. Subsequent studies have shown that most (98% to 99%) of the collagenase is in its latent or zymogen form [9,10]. However, the potential for rapid and extensive degradation of the collagen matrix exists should there be a substantial activation of collagenase. For example, Takahashi et al. [11] reported a two- to three-fold increase in collagenase activity and a more than 50% decrease in infarcted myocardial collagen concentration within 3 h of coronary ligation. The fact that activated MMPs can be inhibited by tissue inhibitors of metalloproteinases (TIMP) may serve to prevent such a catastrophic event. However, as with this example and others discussed below, rapid degradation can occur despite the presence of TIMPs. The reader is referred to the following reviews for in depth descriptions of the functional relationship between MMPs and TIMPs [12–15].

In addition to MMPs, there is another group of enzymes from the metalloproteinase family that are not only capable of degrading ECM components, but can also modify cell–cell and cell–matrix interactions via the integrin receptor and activate key biopeptides, cytokines and growth factors in the interstitium [15,16]. This family of proteins of which there are 29 distinct forms is referred to as ADAM because they are transmembrane proteins that contain A Disintegrin And Metalloprotease domain. Closely related to ADAM proteins are ADAM proteins with a thrombospondin motif (ADAMTS). The difference between these two classes of proteases is that ADAMs are transmembrane proteases whose substrates are other transmembrane proteins while ADAMTS proteins are soluble ECM proteases whose substrates are other extracellular matrix proteins [16]. While it is expected that ADAMs and ADAMTSs play a role in ventricular remodeling, essentially nothing is known regarding this role in response to pressure or volume overload. Therefore, they will not be considered further in this review.


   2. MMP activity in dilated cardiomyopathy
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3. MMP activity in...
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Clinical evidence is accumulating to indicate that MMP activation and the consequent ECM degradation contribute to the dilatation, sphericalization and increased compliance of the cardiomyopathic and failing heart. For example, Gunja-Smith et al. [17] reported a 30-fold increase in collagenase and gelatinase activity and a decrease in TIMP to negligible levels in explanted hearts from patients with documented dilated cardiomyopathy. Subsequently, others have reported similar increases in MMP activity and reduced TIMP in patients with heart failure secondary to dilated cardiomyopathy [18–20]. While these findings represent strong correlative evidence of an association between increased MMP activity and ventricular remodeling, they are "after-the-fact" findings and do not necessarily reflect a cause and effect relationship.

As the cardiomyopathic Syrian hamster closely mimics human idiopathic dilated cardiomyopathy, it is an experimental model from which temporal ventricular remodeling information regarding the relationship between MMP activity, collagen degradation and ventricular dilatation can be gleaned. A distinct advantage of this model is that it has a predictable patho-physiologic course consisting of four histological and clinical phases as follows: prenecrotic (<45 days of age) where the hearts are normal; necrotic (45 to 120 days of age) characterized by the appearance of focal myocytolytic necrosis; hypertrophic compensated (120 to 250 days of age); and terminal (>250 days of age) where congestive heart failure is clinically evident [21]. We assessed myocardial MMP activity and collagen volume fraction (CVF) in cardiomyopathic Syrian hamsters over the age range of 150 to 300 days of age and compared the results to appropriate controls. Throughout the study period, CVF and MMP activity in the control hearts were age-invariant. In contrast, a continual increase in MMP activity occurred during the hypertrophic compensated and heart failure phases in the cardiomyopathic Syrian hamster such that collagen degradation eventually exceeded synthesis and CVF decreased. This coincided with the age at which significant ventricular dilatation and wall thinning develop and, therefore, is indicative of a cause and effect relation between MMP activity and adverse ventricular remodeling [13].


   3. MMP activity in chronic volume overload
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Further insight into the relation between MMP activity and adverse ventricular remodeling was obtained using an aorto-caval (AV) fistula rat model of chronic biventricular volume overload [22]. Based on the morbidity/mortality associated with this model (Fig. 1), the patho-physiologic course post-fistula consisted of an initial phase encompassing the first 14 days (no deaths), a compensated hypertrophic phase which continued until symptoms of congestive heart failure were evident, and a terminal, decompensated phase. As can be seen from Fig. 1, the duration of the compensated stage was variable and morbidity/mortality was 100% by 30 weeks post-fistula.


