S-07-5: ASPROSIN INDUCES VASCULAR ENDOTHELIAL- TO-MESENCHYMAL TRANSITION IN DIABETIC LOWER EXTREMITY PERIPHERAL ARTERY DISEASE

Abstract

Objective: Altered adipokine secretion in dysfunctional adipose tissue facilitates the development of atherosclerotic diseases including lower extremity peripheral artery disease (PAD). Asprosin is a recently identified adipokine and displays potent regulatory role in metabolism, but the relationship between asprosin and lower extremity PAD remains uninvestigated. In this study, we investigated the effect of asprosin accounting for the lower extremity vascular injury in diabetic patients based on the metabolic profiles of PAD. Design and method: 33 type 2 diabetes mellitus (T2DM) patients (DM), 51 T2DM patients with PAD (DM+PAD) and 30 healthy normal control (NC) volunteers were recruited and the blood samples were collected for detecting the circulatory asprosin level and metabolomic screening. RNA sequencing was performed using the aorta tissues from the type 2 diabetic db/db mice and its control db/m mice. Moreover, human umbilical vein endothelial cells (HUVECs) were treated with asprosin to determine its impact on the endothelial-to-mesenchymal transition (EndMT). Results: The circulating levels of asprosin in DM+PAD group were significantly higher than that of NC group and the DM group. Circulating asprosin level was remarkably negatively correlated with ankle-brachial index (ABI), even after adjusting for age, sex, body mass index (BMI) and other traditional risk factors of PAD (P = 0.049). Logistic regression analysis revealed that asprosin is an independent risk factor for PAD (OR:3.944, 95%CI:1.656 − 9.393, P = 0.002) and receiver-operator characteristic (ROC) curve determined a cut-off value at 188.70 ng/ml with a good sensitivity (74.5%) and specificity (74.6%) of asprosin to distinguish PAD (Area under curve:0.788, 95%CI:0.694 − 0.863, P < 0.001). Data from metabolomics displayed a typical characteristics of de novo amino acid synthesis in collagen protein production by myofibroblasts in which TGF-beta signaling pathway might plays a critical role in patients with PAD. In addition, activation of TGF-beta signaling pathway also appeared in the aortic tissue of db/db mice, suggesting a causal relationship between TGF-beta signaling pathway and artery injury. Asprosin directly induces EndMT in HUVECs in a TGF-beta-dependent manner as TGF-beta signaling pathway inhibitor SB431542 erased the promotional effect of asprosin on EndMT. Conclusions: Elevated circulatory asprosin level is an independent risk factor of lower extremity PAD and might serve as a diagnostic marker. Mechanistically, asprosin directly induces EndMT that participates in vascular injury via activation of TGF-beta signaling pathway.