Abstract
Vascular injury is an early manifestation leading to end-organ damage in hypertension pathogenesis, which involves a macrophage-associated immune response. Dendritic cell-associated C-type lectin-1 (Dectin1) is a pivotal player in regulating inflammation-mediated cardiovascular disease. However, its role in hypertension-induced vascular damage and the underlying mechanisms remain unclear. We hypothesized that Dectin1 might accelerate angiotensin II (Ang II)- or deoxycorticosterone acetate-salt (DOCA-salt)-induced vascular injury through proinflammatory actions in macrophages. Macrophage Dectin1 was upregulated in mouse aortic tissues stimulated with Ang II. In the peripheral blood, Ang II also increased CD11b+F4/80+ macrophages in mice. In our constructed Dectin1 knockout mice, Dectin1 deletion protected against Ang II-induced EB extravasation and aortic wall thickness. Deficiency of Dectin1 or its pharmacological inhibition considerably improved fibrosis and inflammation responses, accompanied by a reduction in M1 macrophage polarization as well as proinflammatory cytokines and chemokines induced by Ang II or DOCA-salt. Through the bone marrow (BM) transplantation assay, these effects were verified in the wild type mice reconstituted with Dectin1-deficient BM cells. Mechanistically, Ang II promoted Dectin1 homodimerization, thereby triggering the spleen tyrosine kinase/nuclear factor kappa B pro-inflammatory cascade to induce the expression of inflammatory factors and chemokines in vivo and in vitro. In conclusion, Dectin1 has an essential role in the pathogenic procedure of Ang II-stimulated or DOCA-salt-induced vascular damage in mice and represents a promising therapeutic target for cardiovascular diseases.