Figure 1
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  		Fig. 1 Morbidity/mortality response following the creation of an aorto-caval fistula in rats. Shown is the percent of rats alive at different times following sham or fistula surgery. Based on this response three distinct phases are identified as follows: the initial phase days 0 to 14; the compensated phase lasting until clinical signs of heart failure occur; and the decompensated phase.

 
Besides there being no morbidity/mortality in the initial phase, this phase can also be characterized by the temporal response in MMP activity [23]. Within 12 h of creating the fistula, a significant increase in MMP activity occurred which was sustained for nearly 2 weeks. It is of interest to note that the response of zymographic MMP activity during the initial phase was similar to the response of collagenase gene expression reported for this period of time [24]. As a consequence, CVF was significantly decreased by the third day [23]. However, this damage was quickly repaired as reflected by a marked increase in collagen types I and III gene expression, which reached a peak around day 7 and by an above normal CVF at day 14 [23,24]. The onset of a progressive and significant ventricular dilatation and hypertrophy was apparent at one week post-fistula [22]. This remodeling in the initial phase was considered to be adverse in that it resulted in a significantly depressed chamber contractility and the ventricle was clearly more compliant. Here and elsewhere in this review, intrinsic chamber contractility was assessed by determining the slope of the linear peak isovolumetric pressure–volume relationship, a measurement which has been shown to be a load-independent index of contractility [25].

Throughout the compensated hypertrophy phase, MMP activity and CVF remained at normal values while left ventricular (LV) mass, size and compliance continued to increase and contractility to decrease until the 8 week point. Thereafter, there was little, if any, evidence of further remodeling or declining function until the hearts began to fail [26]. During this final decompensated phase, the following changes were observed relative to compensated hearts with a similar duration of sustained volume overload: 1) body weight increased significantly and lethargy and labored breathing were evident; 2) MMP activity increased; 3) significant fibrosis developed; and 4) LV enlargement, increased compliance and reduced contractility were noted.

It is interesting to note that the failing heart secondary to chronic volume overload resembles closely the dilated cardiomyopathic hamster and human hearts discussed above. While a contribution by elevated MMP activity to the remodeling that occurred in the final phase is suggested by these studies, the recent report by Chancey et al. [27] demonstrates that preventing MMP activation in the initial phase markedly attenuates subsequent ventricular remodeling in the AV fistula model. In this study, rats were treated with a broad spectrum MMP inhibitor for two weeks prior to the creation of an AV fistula with the treatment then continuing until the end of the study at 8 weeks post-surgery. MMP inhibition resulted in significant attenuation of the increase in LV and lung weight, coupled with improved LV contractility and prevention of structural dilatation.

Efficacious findings regarding the ability of MMP inhibitors to attenuate ventricular dilatation have been reported in similar prevention studies using other experimental models of heart failure [28–30]. From these findings, one could conclude that elevations in MMP activity during the early stages of injury or elevated wall stress and the consequent degradation of fibrillar collagen are responsible for the initiation of a progressive remodeling process that eventually leads to heart failure. In the case of chronic volume overload, where the collagen concentration was quickly restored to normal levels, it is quite possible that the replacement fibrillar collagen contains a greater proportion of the more compliant type III collagen or possesses less cross-linking and, therefore, is unable to prevent the progressive increases in ventricular size and compliance that occurred during the compensated hypertrophic phase. It should be noted that reduced collagen cross-linking has been reported by several investigative groups to result in reduced ventricular diastolic stiffness (see review in Ref. [31]).

The elevations in MMP activity and/or fibrillar collagen disruption that occur in the initial phase may also interfere with ECM-cardiomyocyte integrin function, which in turn could affect ventricular remodeling. Zellner et al. [32] using a pig model of tachycardia-induced heart failure found significant reductions in the ability of myocytes isolated from failing hearts to attach to laminin, fibronectin and collagen type IV. Preliminary results from our laboratory using the AV fistula model of volume overload indicate that the temporal response in myocyte adhesion to either collagen type IV or laminin was similar in that, by day 3 post-fistula, the amount of cells adhered to a particular substrate was decreased about 50% from that of control myocytes. This reduced adhesion, which persisted to day 7, was followed by a gradual increase in adhesion to laminin and type IV collagen which was significantly greater than the control group values by 43% and 111%, respectively, at day 21. Thereafter, adhesion to these two substrates progressively declined to the point where in the failing hearts it was significantly below control values.


