Stress-induced mast cell activation contributes to atherosclerotic plaque destabilization

Abstract

Abstract Mast cells accumulate in the perivascular tissue during plaque progression and upon activation release pro-inflammatory cytokines and extracellular matrix degrading enzymes which fuel the inflammatory process and decrease lesion stability. Interestingly, mast cells have been shown to co-localize with peripheral neurons and contain receptors for various hormones and neuropeptides which are released upon exposure to stress. Therefore, we hypothesize that stress-induced neuronal activation of mast cells contributes to plaque destabilization. In apoE−/− mice the acute stress induced by 120′ restraint caused a significant increase in mast cell activation in the heart (37.3 ± 1.8% vs. 50.1 ± 4.9%). In parallel with a rise in serum corticosterone levels we observed a transient increase mast cell-specific β-hexosaminidase levels and the pro-inflammatory cytokine, interleukin-6 in the stressed mice compared to controls (55.9 ± 11.0 pg/ml vs. 29.6 ± 5.49 pg/ml). Subsequent characterization of atherosclerotic lesions in the aortic root revealed a significant reduction in lesion collagen content and a higher incidence of intraplaque hemorrhages, a hallmark of the vulnerable plaque (38.5% vs. 7.7%). Importantly, both these effects were reduced in mice treated with the mast cell stabilizer cromolyn and completely abolished in mast cell deficient (apoE−/−/Kit(W-sh/W-sh)) mice, thus strongly indicating the involvement of a mast cell-dependent response to stress in atherosclerotic plaque destabilization. We demonstrate that acute stress activates mast cells near atherosclerotic lesions and contributes to plaque destabilization, identifying acute stress as a risk factor for acute cardiovascular syndromes.