Atherosclerotic Plaque Stability Is Affected by the Chemokine CXCL10 in Both Mice and Humans

Abstract

Background. The chemokine CXCL10 is specifically upregulated during experimental development of plaque with an unstable phenotype. In this study we evaluated the functional consequences of these findings in mice and humans. Methods and Results. In ApoE−/− mice, we induced unstable plaque with using a flow-altering device around the carotid artery. From week 1 to 4, mice were injected with a neutralizing CXCL10 antibody. After 9 weeks, CXCL10 inhibition resulted in a more stable plaque phenotype: collagen increased by 58% (P = 0.002), smooth muscle cell content increased 2-fold (P = 0.03), while macrophage MHC class II expression decreased by 50% (P = 0.005). Also, the size of necrotic cores decreased by 41% (P = 0.01). In 106 human carotid endarterectomy specimens we found that increasing concentrations of CXCL10 strongly associate with an increase in atheromatous plaque phenotype (ANOVA, P = 0.003), with high macrophage, low smooth muscle cell, and low collagen content. Conclusions. In the present study we showed that CXCL10 is associated with the development of vulnerable plaque in human and mice. We conclude that CXCL10 might provide a new lead towards plaque-stabilizing therapy.

Markers of Inflammation in Recipients of Continuous-Flow Left Ventricular Assist Devices

“…[7][8][9][10][11][12][13] In addition, TNF-α, IL-6, CRP, IP-10, and MDC are implicated in vascular dysfunction, atherosclerotic plaque development, and increased macrophage accumulation. [14][15][16][17][18][19] Chronic elevation of inflammatory markers, which has been shown to have deleterious effects on the heart and vasculature, may prevent optimal recovery in CF-LVAD recipients.…”

“…4 Although the newer generation of CF-LVADs have been shown to confer some advantages over the pulsatile pumps, including durability, smaller size, fewer infections, 5 and lower incidence of thromboembolic events, 6 the effects of CF-LVAD on inflammation are incompletely understood. The relationship between CF-LVAD therapy and systemic cytokines and chemokines is important because these factors may cause cardiac [7][8][9][10][11][12][13] and vascular [14][15][16][17][18][19] dysfunctions, which could ultimately limit the benefits achieved with this therapy.…”

Endothelial pannexin 1 channels control inflammation by regulating intracellular calcium

“…Our data provide further evidence that the expression of other inflammatory chemokines such as CXCL10 are controlled in a Panx1 specific manner. CXCL10 has been proposed to be an important inflammatory marker in atherosclerosis (Szentes et al, 2018; Zernecke et al, 2008), leading to the formation of vulnerable plaques in humans and mice (Heller et al, 2006; Segers et al, 2011). Strategies to lower CXCL10 expression can lead to reduced plaque formation and increased plaque stability (Segers et al, 2011).…”

“…CXCL10 has been proposed to be an important inflammatory marker in atherosclerosis (Szentes et al, 2018; Zernecke et al, 2008), leading to the formation of vulnerable plaques in humans and mice (Heller et al, 2006; Segers et al, 2011). Strategies to lower CXCL10 expression can lead to reduced plaque formation and increased plaque stability (Segers et al, 2011). As previously described, it is possible that these increases correlate with IL-1β signaling pathways (Brown et al, 2015; Dinarello, 2010; Libby and Hansson, 2015; Ridker, 2013, 2019).…”

Ratio of S-adenosylmethionine to S-adenosylhomocysteine as a sensitive indicator of atherosclerosis

“…Atherosclerosis (AS) is a leading contributor to mortality rates in developed countries; it is a complex and multifactorial disease and is affected by genetic and environment factors (1). Due to the methods of diagnosing AS being limited and the poor reversibility of the disease, accurate and timely detection of atherosclerotic lesions is particularly important.…”