   4. MMP activity in chronic pressure overload
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 1. The extracellular matrix...
 2. MMP activity in...
 3. MMP activity in...
 4. MMP activity in...
5. Role of cardiac...
 6. Summary
 References
 
While a detailed temporal response of myocardial MMP activity following the imposition of a chronic pressure overload (PO) state has not been determined, there are several studies which have investigated MMP activity and LV remodeling in pressure overloaded hearts. Nagatomo et al. [33] have evaluated LV MMP activity and the amount of TIMP after acute (6 h) and prolonged (10 days) pressure overload induced by aortic stenosis in dogs. For both acute and chronic PO, total MMP zymographic activity did not differ from that of the control group. However, although MMP-9 abundance was not changed, MMP-9 activity increased over three-fold following 6 h of PO, but then had returned to normal after 10 days of PO. The abundance of both MMP-1 and MMP-2 was significantly reduced relative to control in the prolonged PO group while that of MMP-3 was increased. The authors hypothesized that these reductions in abundance may be due to their activation and subsequent degradation. Takimoto et al. reported myocardial MMP-2 and MMP-9 activity to be significantly elevated together with LV dilatation in wild type mice as a result of 3 to 9 weeks of PO secondary to transverse aortic constriction (TAC). Interestingly, these events were not seen in nitric oxide synthase-3 null mice secondary to TAC, indicating a role of oxidative stress in activating MMPs [34].

Urokinase-generated plasmin has also been shown to activate MMPs [35]. Heymans et al. used the TAC model of PO in mice lacking tissue-type plasminogen activator (PA), urokinase PA, or MMP-9 and in wild type mice after adenoviral gene transfer of PA-inhibitor (PAI-1) or TIMP-1 [36]. While MMP activity was not assessed in this study, the authors did find that in contrast to the wild type and tissue-type PA deficient mice, cardiomyocyte hypertrophy was moderate, there was no fibrosis or dilatation, and systolic function was preserved in the urokinase-PA deficient and in the wild type PAI-1 and TIMP-1 gene transfer mice following 7 weeks of TAC. There was also normal systolic function and no dilatation in the MMP-9 deficient mice, despite significant fibrosis and cardiomyocyte hypertrophy.

Peterson et al. [28] provided definitive proof that an increase in MMP activity occurs in PO which then contributes to ventricular remodeling. They reported the spontaneously hypertensive heart failure (SHHF) rat at 9 to 13 months to have significant elevations in MMP activity. During this interval, clinical signs of congestive heart failure become evident and the heart becomes functionally depressed, markedly enlarged and abnormally compliant, such that it could no longer maintain the elevated pressures. Starting at 9 months of age, treatment with a broad spectrum MMP inhibitor completely prevented the transition to a decompensated state. Similar observations were made in the Dahl salt-sensitive rat model of PO and heart failure by Sakata et al. [37]. They reported an elevation in the gelatinase activity of MMP-2 and MMP-9 at 23 weeks of age. This increase in MMP activity preceded the LV dilatation and onset of heart failure which occurred at 26 weeks. However, these results need to be interpreted with caution in that the increased zymographic results corresponded to the zymogen or inactive forms of MMP-2 and -9. Results for the active MMP-2 and -9 bands were not presented. Also, there was a significant increase in the extent of fibrosis at 26 weeks indicating collagen synthesis exceeded collagen degradation during the 23 to 26 week interval.

Others have assessed MMP protein and activity levels as well as TIMP protein in human PO hearts at the time of aortic valve replacement surgery. Polyakova et al. grouped their patients according to pre-surgery ejection fraction (EF) being either >50%, 30% to 50%, or <30%. Polyakova et al. documented increased MMP activity in human pressure-overloaded hearts (i.e., isolated aortic valve stenosis) [38]. Quantitative analysis by Western blotting and immunoconfocal microscopy revealed an upregulation of MMP-1, -2, -3, -9, -13, and -14 in patients with EF >50% and a further increase in the other two groups of patients. MMP-2 zymographic activity was greater than control by 1.2-, 1.5- and 1.6-fold in the three groups of patients, respectively. Finally TIMPs 1 and 2 were increased while TIMP-4 was decreased relative to control. In the same year, Fielitz et al. published their findings in a similar cohort of patients that were also grouped according to ejection fraction being greater or less than 55% [39]. Both studies were in agreement with respect to the observations that MMP-2 and MMP-3 were increased in the pressure-overloaded myocardium. However, the findings of Fielitz et al. differed from those of Polyakova et al. in that MMP-1, MMP-9, and TIMP-1 were reported to be decreased and TIMP-4 to be increased in patients with aortic stenosis relative to their control group. The reasons for these discrepancies are not clear but may be related to differences in methodology, drug therapy, and tissue sample acquisition location. Also, while the patient population in the study of Polyakova et al. had pure aortic stenosis, there were patients in the report by Fielitz et al. that had one or more of the following complications: hypertension, diabetes mellitus, coronary artery disease, peripheral arterial disease and chronic obstructive pulmonary disease. Nevertheless, both human studies and the experimental animal studies discussed above clearly indicate MMP involvement in the ventricular remodeling process that is responsible for the transition from the compensated to decompensated state in the PO heart.


