Metallothioneins 1 and 2 Modulate Inflammation and Support Remodeling in Ischemic Cardiomyopathy in Mice

Abstract EN

Aims.

Repetitive brief ischemia and reperfusion ( I / R ) is associated with left ventricular dysfunction during development of ischemic cardiomyopathy.

We investigated the role of zinc-donor proteins metallothionein MT1 and MT2 in a closed-chest murine model of I / R .

Methods.

Daily 15-minute LAD-occlusion was performed for 1, 3, and 7 days in SV129 (WT)- and MT1/2 knockout (M T - / - )-mice ( n = 8–10/group).

Hearts were examined with M-mode echocardiography and processed for histological and mRNA studies.

Results.

Expression of MT1/2 mRNA was transiently induced during repetitive I / R in WT-mice, accompanied by a transient inflammation, leading to interstitial fibrosis with left ventricular dysfunction without infarction.

In contrast, M T - / - -hearts presented with enhanced apoptosis and small infarctions leading to impaired global and regional pump function.

Molecular analysis revealed maladaptation of myosin heavy chain isoforms and antioxidative enzymes in MT1/ 2 - / - -hearts.

Despite their postponed chemokine induction we found a higher total neutrophil density and macrophage infiltration in small infarctions in M T - / - -hearts.

Subsequently, higher expression of osteopontin 1 and tenascin C was associated with increased myofibroblast density resulting in predominately nonreversible fibrosis and adverse remodeling in MT1/ 2 - / - -hearts.

Conclusion.

Cardioprotective effects of MT1/2 seem to be exerted via modulation of contractile elements, antioxidative enzymes, inflammatory response, and myocardial remodeling.