Stress-induced mast cell activation contributes to atherosclerotic plaque destabilization

H Maxime Lagraauw,Anouk Wezel,Ilze Bot,Daniël Van Der Velden,Johan Kuiper

doi:10.1038/s41598-019-38679-4

Abstract

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.

Highlights

Acute cardiovascular syndromes (ACS), such as acute myocardial infarction and stroke remain principle causes of death worldwide[1,2]
While absolute mast cell numbers in the perivascular area of the aortoc root were similar in all groups, the percentage of activated mast cells, scored by the presence of granules deposited outside the mast cell (Fig. 2B), was significantly increased upon stress exposure (37.3 ± 1.8% unstressed vs 50.7 ± 5.0% in 120′ stressed mice, Fig. 2C, P < 0.05)
Serum levels of the mast cell-granule derived mediator β-hexosaminidase significantly correlated with the percentage of activated mast cells (Fig. 2D)

Summary

Introduction

Acute cardiovascular syndromes (ACS), such as acute myocardial infarction and stroke remain principle causes of death worldwide[1,2]. Activity of the amygdala, an area of the brain involved in stress, was seen to associate with the incidence of ACS via bone marrow activation and arterial inflammation[6] These data remain associative, the immune system seems to actively participate in stress-induced ACS. We and others have established a key role for the inflammatory mast cell in atherosclerosis and especially in the destabilization of advanced atherosclerotic plaques[7,8]. These experimental animal data are in line with human data, correlating perivascular mast cell numbers and activation status with disease progression and the incidence of ACS9. In this study we evaluated mast cell-dependent effects of acute stress on atherosclerotic lesion stability in mice

Methods

Results

Conclusion