   5. Role of cardiac mast cells in the activation of MMPs
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 1. The extracellular matrix...
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6. Summary
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Connective tissue type mast cells store and release a variety of cytokines, growth factors, proteases, vasoactive agents and other biologically active mediators which influence tissue remodeling [14,40–43]. For example, several mast cell cytokines and growth factors have been shown to induce changes in gene and protein expression and alter fibroblast phenotype [44]. Also, in vitro studies have verified that mast cell proteases are capable of activating collagenase [41]. However, a full discussion of the multiple functions of mast cell mediators is beyond the scope of this review. Therefore, only those mediators such as tryptase, chymase and stromelysin which have the ability to activate MMPs will be considered.

Mature mast cells when stained with toluidine blue are easily visualized by their relatively large size and deep purple color. A nearly four-fold increase in mast cells from a normal value of 5.3 ± 0.7 cells/mm2 has been reported in explanted human hearts [45,46]. Increased myocardial mast cell density has also been reported in experimental animal models as follows: hypertension from a normal density of 0.87 ± 0.05 to 1.3 ± 0.05 cells/mm2 [47]; myocardial infarction from normal value of 1.8 ± 0.3 to 26.3 ± 7.4 cells/mm2 [48]; and chronic volume overload from normal value of 2.1 ± 0.5 to 3.6 ± 1.1 cells/mm2 [23,49]. In the AV fistula model, increases in cardiac mast cell density occurred rapidly (i.e., 75% increase within 12 h post-surgery) and remained significantly elevated for the first five days. By the beginning of the compensated hypertrophy phase, mast cell density had returned to normal values and remained so for the duration of the study (i.e., 8 weeks). Of significance to this review was the observation of a close relationship between mast cell density and MMP activity. Furthermore, when the rats were pretreated prior to creation of an AV fistula with a mast cell stabilizing drug and treatment continued for the duration of the study, there was no increase in either mast cell density or MMP activity during the first three days of volume overload [23]. In another study using the AV fistula model, the long term effects on LV remodeling and morbidity/mortality of continuous pre- and post-surgery treatment to prevent mast cell degranulation were assessed [50]. Mast cell stabilization effectively prevented the LV dilatation, increased compliance and decreased contractility seen in the untreated fistula group in a dose dependent fashion. In addition, the prevention of mast cell degranulation resulted in a significant reduction in the incidence of morbidity/mortality due to heart failure [50]. Further evidence of mast cell involvement in initiating the events leading to adverse ventricular remodeling can be found in our preliminary studies whereby an AV fistula was created in mast cell deficient rats (Ws/Ws) and wild type controls. In contrast to the controls, there was no increase in MMP activity and the degree of ventricular dilatation was markedly attenuated in the Ws/Ws rats [51].

The fact that mast cell density in the normal heart is quite low (see above) raises the issue of whether there are a sufficient number of mast cells to produce a significant activation of cardiac MMPs in the ventricle. Chancey et al. [52] using a blood-perfused isolated normal rat heart and the known mast cell secretagogue, compound 48/80, were able to induce a nearly 100% degranulation of cardiac mast cells. As a consequence, substantial MMP activation (i.e., 126% increase relative to control) and a nearly 50% decrease in myocardial CVF occurred 30 min after inducing mast cell degranulation. A tendency for the LV to dilate was also evident despite a significant increase in myocardial H2O. Thus, one could conclude that the number of mast cells normally present in the heart is sufficient to account for the increase in MMP activity observed during the initial phase of remodeling in response to a sustained volume overload. These results also emphasize that substantial fibrillar collagen degradation can occur rather quickly. This point is further strengthened by observations reported by MacKenna et al. [53] demonstrating similar findings (i.e., a 36% decrease in CVF and a parallel rightward shift in the LV pressure–volume relationship indicating dilatation) in isolated rat hearts after 1 h of perfusion with bacterial collagenase.

