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Innate and acquired immunity is involved in the progression of atherosclerosis. The molecular mechanisms ruling monocyte to macrophage (Mø) differentiation are not yet fully understood. Different subtypes of plaque macrophages that have differentiated from monocytes recruited from circulating blood, have been characterized based on surface epitopes. We have recently shown that LRP5, a member of the LDL receptor superfamily supporting Wnt signalling, has an important role in monocyte to macrophage differentiation. The aim of this study was to investigate whether the CD16- and CD16+ macrophage subsets found in human atherosclerotic plaques have a differential LRP5 expression/function and Wnt signalling potential. We show for the first time that LRP5 expression is significantly higher in human CD16+Mø derived from CD14(+)CD16(+) monocytes than in CD16-Mø macrophages derived from CD14(+)CD16(-) monocytes. LRP5 is not found in human healthy vessel or arterial intimal thickening but is found in advanced human atherosclerotic lesions co-localizing only with the CD16+Mø macrophage subset. LRP5 expressing macrophages infiltrate the deep layers of atherosclerotic plaques towards the intima-media boundaries showing increased migratory activity and higher phagocytic activity. The equivalent for human patrolling CD14(+)CD16(+) monocytes in mice, CD115(+)GR1(low) monocytes, also show an increased expression of LRP5. In summary, classical CD14(+)CD16(-)monocytes that differentiate into CD16-Mø do not express LRP5. Instead, human monocytes expressing LRP5 differentiate into CD16+Mø antiinflammatory macrophages. These antiinflammatory macrophages are found in advanced atherosclerotic human plaques. Thus LRP5 is a signature of the anti-inflammatory defensive phenotype of macrophages., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The extent of cardiac remodeling determines survival after acute MI. However, the mechanisms driving cardiac remodeling remain unknown. We examined the effect of ischemia and reperfusion (R) on myocardial changes up to 6 days post-MI. Pigs underwent 1.5h or 4h mid-LAD balloon occlusion and sacrificed or 1.5h occlusion followed by R and sacrificed at 2.5h, 1 day, 3 days, and 6 days. Ischemic- (IM) and non-ischemic myocardium (NIM) was obtained for molecular analysis of: 1) apoptosis (P-Bcl2, Bax, P-p53, active-caspase-3); 2) the TLR-4-MyD88-dependent and independent pathways; 3) Akt/mTOR/P70(S6K) axis activation; and, 4) fibrosis (TGF-β, collagen1-A1/A3). Histopathology for inflammation, collagen, and fibroblast content, TUNEL staining, and metalloproteinase activity was performed. Apoptosis is only detected upon R in IM cardiomyocytes and progresses up to 6 days post-R mainly associated with infiltrated macrophages. The Akt/mTOR/P70(s6K) pathway is also activated upon R (IM) and remains elevated up to 6 days-R (P<0.05). Ischemia activates the TLR-4-MyD88-dependent (cytokines/chemokines) and -independent (IRF-3) pathways in IM and NIM and remains high up to 6 days post-R (P<0.05). Accordingly, leukocytes and macrophages are progressively recruited to the IM (P<0.05). Ischemia up-regulates pro-fibrotic TGF-β that gradually rises collagen1-A1/-A3 mRNA with subsequent increase in total collagen fibrils and fibroblasts from 3 days-R onwards (P<0.005). MMP-2 activity increases from ischemia to 3 days post-R (P<0.05). We report that there is a timely coordinated cellular and molecular response to myocardial ischemia and R within the first 6 days after MI. In-depth understanding of the mechanisms involved in tissue repair is warranted to timely intervene and better define novel cardioprotective strategies., (Copyright © 2011 Elsevier Ltd. All rights reserved.)