Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non-foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1α and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1α via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1α/VEGF-A pathway.

Blood pressure (BP) is one of the most important contributing factors to pulse wave velocity (PWV), a classic measure of arterial stiffness. Although there have been many non-invasive studies to show the relation between arterial stiffness and BP, the results are controversial. The aim of this study is to evaluate the role of BP as an influencing factor on PWV using invasive method. We observed 174 normotensive and untreated hypertensive subjects using coronary angiography. Arterial stiffness was assessed through aorto-femoral PWV by foot-to-foot velocity method using fluid-filled system. And BP was measured by pressure wave at the right common femoral artery. From univariate analysis, age, diabetes mellitus (DM), hypertension, waist, waist-to-hip ratio, total cholesterol-tohigh-density lipoprotein cholesterol ratio, systolic BP (SBP), pulse pressure (PP) and mean arterial pressure (MAP) showed significant association with PWV. To avoid multiple colinearity among SBP, PP and MAP, we performed multiple regression analysis predicting PWV thrice. Age, DM and each BP were significantly and consistently correlated to PWV. In the first and third modules, compared to age, SBP and MAP were less strong predictors, respectively. However, PP was the stronger predictor than age and DM in the second module. Lastly, we simultaneously forced MAP and PP with other variables in the fourth multivariate analysis. Age, DM and PP remained significantly correlated with PWV, but the significance of MAP was lost. This is the first invasive study to suggest that PP has the strongest correlation with PWV among a variety of BP parameters.

EAT(total) and thickness of periatrial EAT were significantly larger in AF subjects compared to those of the matched controls and were closely related to the chronicity of AF. Moreover, EAT(total) and IAS thickness were independently associated with LAV in subjects with AF.

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Macrophages are an essential component of the immune response to ischaemic injury and play an important role in promoting inflammation and its resolution, which is necessary for tissue repair. The type I transmembrane glycoprotein CD163 is exclusively expressed on macrophages, where it acts as a receptor for haemoglobin:haptoglobin complexes. An extracellular portion of CD163 circulates in the blood as a soluble protein, for which no physiological function has so far been described. Here we show that during ischaemia, soluble CD163 functions as a decoy receptor for TWEAK, a secreted pro-inflammatory cytokine of the tumour necrosis factor family, to regulate TWEAK-induced activation of canonical nuclear factor-κB (NF-κB) and Notch signalling necessary for myogenic progenitor cell proliferation. Mice with deletion of CD163 have transiently elevated levels of TWEAK, which stimulate muscle satellite cell proliferation and tissue regeneration in their ischaemic and non-ischaemic limbs. These results reveal a role for soluble CD163 in regulating muscle regeneration after ischaemic injury.