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

Abstract

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.

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

“…Numerous studies have implicated a direct contribution of MMPs in the pathophysiological dilatation that occurs in the failing heart (22,39). However, the findings here implicate ET-1 in causing the acute stimulation of cardiac mast cellmediated activation of MMPs in chronic volume overload.…”

“…The nonselective (ETA/ETB) endothelin receptor antagonist, bosentan (100 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), was dissolved in gum arabic and delivered via oral gavage once a day, initiated 24 h before surgery, and continued for the duration of the specified experimental time group. Shamoperated (Sham), untreated fistula (Fist), and bosentan-treated (Fist ϩ Bos) groups at the 1 and 5 day time points (n ϭ 6 -8 animals/group) were used to determine whether bosentan treatment could prevent the acute increase in mast cell density and MMP-2 activation, as well as prevent the myocardial extracellular collagen matrix degradation typical of the initial phase of remodeling in this model (22). Corresponding bosentan-treated sham-operated groups (Sham ϩ Bos, n ϭ 4 -6 animals/time point) were also evaluated at the 1-and 5-day time points.…”

“…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).…”

Tobacco smoke‐induced left ventricular remodelling is not associated with metalloproteinase‐2 or ‐9 activation

“…In fact, our study did not detect any differences in MMP-2 and MMP-9 expression between those animals exposed to tobacco smoke and the control animals, although cardiac remodelling was observed in the animals exposed to tobacco smoke. This finding is surprising because MMP-2 and MMP-9 are increased in different models of cardiac injury, such as myocardial infarction, pressure and volume overload, and heart failure induced by pacing [5][6][7][19][20][21][22]. In addition, although fibrosis is considered to be a hallmark modulator of myocardial function, this study did not show collagen accumulation.…”

Aldosterone receptor antagonists - how cardiovascular actions may explain their beneficial effects in heart failure

“…Aldosterone receptor antagonists 111 ventricular sphericalization and wall thinning can occur (Janicki et al, 2006). However, in naturally occurring mitral valve disease, ventricular remodelling results in dilation of the left ventricle but this is accompanied by an increase in ventricular muscle mass (eccentric hypertrophy).…”