A source for the rapid increase in mast cell density remains to be determined. Frangogiannis et al. [40] noted an increase in mast cell number in the reperfused ischemic region of the heart which was not due to proliferation. However, they did detect intravascular cells that were expressing the mast cell-specific protease, tryptase, in the reperfused myocardium. Based on this observation, they hypothesized that chemotaxis of circulating mast cell precursors may have been responsible for the mast cell accumulation. An alternative possibility is suggested by recent observations from our laboratory demonstrating the rapid maturation of resident cardiac mast cell precursors [54]. The maturation and differentiation of resident mast cell precursors are known to be associated with progressive sulfation of heparin and the formation of mast cell chymase and histamine. As a result of this maturation process, four stages of mast cell maturation have been identified based on their staining characteristics using alcian and safranin stains whereby stage I or immature mast cells are those that are completely blue and stage IV or totally differentiated, mature mast cells appear completely brick-red; stages II and III are associated with cells that are either predominantly (i.e., >60%) blue or red, respectively [55]. Using this technique, a significant decrease in immature or stages I and II and a significant increase in mature or stages III and IV cardiac mast cells relative to sham-operated rats were observed within 24 h of initiating a volume overload. Furthermore, this shift from immature to mature mast cell did not occur in AV fistula rats that were treated with a mast cell stabilizing drug [54].

From the above one can conclude that the acute increase in cardiac mast cell density following the onset of a volume overload condition appears to be due to the maturation/differentiation of resident immature mast cells and that the initiation of this maturation process in all likelihood is triggered by the degranulation of mature mast cells. One possible candidate responsible for this degranulation is endothelin-1 (ET-1) which has been shown to cause degranulation in noncardiac mast cells [56,57]. Also, a study by Brown et al. [58] using the AV fistula model demonstrated increased cardiac mRNA expression of ET-1 and ETA receptor subtype. Murray et al. [59] recently demonstrated that the administration of 20 pg/ml of ET-1 to blood perfused isolated rat hearts resulted in extensive mast cell degranulation. Comparable to the findings reported by Chancey et al. [52] in isolated rat hearts administered compound 48/80, a 4.6% increase in myocardial H2O, a 107% increase in MMP activity, a 30% decrease in CVF and moderate ventricular dilatation was observed within 30 min of ET-1 administration. Importantly, these ET-1 induced events were not seen in hearts from rats that were pretreated with a mast cell membrane stabilizing drug [59]. Thus based on the above, one can propose the following sequence of events: an AV fistula causes an increase in ET-1; increased levels of ET-1 result in mast cell degranulation; yet to be defined secreted substances stimulate rapid maturation of stages I and II mast cells; other mast cell secretory products, including tryptase, chymase and stromelysin, either directly or indirectly result in MMP activation; and finally the MMP-induced degradation of the fibrillar collagen matrix leads to ventricular dilatation (Fig. 2).


Figure 2
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  		Fig. 2 Schematic depiction of course of events, associated with a sustained elevation in myocardial wall stress, that result in adverse myocardial remodeling. An elevation in stress will increase or activate a mast cell secretagogue such as endothelin-1 (ET-1) causing mast cell degranulation. Mast cell secretory products, such as tryptase, chymase or tumor necrosis factor-alpha (TNF-{alpha}), will cause matrix metalloproteinase (MMP) activation as well as stimulate immature resident mast cell maturation. Increased MMP activity will result in collagen matrix degradation which in turn causes myocardial remodeling.

 
Evidence to indicate that mast cells may also be involved in the transition from compensated to decompensated hypertrophy secondary to PO has been put forward by Hara et al. [60]. They compared LV performance in wild type and mast cell deficient mice that were subjected to PO induced by an aortic constriction. Decreased LV performance, ventricular dilatation and pulmonary congestion occurred in the wild type mice 15 weeks following creation of PO. In contrast, the mast cell deficient mice maintained normal LV function and size and pulmonary congestion was not apparent. Results similar to those in the mast cell deficient mice were obtained in aortic banded mice that were treated with the mast cell membrane stabilizing drug, tranilast. While Hara et al. did not document mast cell density and MMP activity in this study, the findings of Olivetti et al. [47] indicating a significant increase in mast cell density in this model of PO, together with those of Peterson et al. [28] demonstrating the ability of an MMP inhibitor to prevent decompensation in the SHHF rat, suggest a similar mast cell–MMP activation–ECM degradation–ventricular dilatation scenario as that discussed above for chronic volume overload. However, it remains to be determined whether ET-1 or some other factor is responsible for mast cell degranulation in pressure overload.

