Stress-induced mast cell activation contributes to atherosclerotic plaque destabilization

Mast cells accumulate in the perivascular tissue during atherosclerotic plaque progression and contribute to plaque destabilization. However, the specific triggers for mast cell activation in atherosclerosis remain unresolved. We hypothesized that psychological stress-induced activation of mast cells may contribute to plaque destabilization. To investigate this, apoE(-/-) mice on Western-type diet were exposed to 120' restraint stress. A single episode of restraint caused a significant increase in mast cell activation in the heart. In addition to a rise in serum corticosterone and changes in circulating leukocyte populations, we observed an increase in the circulating pro-inflammatory cytokine interleukin (IL)-6 in the stressed mice. Subsequent characterization of the atherosclerotic plaques revealed a high incidence and larger size of intraplaque hemorrhages in stressed mice. In mast cell-deficient apoE(-/-) mice, restraint stress affected circulating leukocyte levels, but did not increase plasma IL-6 levels. Furthermore, we did not observe any intraplaque hemorrhages in these mice upon stress, strongly indicating the involvement of a mast cell-dependent response to stress in atherosclerotic plaque destabilization. In conclusion, we demonstrate that acute stress activates mast cells, which induces the incidence of intraplaque hemorrhage in vivo, identifying acute stress as a risk factor for atherosclerotic plaque destabilization.