P359Osteopontin-1 is involved in inflammation and remodelling via macrophage modulation in the pathogenesis of murine ischemic cardiomyopathy

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Abstract

Purpose

Repetitive brief ischemia and reperfusion (I/R) is associated with ventricular dysfunction in development of ischemic cardiomyopathy and myocardial hibernation. Repetitive I/R leads to a transient chemokine induction and reversible fibrosis in our murine model of ischemic cardiomyopathy. We investigated the role of matricellular protein and macrophage maturation marker osteopontin-1 (OPN) in this model.

Methods

Daily 15 min. LAD occlusion followed by reperfusion was performed for 3, 5 and 7 consecutive days in C57/Bl6 wildtype (WT) and OPN-/- mice (n=8/group). Hearts were examined echocardiographically and processed for histological and mRNA-studies (Taqman).

Results

WT mice showed 15-fold OPN mRNA-expression after 3 d of I/R followed by a transient macrophage infiltration and interstitial fibrosis with left ventricular (LV) dysfunction without myocardial infarction after 7 d I/R. In contrast, OPN-/- mice showed microinfarctions in the ischemic region after 3 d I/R followed by a scar formation after 7 d. The total collagen stained area was comparable between the strains. The microinfarctions in OPN-/- mice showed dense collagen deposition (picrosirius red) and a strong macrophage infiltration after 5 d I/R (27.9 ± 12.7 cells/400X-field, F4/80). The non-infarcted ischemic area in OPN-/- mice showed only loose interstitial collagen deposition and lower macrophage density (7.0 ± 1.6/field) when compared to the WT mice (33.3 ± 8.2/field; p < 0.05). Anterior wall thickening as a regional LV function parameter was lower in the OPN-/- mice (32.1 ± 6.1 % vs. WT 51.8 ± 5.6 %; p < 0.05), and fractional shortening as a global LV function parameter was comparable between the strains. mRNA-induction of CCL2 and CCL4 was significantly decreased in the OPN-/- hearts and accompanied by up to 5-fold lower mRNA-induction of glutathione peroxidase 1, heme oxygenase 1 and zinc-storage proteins metalothionein 1 & 2 when compared to the WT hearts. Furthermore, a weak induction of tenascin C and TGF-beta 1 was found in vivo and accompanied by a lack of MMP-9 and tenascin C induction in cultured myofibroblasts in vitro.

Conclusion

OPN seems to exert its cardioprotective role through modulation of both inflammatory response and interstitial remodeling in murine ischemic cardiomyopathy.

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