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

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.