ctrp1 aggravates cardiac fibrosis by regulating the nox2/p38 pathway in macrophages

Objective: c1q/tnf-related proteins 1 (ctrp1) is a recently identified adiponectin associated with obesity-linked disorders and adverse cardiovascular events. the effect of ctrp1 on cardiac fibrosis has not yet been fully elucidated; thus, we aimed to explore this association. materials and methods: in this experimental study, a mouse model of cardiac fibrosis was established by administering isoproterenol (iso) (subcutaneously injecting 10 mg/kg/day for 3 days and then 5 mg/kg/day for 11 days). mice were also injected with recombinant ctrp1 protein (200 μg/kg) 14 days after the final iso administration. adult mouse fibroblasts were isolated and stimulated with transforming growth factor (tgf) β1, followed by treatment with recombinant ctrp1. primary bone marrow-derived macrophages were isolated from c57bl/6j mice and treated with recombinant ctrp1 as well. results: ctrp1 level was increased in mouse plasma and heart tissue 2 weeks after iso injection. our findings indicated that recombinant ctrp1 injection aggravated iso-induced cardiac fibrosis and dysfunction. however, recombinant ctrp1 did not alter tgfβ1-induced fibroblast proliferation and activation or collagen transcription. recombinant ctrp1 exacerbated iso-induced macrophage infiltration and inflammatory response. we determined that macrophages treated with recombinant ctrp1 showed increased pro-inflammatory cytokine release. fibroblasts co-cultured with macrophages treated with recombinant ctrp1 showed increased proliferation and collagen transcription. we also found that ctrp1 upregulated the nadph oxidase 2 (nox2)/p38 pathway in macrophages. when we inhibited p38 signaling, the pro-inflammatory effect of ctrp1 on macrophages was counteracted. fibroblasts co-cultured with macrophages treated with a p38 inhibitor also showed limited proliferation and collagen transcription. conclusion: cardiac fibrosis was aggravated with the activation of the nox2/p38 pathway in macrophages after ctrp1 treatment.