Differential effects of pressure or volume overload on myocardial MMP levels and inhibitory control

Abstract

Left ventricular (LV) pressure (PO) or volume (VO) overload is accompanied by myocardial remodeling, but mechanisms that contribute to this progressive remodeling process remain unclear. The matrix metalloproteinases (MMPs) contribute to tissue remodeling in a number of disease states. This study tested the hypothesis that increased MMP expression and activity occur after the induction of an LV overload, which is accompanied by a loss of endogenous MMP inhibitory control. LV MMP zymographic activity and species abundance were measured in dogs under the following conditions: acute PO induced by ascending aortic balloon inflation (6 h, n = 9), prolonged PO by aortic banding (10 days, n = 5), acute VO through mitral regurgitation secondary to chordal rupture (6 h, n = 6), prolonged VO due to mitral regurgitation (14 days, n = 7), and sham controls (n = 11). MMP zymographic activity in the 92-kDa region, indicative of MMP-9 activity, increased over threefold in acute PO and VO and fell to control levels in prolonged PO and VO. The MMP-9 activity-to-abundance ratio increased by over fourfold with acute VO and twofold in acute PO, suggesting a loss of inhibitory control. Endogenous MMP inhibitor content was unchanged with either PO or VO. Interstitial collagenase (MMP-1) content decreased by 50% with acute VO but not with acute PO. Stromelysin (MMP-3) levels increased by 40% with acute VO and increased by 80% with prolonged PO. Although changes in LV myocardial MMP activity and inhibitory control occurred in both acute and prolonged PO and VO states, these changes were not identical. These results suggest that the type of overload stimulus may selectively influence myocardial MMP activity and expression, which in turn would affect the overall LV myocardial remodeling process in LV overload.

TNF-α and myocardial matrix metalloproteinases in heart failure: relationship to LV remodeling

“…However, it must be recognized that this study did not definitively establish that TNF-␣ receptor activation resulted in MMP species induction. Moreover, this study only examined a limited number of MMPs that have been identified within the myocardium (18,24,28,29,31). Nevertheless, the present study provided in vivo evidence to suggest a mechanistic link between TNF-␣ induction of MMPs and the remodeling process in a model of heart failure.…”

“…For example, myocardial MMP-9 levels have been shown to be increased in both human and animal models of LV remodeling (24,30,32). Moreover, recent studies (8) in transgenic mice suggest that this MMP species plays a role in postinfarction myocardial remodeling.…”

“…Quantitative ELISA analysis for TIMP-1 was performed using previously described methods (4,24,28). TIMP-1 standards and LV myocardial samples were incubated in microtiter wells coated with a TIMP-1 antibody (RPN 2611, Amersham Pharmacia Biotech; Piscataway, NJ).…”

Promoter polymorphism of the matrix metalloproteinase 3 gene is associated with regurgitation and left ventricular remodelling in mitral valve prolapse patients

“…MMP-3 is particularly important because of its broad substrate specificity including collagen, fibronectin, laminin, elastin and proteoglycan [9]. It is known that in volume overload states, such as in mitral regurgitation, myocardial MMP levels are increased [26]. In keeping with this, changes of MMPs and TIMP levels including MMP-3 have been demonstrated in the myocardium in congestive heart failure [27] and hypertensive heart disease [28].…”

Circulating matrix metalloproteinases and tissue inhibitors of metalloproteinases levels in pediatric patients with congenital heart disease: Relationship to cardiac functions

“…However matrix metalloproteinase activity increased in the decompensated phase, and also severe fibrosis, left ventricular enlargement, increase in compliance and decrease in contractility were determined. Nagatomo et al (21) generated mitral insufficiency leading acute volume loading due to chordal rupture in dogs and reported that matrix metalloproteinase activity increased more than threefold during acute volume overload but decreased to the levels of control group. Also, they reported that proportion of matrix metalloproteinase activity to total amount of matrix metalloproteinase increased more than fourfold in the acute volume overload and, therefore, indicated the loss of inhibitory control.…”