P360Metallothionein 1 and 2 modulate inflammation and support remodelling in a murine model of Ischemic cardiomyopathy

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Abstract

Purpose

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 by 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 differential macrophage infiltration and collagen deposition in ischemic myocardium.

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