Asprosin induces vascular endothelial-to-mesenchymal transition in diabetic lower extremity peripheral artery disease

Abstract

Background 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. Methods 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 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. Logistic regression analysis revealed that asprosin is an independent risk factor for PAD and receiver-operator characteristic (ROC) curve determined a good sensitivity (74.5%) and specificity (74.6%) of asprosin to distinguish PAD. Data from metabolomics displayed a typical characteristics of de novo amino acid synthesis in collagen protein production by myofibroblasts in patients with PAD and activation of TGF-β signaling pathway appeared in the aortic tissue of db/db mice. Asprosin directly induces EndMT in HUVECs in a TGF-β-dependent manner as TGF-β 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-β signaling pathway. Trial registration This trial was registered at clinicaltrials.gov as NCT05068895

Asprosin aggravates vascular endothelial dysfunction via disturbing mitochondrial dynamics in obesity models

“…AR, aspect ratio; ASP, asprosin; BIN, binarization; Ctrl, control; FF, form factor; PA, palmitic acid; RTAEC, rat thoracic aortic endothelial cell. ***p < 0.001 vs. Ctrl group; ### p < 0.001 vs. PA group; $$ p < 0.01, $$$ p < 0.001 vs. ASP group [Color figure can be viewed at wileyonlinelibrary.com] participated in the vascular dysfunction of lower-extremity PAD [15].…”

“…The injury and dysfunction of vascular endothelial cells (ECs) induced by hyperglycemia and/or hypertriglyceridemia are the first triggers for blood vessel dysfunction in obesity [12]. Coincidentally, recent studies have shown that ASP is involved in cardiovascular diseases (CVD) [13,14] and that pathologically elevated ASP levels may be an independent risk factor for lower-extremity peripheral arterial disease (PAD) [15]. Mitochondria are the main organelles in charge of cell energy metabolism.…”

Asprosin in health and disease, a new glucose sensor with central and peripheral metabolic effects

“…Notably, a significant asprosin levels were detected in T2DM patients with carotid plaque compared to non-carotid plaque T2DM group ( 74 ). Furthermore, elevated plasma asprosin levels was reported in T2DM patients suffering from diabetic lower extremity peripheral artery disease (PAD) ( 73 ). Asprosin induced TGF-β signaling pathway activation that directly affects endothelial-to-mesenchymal transition (EndMT) ( 73 ).…”

“…Furthermore, elevated plasma asprosin levels was reported in T2DM patients suffering from diabetic lower extremity peripheral artery disease (PAD) ( 73 ). Asprosin induced TGF-β signaling pathway activation that directly affects endothelial-to-mesenchymal transition (EndMT) ( 73 ).…”

Assessment of asprosin level and some of physiological variables in patients with cardiovascular diseases in Kirkuk city, Iraq

“…Asprosin is a novel hormone discovered in 2016 is secreted by the white adipose tissue of the body (8). Asprosin, is expressed by the gene Fibrillin1, present in most cells of the body including human cutaneous fibroblasts, pancreatic B cells, peripheral tissues and organs (8,9,10). Asprosin, has been shown to be associate in metabolic disorders such as cardiovascular disease, diabetes, polycystic ovarian syndrome, obesity and implicated as a diagnostic biomarker in these disorders (11).…”