Signaling control of myocardial survival249Endocannabinoids and cannabinoid receptor CB2 act cardioprotective in a murine model of ischemic cardiomyopathy

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Abstract

Purpose

Murine ischemic cardiomyopathy development is associated with repetitive short ischemia episodes leading to an inflammatory response with reversible myocardial remodeling and fibrosis. Endogenous cannabinoids have been suggested to modulate inflammation and tissue remodeling through cannabinoid receptor 2 (CB2) and therefore we investigated the role of the CB2 in pathogenesis of ischemic cardiomyopathy.

Methods

Repetitive daily 15 min LAD occlusion was followed by 24 h reperfusion (I/R) over 1, 3, 5 and 7 days in C57/Bl6 (WT) and CB2-/- mice (n=8/group). Functional, immunohistochemical, molecular and cellular analyses were performed including cardiomyocyte and macrophage cell culture.

Results

CB2-/- mice showed irreversible loss of cardiomyocytes - microinfarctions - and persistent left ventricular dysfunction 60 days after discontinuation of I/R, whereas WT mice presented with intact morphology and full functional recovery (fractional shortening in CB2-/- 31,48 ± 1,28 % vs. WT 43,59 ± 2,73 %; p < 0,05). CB2-/- mice were unable to dynamically express antioxidative enzymes, chemokines and cytokines during ischemia, in contrast to transient up regulation of these mediators in WT mice. Cardiomyocyte cell culture revealed dynamic regulation of CB2 and anti oxidative enzymes under hypoxia in WT cells, which were absent in CB2-/- cells. Also, macrophage persistance caused continuous proinflammatory response in CB2-/- mice,thus leading to adverse, prolonged myocardial remodeling with microinfarctions (microinfarcted area as percentage of total area: CB2-/- 18,39 ± 3,34% vs. WT 1,08 ± 0,46 %; p < 0,05). In addition, mRNA up regulation of remodeling-related tenascin C and CTGF was absent in CB2-/- mice. Tissue concentration of the endocannabinoid anandamide was transiently increased parallel to the inflammatory response in WT mice, whereas CB2-/- mice experienced an increasing anandamide concentration during I/R.

Conclusions

Our study revealed novel aspects ofcardioprotective mechanisms involving endocannabinoids and CB2 receptor with differential effects on specific cell types during development of murine ischemic cardiomyopathy.

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