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DOI: 10.1055/s-0030-1268924
Metallothionein 1/2 deficiency leads to irreversible myocardial damage in a murine model of ischemic cardiomyopathy
Aims: Repetitive brief ischemia and reperfusion (I/R) is associated with left ventricular (LV) dysfunction in development of ischemic cardiomyopathy. We investigated the role of zinc donor proteins metallothionein (MT) 1 and 2 in our closed-chest murine model of repetitive I/R.
Methods: Daily 15-minutes LAD-occlusion followed by reperfusion was performed for 1, 3, 5 and 7 consecutive days in C57/Bl6 (WT)- and MT1/2–/–-mice (n=8/group). Hearts were examined echocardiographically and processed for histological and mRNA-studies.
Results: MT1 and 2 mRNA-expression was induced in Taqman-RT-qPCR during I/R in WT-mice. In contrast to WT mice, repetitive I/R led to microinfarctions in MT1/2–/–-hearts. Planimetrical evaluation revealed comparable collagen deposition in both strains, but collagen was mainly located in microinfarcted areas in MT1/2–/–-mice after 7 days. Microinfarctions were accompanied with a significantly impaired global and regional LV-function in MT1/2–/–-mice. Macrophage accumulation preceded development of fibrosis and consequently LV-dysfunction. Total macrophage density was comparable between the strains, but macrophages were mainly located in microinfarctions after 5 days I/R in MT1/2–/–-mice. Repetitive I/R led to significantly lower induction of heme oxygenase-1 and subsequently lower induction of proinflammatory cytokines and chemokines in MT1/2–/–-mice, while remodeling-related mediators were not affected in these mice.
Conclusion: Zinc donor proteins MT1 and 2 seem to prevent irreversible loss of cardiomyocytes and LV-dysfunction by modulating induction of antioxidative enzymes. Subsequent induction of inflammatory mediators is leading to differenzial macrophage infiltration and collagen deposition in ischemic myocardium.