Simulative and experimental investigation on the cleavage site that generates the soluble human LOX-1.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor that mediates the recognition, the binding and internalization of ox-LDL. A truncated soluble form of LOX-1 (sLOX-1) has been identified that, at elevated levels, has been associated to acute coronary syndrome. Human sLOX-1 is the extracellular part of membrane LOX-1 which is cleaved in the NECK domain with a mechanism that has not yet been identified. Purification of human sLOX-1 has been carried out to experimentally identify the cleavage site region within the NECK domain. Molecular modelling and classical molecular dynamics simulation techniques have been used to characterize the structural and dynamical properties of the LOX-1 NECK domain in the presence and absence of the CTLD recognition region, taking into account the obtained proteolysis results. The simulative data indicate that the NECK domain is stabilized by the coiled-coil heptad repeat motif along the simulations, shows a definite flexibility pattern and is characterized by specific electrostatic potentials. The detection of a mobile inter-helix space suggests an explanation for the in vivo susceptibility of the NECK domain to the proteolytic cleavage, validating the assumption that the NECK domain sequence is composed of a coiled-coil motif destabilized in specific regions of functional significance.

Circulatory soluble LOX-1 is a novel predictor for coronary artery disease patients.

BACKGROUND: This study investigated the biomarker effect of soluble lectin-like oxidised low-density lipoprotein (sLOX-1) levels for the evaluation of stable and unstable coronary heart disease, correlating it with aging. METHODS: This case-control study was conducted at the Cardiology Department of Xiangya Hospital between June 2015 and September 2018. Stable coronary artery disease (CAD) patients were confirmed by an invasive coronary angiogram, and American College of Cardiology as well as European Cardiology Society clinical protocols were used for the diagnosis of unstable CAD subjects. Plasma sLOX-1 levels were determined from 226 stable CAD patients, 138 unstable CAD subjects and 75 healthy participants by enzyme-linked immunosorbent assay. RESULTS: Plasma sLOX-1 expressions were significantly elevated in stable CAD patients (4.5-fold) and unstable CAD patients (5.8-fold) above that of volunteer healthy participants. Moreover, between the stable and unstable patient groups, sLOX-1 concentrations were also statistically significantly different (p < 0.001). Levels of plasma sLOX-1 in the healthy female (30-60 years), and stable and unstable CAD female subjects (61-84 years) were markedly elevated compared with healthy male (30-60 years), as well as stable and unstable CAD male patients (61-84 years) (p < 0.001). Besides, in the female unstable CAD (61-84 years) subjects, circulatory sLOX-1 expressions were much higher than in the younger female unstable CAD (30-60 years) patients (p < 0.001). The stable CAD patients were clearly differentiated from healthy subjects with a high sensitivity of the area under the curve (AUC = 0.895). Unstable CAD patients and healthy subjects were also markedly different with a high sensitivity, as shown by AUC (0.902). Stable and unstable CAD subjects were differentiated with an AUC of 0.867. CONCLUSIONS: Elevated plasma sLOX-1 levels could be regarded as a novel biomarker for detecting CAD patients and there was a significant association with gender and aging.

Associations of Tissue and Soluble LOX-1 with Human Abdominal Aortic Aneurysm.

Background Indication for prophylactic surgical abdominal aortic aneurysm (AAA) repair depends on the maximal aortic diameter. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for uptake of oxidized low-density lipoprotein cholesterol and is implicated in atherosclerosis. A soluble form of LOX-1 (sLOX-1) has been discussed as a novel biomarker in coronary artery disease and stroke. Herein, we assessed the regulation of aortic LOX-1 as well as the diagnostic and risk stratification potential of sLOX-1 in patients with AAA. Methods and Results Serum sLOX-1 was assessed in a case-control study in AAA (n=104) and peripheral artery disease (n=104). sLOX-1 was not statistically different between AAA and peripheral artery disease but was higher in AAA (ß=1.28, P=0.04) after adjusting for age, atherosclerosis, type 2 diabetes, prescription of statins, ß-blockers, ACE inhibitors, and therapeutic anticoagulation. sLOX-1 was not associated with the aortic diameter, AAA volume, or the thickness of the intraluminal thrombus. Aortic LOX-1 mRNA expression tended to be higher in AAA when compared with disease, and expression was positively associated with cleaved caspase-3, smooth muscle actin, collagen, and macrophage content. Conclusions In AAA, sLOX-1 was differently affected by age, cardiometabolic diseases, and corresponding medical therapies. Comparison with nonatherosclerotic disease would be beneficial to further elucidate the diagnostic potential of sLOX-1, although it was not useful for risk stratification. Aneurysmal LOX-1 mRNA expression was increased and positively associated with smooth muscle cells and collagen content, suggesting that LOX-1 is eventually not deleterious in human AAA and could counteract AAA rupture.

Effects of Tofogliflozin and Anagliptin Alone or in Combination on Glucose Metabolism and Atherosclerosis-Related Markers in Patients with Type 2 Diabetes Mellitus.

Purpose: In people with type 2 diabetes mellitus (T2DM), both glucose metabolism abnormalities and atherosclerosis risk are significant concerns. This study aims to investigate the effects of the sodium-glucose cotransporter 2 inhibitor tofogliflozin (TOFO) and the dipeptidyl peptidase-4 inhibitor anagliptin (ANA) on markers of glucose metabolism and atherosclerosis when administered individually or in combination. Methods: Fifty T2DM patients were divided into two groups (receiving either TOFO or ANA monotherapy) and observed for 12 weeks (observation points: 0 and 12 weeks). The TOFO and ANA groups were then further treated with ANA and TOFO, respectively, and the patients were observed for an additional 36 weeks (observation points: 24 and 48 weeks). Therapeutic effects and various biomarkers were compared between the two groups at the observation points. Results: Combination therapy led to significant improvements in HbA1c levels and atherosclerosis markers. Additionally, the TOFO pretreatment group exhibited significant reductions in sLOX-1 and IL-6 levels. Conclusion: The increase in sLOX-1 and IL-6 levels, which indicates the response of scavenger receptors to oxidized low-density lipoproteins in people with T2DM, is mitigated following TOFO and ANA combination therapy. TOFO alone or in combination with ANA may be beneficial for preventing atherosclerosis development in people with T2DM, in addition to its effect on improving HbA1c levels.