Senescence in vascular smooth muscle cells (VSMCs) is involved in vascular remodeling of aged mice. ProstaglandinF2α- (PGF2α-) FP receptor plays a critical role in cardiovascular diseases (CVDs), hypertension, and cardiac fibrosis. However, its role in senescence-induced arteriosclerosis is yet to be fully elucidated. In this study, we found that FP receptor expression increased in aged mouse aortas and senescence VSMCs. FP receptor gene silencing can ameliorate vascular aging and inhibit oxidative stress, thereby reducing the expression of PAI-1, inhibiting the activation of MMPs, and ultimately improving the excessive deposition of ECM and delaying the process of vascular fibrosis. FP receptor could promote VSMC senescence by upregulated Src/PAI-1 signal pathway, and inhibited FP receptor/Src/PAI-1 pathway could ameliorate VSMCs aging in vitro, evidenced by the decrease of senescence-related proteins P16, P21, P53, and GLB1 expressions. These results suggested that FP receptor is a promoter of vascular aging, by inducing cellular aging, oxidative stress, and vascular remodeling via Src and PAI-1 upregulation.
Background: Endothelial microparticles (EMPs) carrying the protein disulfide isomerase (PDI) might play a key role in promoting platelet activation in diabetes. This study aimed to examine the activation of platelets, the amounts of MPs, PMPs, and EMPs, and the concentration and activity of PDI in patients with diabetic coronary heart disease (CHD) and non-diabetic CHD. Methods: Patients with CHD (n=223) were divided as non-diabetic CHD (n=121) and diabetic CHD (n=102). Platelet activation biomarkers, circulating microparticles (MPs), the concentration of protein disulfide isomerase (PDI), and MP-PDI activity were determined. The effect of EMPs on platelet activation was investigated in vitro . Allosteric GIIb/IIIa receptors that bind to PDI were detected by a proximity ligation assay (PLA). Results: Platelet activation, platelet-leukocyte aggregates, circulating MPs, EMPs, PDI, and MP-PDI activity in the diabetic CHD group were significantly higher than in the non-diabetic CHD group ( P <0.05). Diabetes ( P =0.006) and heart rate <60 bpm ( P =0.047) were associated with elevated EMPs. EMPs from diabetes increased CD62p on the surface of the platelets compared with the controls ( P< 0.01), which could be inhibited by the PDI inhibitor RL90 ( P< 0.05). PLA detected the allosteric GIIb/IIIa receptors caused by EMP-PDI, which was also inhibited by RL90. Conclusions: In diabetic patients with CHD, platelet activation was significantly high. Diabetes and heart rate <60 bpm were associated with elevated EMPs and simultaneously increased PDI activity on EMP, activating platelets through the allosteric GPIIb/IIIa receptors.
Background The prevalence of metabolic syndrome (Mets) is closely related to an increased incidence of cardiovascular events. Angiopoietin-like protein 4 (ANGPTL4) is contributory to the regulation of lipid metabolism, herein, may provide a target for gene-aimed therapy of Mets. This observational case control study was designed to elucidate the relationship between ANGPTL4 gene single nucleotide polymorphism (SNP) rs1044250 and the onset of Mets, and to explore the interaction between SNP rs1044250 and weight management on Mets. Methods We have recruited 1018 Mets cases and 1029 controls in this study. The SNP rs1044250 was genotyped with blood samples, base-line information and Mets-related indicators were collected. A 5-year follow-up survey was carried out to track the lifestyle interventions and changes in Mets-related indicators. Results ANGPTL4 gene SNP rs1044250 is an independent risk factor for increased waist circumference (OR 1.618, 95% CI [1.119–2.340]; p = 0.011), elevated blood pressure (OR 1.323, 95% CI [1.002–1.747]; p = 0.048), and Mets (OR 1.875, 95% CI [1.363–2.580]; p < 0.001). The follow-up survey shows that rs1044250 CC genotype patients with weight gain have an increased number of Mets components (M [Q1, Q3]: CC 1 (0, 1), CT + TT 0 [− 1, 1]; p = 0.021); The interaction between SNP rs1044250 and weight management is a risk factor for increased systolic blood pressure (β = 0.075, p < 0.001) and increased diastolic blood pressure (β = 0.097, p < 0.001), the synergistic effect of weight management and SNP rs1044250 is negative (S < 1). Conclusion ANGPTL4 gene SNP rs1044250 is an independent risk factor for increased waist circumference and elevated blood pressure, therefore, for Mets. However, patients with wild type SNP 1044250 are more likely to have Mets when the body weight is increased, mainly due to elevated blood pressure.
Aims: Deep vein thrombosis (DVT) is a prevalent cardiovascular condition. Endothelial-derived extracellular vesicles (EVs) may play a crucial role in platelet-dependent DVT development via platelet activation, but the mechanism is not clear yet. This research aims to understand how platelets and endothelial-derived EVs work in DVT. Methods: The interaction between protein disulfide isomerase (PDI) and glucose-regulated protein 94 (GRP94) was founded by molecular docking. Inferior vena cava stasis–induced mice received PDI and GRP94 inhibitor treatments. Platelet activation, endothelial-derived EVs, and PDI were measured using flow cytometry. The expression of PDI and dimetric GRP94 in platelets co-cultured with hypoxic endothelial cells was confirmed by Western blot or native PAGE. The fluorescence resonance energy transfer assay shows conformational changes in GPIIb/IIIa on platelet surfaces. A tracking experiment was performed using PKH26, which labelled endothelial-derived EVs, and the endocytosis of EVs by platelets was tracked by confocal microscope. Results: In a DVT mouse model, platelets enhance venous thrombus formation in a coagulation-independent manner, instead, platelet activation and the length of the thrombus are related to PDI and GRP94 activity. Next, we found that the expression level of endothelial-derived EVs carrying PDI is significantly increased in plasma. Endothelial-derived EVs carrying PDI are endocytosed by platelets, in which the content of GRP94 dimer is elevated, and consequently increases the expression of surface GPIIb/IIIa. In addition, PDI allosterically interacts with GPIIb/IIIa, which is re-configurated into an activated form. Conclusion: Endothelial-derived EVs carrying PDI induce DVT via interplay with GRP94 and GPIIb/IIIa in platelets. These findings emphasize the significance of platelets in DVT formation, and PDI may be a suitable target in DVT prevention.
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