CTRP12 ameliorates atherosclerosis by promoting cholesterol efflux and inhibiting inflammatory response via the miR-155-5p/LXRα pathway

Abstract

C1q tumor necrosis factor-related protein 12 (CTRP12), a conserved paralog of adiponectin, is closely associated with cardiovascular disease. However, little is known about its role in atherogenesis. The aim of this study was to examine the influence of CTRP12 on atherosclerosis and explore the underlying mechanisms. Our results showed that lentivirus-mediated CTRP12 overexpression inhibited lipid accumulation and inflammatory response in lipid-laden macrophages. Mechanistically, CTRP12 decreased miR-155-5p levels and then increased its target gene liver X receptor α (LXRα) expression, which increased ATP binding cassette transporter A1 (ABCA1)- and ABCG1-dependent cholesterol efflux and promoted macrophage polarization to the M2 phenotype. Injection of lentiviral vector expressing CTRP12 decreased atherosclerotic lesion area, elevated plasma high-density lipoprotein cholesterol levels, promoted reverse cholesterol transport (RCT), and alleviated inflammatory response in apolipoprotein E-deficient (apoE−/−) mice fed a Western diet. Similar to the findings of in vitro experiments, CTRP12 overexpression diminished miR-155-5p levels but increased LXRα, ABCA1, and ABCG1 expression in the aortas of apoE−/− mice. Taken together, these results suggest that CTRP12 protects against atherosclerosis by enhancing RCT efficiency and mitigating vascular inflammation via the miR-155-5p/LXRα pathway. Stimulating CTRP12 production could be a novel approach for reducing atherosclerosis.

The Extensive Regulation of MicroRNA in Immune Thrombocytopenia

“… 101 , 102 Inhibition of miR-155 can polarize macrophages to M2. 103 There are M1 polarization dominance and M2 marker expression impairment in spleen and peripheral macrophages of patients with ITP, and the proportion of M2 increases after treatment, suggesting that they may be involved in the pathogenesis of ITP. 104 , 105 These results suggest that miR-155 is involved in the pathogenesis of ITP by regulating the polarization of macrophage M1/M2.…”

C1q Tumor Necrosis Factor–Related Protein 1: A Promising Therapeutic Target for Atherosclerosis

“…We and other groups have reported that some members, including CTRP3, CTRP9, CTRP12, and CTRP13, mitigate atherosclerosis. [46][47][48][49] However, other members, such as CTRP5, exert a proatherogenic effect. 50 Like these members, CTRP1 is closely associated with the occurrence and development of atherosclerosis.…”

The Role of Anti-Inflammatory Adipokines in Cardiometabolic Disorders: Moving beyond Adiponectin

“…CTRP3 remarkably decreases the inflammatory cytokines, suppresses cellular apoptosis, and equilibrates the opposing effects of endothelin-1 and NO by prompting the phosphatidylinositol 3-kinase (PI3K), Akt, and eNOS expressions [132]. CTRP12, also referred to as adipolin, is inversely correlated with IL-6 and TNF-α, and encourages the M2 phenotype of macrophage polarization [133,134]. CTRP3 inhibits hepatic glucose output [135], and both CTRP12 and CTRP13 repress gluconeogenesis, intensify the glucose uptake of various organs, and relieve hepatic insulin resistance mboxciteB136-ijms-1473452,B137-ijms-1473452.…”

“…CTRP3 inhibits hepatic glucose output [135], and both CTRP12 and CTRP13 repress gluconeogenesis, intensify the glucose uptake of various organs, and relieve hepatic insulin resistance mboxciteB136-ijms-1473452,B137-ijms-1473452. Additionally, CTRP12 disturbs the neointimal thickening by alleviating vascular cell proliferation and lipid accumulation following the promotion of ABCA1-mediated cholesterol efflux [134,138]. CTRP13-infused mice are protected from atherosclerotic plaque formation with accelerated autophagy, downregulated lipid uptake, and inhibited foam cell migration [139].…”