Other evidence of mast cell involvement in activating MMPs can be found in several recent studies regarding ventricular remodeling in female rats subjected to sustained volume overload. Gardner et al. [61] using the AV fistula model reported complete cardioprotection in intact females maintained on a high phytoestrogen diet. That is, unlike in males and ovariectomized females [61], there were no increases in lung weight and ventricular size and compliance, and morbidity/mortality was 10-fold less at 8 weeks after the creation of an AV fistula. With this gender difference in mind, our laboratory sought to determine whether differences in the response to acute, chemically induced degranulation (i.e., compound 48/80) of cardiac mast cells exist among intact females, ovariectomized females and ovariectomized females receiving estrogen [62]. In the ovariectomized group, the response after degranulation was similar to that seen in male hearts subjected to compound 48/80 [52]. That is, a significant increase in MMP activity (133%), a decrease in CVF (37%), and LV dilatation (15%) occurred within 30 min following the administration of compound 48/80. In contrast, compound 48/80 had no effect on the intact and ovariectomized+estrogen female hearts, even though significant mast cell degranulation was noted in all three groups.

Based on these observations in female hearts, one could conclude that estrogen markedly reduces or eliminates the mast cell contents responsible for MMP activation. This conclusion is further strengthened by the results of Harnish et al. [63] who demonstrated that estrogen treatment of bone marrow-derived mast cells repressed production of several cytokines including tumor necrosis factor-alpha (TNF-{alpha}). TNF-{alpha} is of particular interest because of recent findings indicating 1) cardiac TNF-{alpha} to be localized in the mast cell [40,64], 2) the increase in cardiac tissue TNF-{alpha} following ischemia/reperfusion was prevented in hearts pretreated with mast cell membrane stabilizing drugs [64], and 3) administration of a TNF-{alpha} blocking protein prevented the activation of certain MMPs and altered the course of myocardial remodeling in supraventricular tachycardia induced cardiomyopathy [65]. In addition, chronic infusions of TNF-{alpha} have been shown to result in adverse remodeling similar to that associated with sustained volume overload [66]. Finally, preliminary data from our laboratory indicate that 1) cardiac tissue levels of TNF-{alpha} and MMP activity are elevated following creation of an AV fistula in wild type but not in mast cell deficient rats [51], and 2) remodeling secondary to volume overload can be markedly attenuated with pre- and continued treatment using the TNF-{alpha} antagonist, etanercept.

Another potential pathway by which mast cells might mediate MMP activation is via the plasminogin/plasmin system. Human pulmonary mast cell derived tryptase has been shown to activate the zymogen form of urinary-type plasminogen [67]. As stated earlier, the subsequent urokinase-generated plasmin then has the potential to activate MMPs [35]. Thus, it is quite possible that the findings of Heymans et al. [36] comparing TAC-related ventricular remodeling in wild type and urokinase PA deficient mice (discussed above) involved cardiac mast cells (see Fig. 2).


   6. Summary
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 Abstract
 1. The extracellular matrix...
 2. MMP activity in...
 3. MMP activity in...
 4. MMP activity in...
 5. Role of cardiac...
 6. Summary
References
 
Ventricular volume or pressure overload produces a sustained abnormal elevation in myocardial wall stress for which the heart attempts to compensate. In the case of a sustained volume overload, MMP activation clearly plays a key role in the initiation of the remodeling process which then involves the extracellular matrix and cardiomyocyte. Whether MMPs function in a similar fashion during the early phases of pressure overload has not been investigated. However, there is little doubt that in both types of overload, MMP activation is responsible for the adverse remodeling associated with decompensation and heart failure. Emerging evidence indicates that secretory products from degranulating cardiac mast cells, such as TNF-{alpha} and/or tryptase (via increased urokinase PA generated plasmin), are responsible for activation of MMPs. While there are several potential endogenous mast cell secretagogues, endothelin-1 has been shown to act as one in causing cardiac mast cell degranulation in response to volume overload.


   Acknowledgements
 
This work was supported in part by grants from: NHLBI (JSJ–#s RO1-HL-59981, HL-62228, HL-73990 and MFF-F32 HL072566) and American Heart Association (JDG–0435298N and DBM–035228B).


   Notes
 
Time for primary review 19 days


   References
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 Abstract
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