Background-Matrix metalloproteinases (MMPs) contribute to matrix remodeling in disease states such as tumor metastases. Extracellular matrix metalloproteinase inducer (EMMPRIN) has been reported to increase MMP expression, and membrane-type MMP or MT1-MMP has been implicated to activate MMPs. The present study examined whether and to what degree EMMPRIN and MT1-MMP were expressed in human left ventricular (LV) myocardium as well as the association with MMP activity and expression in dilated cardiomyopathy (DCM). Methods and Results-LV myocardial zymographic MMP activity increased by Ͼ2-fold with both nonischemic DCM (nϭ21) and ischemic DCM (nϭ16) compared with normal (nϭ13). LV myocardial abundance of MMP-9 was increased with both forms of DCM. MMP-2 and MMP-3 were increased with nonischemic DCM. MMP-1 levels were decreased with both forms of DCM. EMMPRIN increased by Ͼ250% and MT1-MMP increased by Ͼ1000% with both forms of DCM. Conclusions-Increased LV myocardial MMP activity and selective upregulation of MMPs with nonischemic and ischemic forms of DCM occurred. Moreover, a local MMP induction/activation system was identified in isolated normal human LV myocytes that was upregulated with DCM. The control of MMP activation and expression in the failing human LV myocardium represents a new and potentially significant therapeutic target for this disease process.

Abstract-Aldosterone classically promotes unidirectional transepithelial sodium transport, thereby regulating blood volume and blood pressure. Recently, both clinical and experimental studies have suggested additional, direct roles for aldosterone in the cardiovascular system. To evaluate aldosterone activation of cardiomyocyte mineralocorticoid receptors, transgenic mice overexpressing 11␤-hydroxysteroid dehydrogenase type 2 in cardiomyocytes were generated using the mouse ␣-myosin heavy chain promoter. This enzyme converts glucocorticoids to receptor-inactive metabolites, allowing aldosterone occupancy of cardiomyocyte mineralocorticoid receptors. Transgenic mice were normotensive but spontaneously developed cardiac hypertrophy, fibrosis, and heart failure and died prematurely on a normal salt diet. Eplerenone, a selective aldosterone blocker, ameliorated this phenotype. These studies confirm the deleterious consequences of inappropriate activation of cardiomyocyte mineralocorticoid receptors by aldosterone and reveal a tonic inhibitory role of glucocorticoids in preventing such outcomes under physiological conditions. In addition, these data support the hypothesis that aldosterone blockade may provide additional therapeutic benefit in the treatment of heart failure.

A fundamental structural event in the progression of heart failure due to dilated cardiomyopathy is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) are an endogenous family of enzymes which contribute to matrix remodeling in several disease states. The goal of this report is to summarize recent findings regarding the myocardial MMP system and the relation to matrix remodeling in the failing heart. In both experimental and clinical forms of dilated cardiomyopathy (DCM), increased expression of certain species of myocardial MMPs have been demonstrated. Specifically, increased myocardial levels of the gelatinase, MMP-9 has been identified in both ischemic and non-ischemic forms of human DCM. In addition, stromelysin or MMP-3 increased by over four-fold in DCM. The increased levels of MMP-3 in DCM may have particular importance since this MMP degrades a wide range of extracellular proteins and can activate other MMPs. In normal human LV myocardium, the membrane type 1 MMP (MT1-MMP) was detected. These MT-MMPs may provide important sites for local MMP activation within the myocardium. In a pacing model of LV failure, MMP expression and activity increased early and were temporally associated with LV myocardial matrix remodeling. Using a broad-spectrum pharmacological MMP inhibitor in this pacing model, the degree of LV dilation was attenuated and associated with an improvement in LV pump function. Thus, increased LV myocardial MMP expression and activity are contributory factors in the LV remodeling process in cardiomyopathic disease states. Regulation of myocardial MMP expression and activity may be an important therapeutic target for controlling myocardial matrix remodeling in the setting of developing heart failure.

Changes in myocardial matrix metalloproteinase (MMP) activity and expression have been associated with left ventricular (LV) remodeling. A recent study demonstrated that LV myocytes synthesize and release MMPs, which suggests that LV myocytes may participate in myocardial remodeling. However, extracellular stimuli that may potentially influence LV myocyte MMP production remains to be defined. In the present study MMP activity and expression were measured in porcine LV myocyte preparations (10(5) total cells; n = 6) following incubation (6 h) with endothelin-1 (ET-1;50 pM), angiotensin II (ANG II; 1 microM), or the beta-receptor agonist isoproterenol (Iso; 10 nM). LV myocyte-conditioned media were then subjected to gelatin zymography and an MMP-2 antibody capture assay. MMP zymographic gelatinase activity and MMP-2 content were increased by over 40% in LV myocyte-conditioned media after incubation with ET-1 or ANG II (P < 0.05). Exposure to the phorbol ester phorbol 12-myristate 13-acetate (PMA; 50 ng/ml) resulted in a 30% increase in zymographic gelatinase activity and a 63% increase in MMP-2 content (P < 0.05), suggesting that protein kinase C activation may be an intracellular mechanism for MMP induction. With the use of a confocal microscopy, membrane type-1 MMP (MT1-MMP) was localized to porcine LV myocytes, and immunoblotting for MT1-MMP using LV myocyte extracts revealed that after exposure to Iso, ET-1, ANG II, or PMA (P < 0.05), MT1-MMP abundance increased over 50%. Thus stimulation of specific neurohormonal systems that are relevant to LV remodeling influences LV myocyte MMP synthesis and release.

α-Sulfone-α-piperidine and α-tetrahydropyranyl hydroxamates were explored that are potent inhibitors of MMP's-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. α-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while α-piperidine and α-tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds.

Systemic and pulmonary arterial endothelin levels remained increased for at least 24 hours postoperatively. Prolonged pharmacologic management and increased intensive care unit stay were associated with increased systemic endothelin release and heightened graft-conduit sensitivity to endothelin.

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