Mast cells (MCs) are commonly recognized for their crucial involvement in the pathogenesis of allergic diseases, but over time, it has come to light that they also play a role in the... Show moreMast cells (MCs) are commonly recognized for their crucial involvement in the pathogenesis of allergic diseases, but over time, it has come to light that they also play a role in the pathophysiology of non-allergic disorders including atherosclerosis. The involvement of MCs in the pathology of atherosclerosis is supported by their accumulation in atherosclerotic plaques upon their progression and the association of intraplaque MC numbers with acute cardiovascular events. MCs that accumulate within the atherosclerotic plaque release a cocktail of mediators through which they contribute to neovascularization, plaque progression, instability, erosion, rupture, and thrombosis. At a molecular level, MC-released proteases, especially cathepsin G, degrade low-density lipoproteins (LDL) and mediate LDL fusion and binding of LDL to proteoglycans (PGs). Through a complicated network of chemokines including CXCL1, MCs promote the recruitment of among others CXCR2+ neutrophils, therefore, aggravating the inflammation of the plaque environment. Additionally, MCs produce extracellular traps which worsen inflammation and contribute to atherothrombosis. Altogether, evidence suggests that MCs actively, via several underlying mechanisms, contribute to atherosclerotic plaque destabilization and acute cardiovascular syndromes, thus, making the study of interventions to modulate MC activation an interesting target for cardiovascular medicine. Show less
Thondapu, V.; Mamon, C.; Poon, E.K.W.; Kurihara, O.; Kim, H.O.; Russo, M.; ... ; Jang, I.K. 2021
Aims To investigate local haemodynamics in the setting of acute coronary plaque rupture and erosion.Methods and results Intracoronary optical coherence tomography performed in 37 patients with... Show moreAims To investigate local haemodynamics in the setting of acute coronary plaque rupture and erosion.Methods and results Intracoronary optical coherence tomography performed in 37 patients with acute coronary syndromes caused by plaque rupture (n=19) or plaque erosion (n=18) was used for three-dimensional reconstruction and computational fluid dynamics simulation. Endothelial shear stress (ESS), spatial ESS gradient (ESSG), and oscillatory shear index (OSI) were compared between plaque rupture and erosion through mixed-effects logistic regression. Lipid, calcium, macrophages, layered plaque, and cholesterol crystals were also analysed. By multivariable analysis, only high ESSG [odds ratio (OR) 5.29, 95% confidence interval (CI) 2.57-10.89, P<0.001], lipid (OR 12.98, 95% CI 6.57-25.67, P<0.001), and layered plaque (OR 3.17, 95% CI 1.82-5.50, P<0.001) were independently associated with plaque rupture. High ESSG (OR 13.28, 95% CI 6.88-25.64, P<0.001), ESS (OR 2.70, 95% CI 1.34-5.42, P=0.005), and OSI (OR 2.18, 95% CI 1.33-3.54, P=0.002) independently associated with plaque erosion. ESSG was higher at rupture sites than erosion sites [median (interquartile range): 5.78 (2.47-21.15) vs. 2.62 (1.44-6.18) Pa/mm, P=0.009], OSI was higher at erosion sites than rupture sites [1.04 x 10(-2) (2.3 x 10(-3)-4.74 x 10(-2)) vs. 1.29 x 10(-3) (9.39 x 10(-5)-3.0 x 10(-2)), P<0.001], but ESS was similar (P=0.29).Conclusions High ESSG is independently associated with plaque rupture while high ESSG, ESS, and OSI associate with plaque erosion. While ESSG is higher at rupture sites than erosion sites, OSI is higher at erosion sites and ESS was similar. These results suggest that ESSG and OSI may play critical roles in acute plaque rupture and erosion, respectively. Show less
Ouweneel, A.B.; Verwilligen, R.A.F.; Eck, M. van 2019
Atherothrombotic events such as myocardial infarction and ischemic stroke are a major cause of morbidity and mortality worldwide. Understanding the molecular and cellular mechanisms of... Show moreAtherothrombotic events such as myocardial infarction and ischemic stroke are a major cause of morbidity and mortality worldwide. Understanding the molecular and cellular mechanisms of atherosclerotic plaque destabilization or erosion, and developing new therapeutics to prevent acute cardiovascular events is important for vascular biology research and clinical cardiovascular medicine. However, basic research on plaque destabilization, rupture and erosion is hampered by the lack of appropriate animal models of atherothrombosis. Unprovoked atherothrombosis is very scarce in commonly used mouse models for atherosclerosis, the low-density lipoprotein receptor knockout and apolipoprotein E knockout mice. Therefore, specific interventions are required to induce atherothrombosis in these models. Two strategies can be employed to induce atherothrombosis: 1) plaque destabilization and 2) induction of blood hypercoagulability. Although the individual strategies yield atherothrombosis at low incidence, it appears that the combination of both plaque destabilization and an increase in blood coagulability is the most promising strategy to induce atherothrombosis on a larger scale. In this review, we summarize the recent developments on mouse models for the investigation of atherothrombosis. Show less
