Impaired macrophage trafficking and increased helper T-cell recruitment with loss of cadherin-11 in atherosclerotic immune response.

Inflammation caused by infiltrating macrophages and T cells promotes plaque growth in atherosclerosis. Cadherin-11 (CDH11) is a cell-cell adhesion protein implicated in several fibrotic and inflammatory diseases. Much of the research on CDH11 concerns its role in fibroblasts, although its expression in immune cells has been noted as well. The objective of this study was to assess the effect of CDH11 on the atherosclerotic immune response. In vivo studies of atherosclerosis indicated an increase in Cdh11 in plaque tissue. However, global loss of Cdh11 resulted in increased atherosclerosis and inflammation. It also altered the immune response in circulating leukocytes, decreasing myeloid cell populations and increasing T-cell populations, suggesting possible impaired myeloid migration. Bone marrow transplants from Cdh11-deficient mice resulted in similar immune cell profiles. In vitro examination of Cdh11-/- macrophages revealed reduced migration, despite upregulation of a number of genes related to locomotion. Flow cytometry revealed an increase in CD3+ and CD4+ helper T-cell populations in the blood of both the global Cdh11 loss and the bone marrow transplant animals, possibly resulting from increased expression by Cdh11-/- macrophages of major histocompatibility complex class II molecule genes, which bind to CD4+ T cells for coordinated activation. CDH11 fundamentally alters the immune response in atherosclerosis, resulting in part from impaired macrophage migration and altered macrophage-induced T-cell activation.NEW & NOTEWORTHY Cadherin-11 is well known to contribute to inflammatory and fibrotic disease. Here, we examined its role in atherosclerosis progression, which is predominantly an inflammatory process. We found that while cadherin-11 is associated with plaque progression, global loss of cadherin-11 exacerbated the disease phenotype. Moreover, loss of cadherin-11 in bone marrow-derived immune cells resulted in impaired macrophage migration and an unexplained increase in circulating helper T cells, presumably due to altered macrophage function without cadherin-11.

Side-specific valvular endothelial-interstitial cell mechano-communication via cadherin-11.

Calcific aortic valve disease (CAVD) is a condition causing stiffening of the aortic valve, impeding cardiac function and resulting in significant morbidity worldwide. CAVD is thought to be driven by the persistent activation of the predominant cell type in the valve, aortic valve interstitial cells (AVICs), into myofibroblasts, resulting in subsequent calcification and stenosis of the valve. Although much of the research into CAVD focuses on AVICs, the aortic valve endothelial cells (AVECs) have been shown to regulate AVICs and maintain tissue homeostasis. Exposed to distinct flow patterns during the cardiac cycle, the AVECs lining either side of the valve demonstrate crucial differences which could contribute to the preferential formation of calcific nodules on the aorta-facing (fibrosa) side of the valve. Cadherin-11 (CDH11) is a cell-cell adhesion protein which has been previously associated with AVIC myofibroblast activation, nodule formation, and CAVD in mice. In this study, we investigated the role of CDH11 in AVECs and examined side-specific differences. The aorta-facing or fibrosa endothelial cells (fibAVECs) express higher levels of CDH11 than the ventricle-facing or ventricularis endothelial cells (venAVECs). This increase in expression corresponds with increased contraction of a free-floating collagen gel compared to venAVECs. Additionally, co-culture of fibAVECs with AVICs demonstrated decreased contraction compared to an AVIC + AVIC control, but increased contraction compared to the venAVECs co-culture. This aligns with the known preferential formation of calcific nodules on the fibrosa. These results together indicate a potential role for CDH11 expression by AVECs in regulating AVIC contraction and subsequent calcification.

Celecoxib Is Associated With Dystrophic Calcification and Aortic Valve Stenosis.

Calcific aortic valve disease is a progressive fibrocalcific process that can only be treated with valve replacement. Cadherin-11 has recently been identified as a potential therapeutic target for calcific aortic valve disease. The already approved drug celecoxib, a cyclooxygenase-2 inhibitor, binds cadherin-11, and was investigated as a therapeutic against calcific aortic valve disease. Unexpectedly, celecoxib treatment led to hallmarks of myofibroblast activation and calcific nodule formation in vitro. Retrospective electronic medical record analysis of celecoxib, ibuprofen, and naproxen revealed a unique association of celecoxib use and aortic stenosis.