Myocardial Glutathione Alterations in Acute Coronary Occlusion in the Dog

Romero, Francisco J.; Montoro, A; Sáez, Guillermo T.; Alberola, Antonio; Gil, Francisco Manuel Tortosa; Viña, José; Such, Luis

doi:10.3109/10715768709088085

Cited by 9 publications

(2 citation statements)

References 10 publications

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“…A high level of GSSG is generated at the site of tissue injury. Also, the hypoxic, acute coronary occlusion and ischemic/reperfusion conditions increase oxidized glutathione in cardiac interstitium [Park et al, 1991;Romero et al, 1987;Curello et al, 19851 which leads to the change in the redox-state of interstitium which surrounds the fibroblast cells. We hypothesize that the change in the oxidative environment around the fibroblast induces extracellular matrix (ECM) proteinases and induces inhibitor gene expression.…”

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confidence: 99%

Reduction-oxidation (redox) state regulation of extracellular matrix metalloproteinases and tissue inhibitors in cardiac normal and transformed fibroblast cells

1996

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Latent matrix metalloproteinases (MMPs) in normal myocardium are activated in end-stage heart failure. In vitro oxidized glutathione (GSSG) activates myocardial MMPs which contains a cysteine residue. In vivo GSSG induce the collagen lysis and cardiac dilatation. To assess whether thiol and non-thiol reducing agents have direct effect on the interstitial human heart fibroblast (HHF) proliferation and MMP expression, HHF and polyoma virus transformed fibroblast cells were cultured with or without the thiol-containing reduced (GSH) or oxidized (GSSG) glutathiones, pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC), and non-thiol ascorbic acid. After 100 micrograms/ml (approximately 0.3 mM) GSH or PDTC treatment the proliferative (synthetic) phenotype of transformed fibroblast cells was changed to quiescent (contractile) phenotype. Also, after GSH, PDTC, and ascorbic acid treatment the medium was then analyzed for MMP activity by zymography. The results indicate reduction in MMP expression in transformed fibroblast cells after GSH and PDTC treatments and no effect after ascorbic acid treatment. Based on reverse zymography, we observed the level of tissue inhibitor of metalloproteinase (TIMP) at a decreased level in transformed cells. The effect of the reducing agent at the gene transcription was measured by estimating mRNA (Northern blot analysis) of MMP and of TIMP in the cells that were cultured in medium in the presence and absence of GSH. These results indicate that GSH induces MMP-2 and MMP-1 expression in normal HHF and that GSH reduces MMP-2 and MMP-1 in transformed fibroblast cells. After the treatment, the TIMP-2 level was repressed in normal HHF and TIMP-2 level increased in transformed fibroblast cells. These events are dependent on the nuclear transcription factor activity on the collagenase promoter in normal HHF cells. On the other hand, in polyoma transform fibroblast cells these events are not dependent on this collagenase promoter. These results suggest that oxidative environment induces normal HHF cell proliferation, and the reducing agent decreases normal HHF cell proliferation by inducing MMP and repressing TIMP gene transcription. In transformed cells reducing agents inhibit MMP expression and increase TIMP levels, which suggests a role of antioxidants in preventing tumorigenesis.

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confidence: 99%

Reduction-oxidation (redox) state regulation of extracellular matrix metalloproteinases and tissue inhibitors in cardiac normal and transformed fibroblast cells

1996

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“…These results indicate that the collagenolytic activity resides in the heart, not in the plasma, that activation occurs with I hr exposure to disulfides, and that there is no 5 min of starting a perfusion, DTNB is present in the urine. Unless the disulfides are very concentrated in heart tissue, the amount ofGSSG delivered to the heart is well below the concentrations ofGSSG produced by ischemic heart tissue, which have been measured at 50 J,Lmol/g heart (14,32). Sections of all hearts were examined by SEM and bright field and polarizing light microscopy.…”

Section: Disulfidesmentioning

confidence: 99%

Myocardial Connective Tissue Alterations

Caulfield

Wolkowicz

1990

Toxicol Pathol

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There is a complex network of collagen throughout the heart. It is composed of a hierarchy of fibrils and fibers ranging from 10 nm to 2–3 microns in diameter. This network can be broken down by ischemia, adriamycin administration, or disulfide administration in laboratory animals. Following loss due to coronary artery ligation, the ischemic area begins bulging within 3 h. General loss of portions of the collagen matrix is induced by intravenous oxidizing glutathione, and results in marked diffuse ventricular dilatation. Generalized collagen loss in the ventricles, as induced by disulfide administration or adriamycin infusion, persists for 6 months at which time evidence of some replacement is visible, and evidence of diffuse fibrosis is present. In humans, cardiac dilatation occurs in a variety of disease states without overstretch of sarcomeres. This presumes rearrangement of the muscle bundles, which can only occur with marked alterations of the collagen matrix. Ventricular dilatation, associated with viral myocarditis or puerperal cardiomyopathy, may persist for months, suggesting the collagen loss, as with the experimental animals, takes many months to repair. The cardiac dilatation may ameliorate, or, in some patients, deteriorate into heart failure. The animal experiments with loss of the collagen matrix, ventricular dilatation, and failure to replace the matrix for many months provide an explanation for persistent cardiac dilatation in various human diseases.

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