# Decreased adipokine CTRP4 in CAD patients: CTRP4 attenuates atherosclerosis via inhibition of RAGE and TLR4

## TL;DR

Lower levels of the adipokine CTRP4 are linked to coronary artery disease, and CTRP4 helps prevent atherosclerosis by reducing inflammation through RAGE and TLR4 inhibition.

## Contribution

CTRP4 is identified as a novel anti-inflammatory and anti-atherogenic adipokine with therapeutic potential for coronary artery disease.

## Key findings

- CTRP4 levels are decreased in CAD patients' serum and epicardial adipose tissue.
- CTRP4 supplementation reduces atherosclerosis in mice by inhibiting RAGE and TLR4.
- CTRP4 deficiency promotes atherosclerosis in ApoE−/− mice.

## Abstract

C1q/TNF‐related proteins (CTRPs) belong to the adipokine family. Here, we aimed to assess the relation of CTRP4 levels in serum and perivascular adipose tissue (PVAT) with coronary artery disease (CAD), and investigate the effect of CTRP4 on atherosclerosis and the underlying mechanisms.

CTRP4 levels were examined in serum and epicardial adipose tissue (a major PVAT) from patients with CAD. Atherosclerotic lesions were analysed in CTRP4‒/‒/ApoE‒/‒ and ApoE‒/‒ mice. The paracrine effects of CTRP4 on atherosclerosis were tested by supplementation with CTRP4, either via PVAT transplantation or tail vein injection in CTRP4−/−/ApoE−/− mice. CTRP4‐interacting proteins were identified using immunoprecipitation and mass spectrometry.

CTRP4 levels were lower in serum and epicardial adipose tissue of patients with CAD compared to non‐CAD controls. CTRP4 knockout promoted atherosclerosis in ApoE‒/‒ mice. Supplementation of CTRP4, but not receptor for advanced glycation end‐products (RAGE)‐ and toll‐like receptor 4 (TLR4)‐binding incompetent CTRP4 mutant, either through adipose tissue transplantation from wild‐type mice or intravenous injection of recombinant protein, attenuated atherosclerosis in CTRP4‒/‒/ApoE‒/‒ mice. In macrophages, CTRP4 protein, but not the mutant, suppressed the expression of lipopolysaccharide‐induced inflammatory cytokines. Mechanistically, the anti‐atherogenic effects of CTRP4 were mediated by the engagement and inhibition of RAGE and TLR4.

Decreased CTRP4 levels in serum and epicardial adipose tissue are associated with CAD in patients. CTRP4 deficiency promotes the development of atherosclerosis in ApoE‒/‒ mice, whereas CTRP4 supplementation attenuates atherosclerosis via binding and inhibition of RAGE and TLR4. These results suggest that CTRP4 is a novel anti‐inflammatory and anti‐atherogenic adipokine inversely associated with CAD and a potential therapeutic target.

1. CTRP4 is a key endogenous inhibitor of vascular inflammation and atherogenesis. Deficiency of CTRP4 promotes atherosclerosis in ApoE‒/‒ mice.

2. CTRP4 supplementation either via PVAT transplantation or injection of recombinant protein antagonise atherosclerosis in ApoE‒/‒ mice.

3. The anti‐atherogenic effect of CTRP4 is mediated through RAGE and TLR4 engagement and inhibition.