December 1, 2022Open Access

CTRP1 Aggravates Cardiac Fibrosis by Regulating The NOX2/P38 Pathway in Macrophages.

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Why the study?

CTRP1 is associated with obesity-linked disorders and adverse cardiovascular events, but its effect on cardiac fibrosis had not yet been fully elucidated.

Does recombinant CTRP1 aggravate cardiac fibrosis and dysfunction in a mouse model of isoproterenol-induced cardiac injury?

Structured PICO

Does recombinant CTRP1 aggravate cardiac fibrosis and dysfunction in a mouse model of isoproterenol-induced cardiac injury?

Population

C57BL6J male mice (in vivo model of isoproterenol-induced cardiac fibrosis), adult mouse fibroblasts (4-6 weeks old), and primary bone marrow-derived macrophages (6-8 weeks old).

Intervention

Recombinant CTRP1 full-length protein (200 μg/kg for 2 weeks via osmotic minipump in vivo; up to 8 μg/mL in vitro).

Comparator

Vehicle solution (normal saline in vivo; PBS containing 0.1% BSA in vitro).

Outcome

Cardiac fibrosis (LV collagen volume by Picrosirius red staining, fibrosis markers by RT-PCR) and cardiac function (LVEF, LVFS, E/A ratio by echocardiography).surrogate

Recombinant CTRP1 aggravates isoproterenol-induced cardiac fibrosis and dysfunction by promoting macrophage pro-inflammatory activation via the NOX2/p38 pathway.

Implication

CTRP1-cardiac fibrosis link remains unproven in humans; leaves open any therapeutic targeting potential.

Abstract

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.