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Home-based exercise is an alternative exercise mode to a structured supervised program to improve symptoms in patients with peripheral artery disease (PAD), but little is known about whether the slow-paced and less intense home program also elicits changes in vascular and inflammatory biomarkers. In an exploratory analysis from a randomized controlled trial, we compared changes in vascular and inflammatory biomarkers in patients with symptomatic PAD (typical and atypical of claudication) after home-based exercise and supervised exercise programs and in an attention-control group. A total of 114 patients were randomized into one of the three groups (n = 38 per group). Two groups performed exercise interventions, consisting of home-based and supervised programs of intermittent walking to mild to moderate claudication pain for 12 weeks; a third group performed light resistance training as a nonwalking attention-control group. Before and after intervention, patients were characterized on treadmill performance and endothelial effects of circulating factors present in sera by a cell culture-based bioassay on primary human arterial endothelial cells, and they were further evaluated on circulating vascular and inflammatory biomarkers. Treadmill peak walking time increased (P =.008) in the two exercise groups but not in the control group (P >.05). Cultured endothelial cell apoptosis decreased after home-based exercise (P <.001) and supervised exercise (P =.007), and the change in the exercise groups combined was different from that in the control group (P =.005). For circulating biomarkers, increases were found in hydroxyl radical antioxidant capacity (P =.003) and vascular endothelial growth factor A (P =.037), and decreases were observed in E-selectin (P =.007) and blood glucose concentration (P =.012) after home-based exercise only. The changes in hydroxyl radical antioxidant capacity (P =.005), vascular endothelial growth factor A (P =.008), and E-selectin (P =.034) in the exercise groups combined were different from those in the control group. This exploratory analysis found that both home-based and supervised exercise programs are efficacious to decrease cultured endothelial cell apoptosis in patients with symptomatic PAD. Furthermore, a monitored home-based exercise program elicits additional vascular benefits by improving circulating markers of endogenous antioxidant capacity, angiogenesis, endothelium-derived inflammation, and blood glucose concentration in patients with symptomatic PAD. The novel clinical significance is that important trends were found in this exploratory analysis that a contemporary home-based exercise program and a traditional supervised exercise program may favorably improve vascular and inflammatory biomarkers in addition to the well-described ambulatory improvements in symptomatic patients with PAD. [ABSTRACT FROM AUTHOR]

Cyclophilin A (CyPA), which is encoded by PPIA , is a ubiquitously expressed intracellular protein and is secreted in response to inflammatory stimuli. CyPA stimulates proinflammatory signaling pathways in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), promotes VSMC migration and proliferation, EC adhesion molecules expression, and inflammatory cell chemotaxis and apoptosis. Moreover, CyPA activates mitogen-activated protein kinases, including ERK1/2, JNK, and p38, and stimulates IkB-α phosphorylation, NF-kB activation, and vascular cell adhesion molecule-1 and E-selectin expression in human umbilical vein ECs. Therefore, we hypothesized that CyPA regulated transcription factor FoxO1 phosphorylation and transcriptional activity and the expression of downstream genes involved in vascular EC activation, thus activated vascular ECs in vitro. We found that intracellular CyPA promoted FoxO1 dephosphorylation at Ser256, nuclear accumulation, and transcriptional activity by interacting with it. Moreover, CyPA induced FoxO1-dependent expression of downstream genes involved in EC chemotaxis and apoptosis, including monocyte chemoattractant protein-1 and BCL-2-interacting mediator of cell death, and stimulated the apoptosis of human umbilical vein ECs in vitro. • CyPA promoted FoxO1 dephosphorylation at Ser256 by interacting with it in human umbilical vein ECs. • CyPA increased FoxO1 nuclear accumulation and transcriptional activity in human umbilical vein ECs. • CyPA induced FoxO1-dependent expression of genes associated with EC chemotaxis and apoptosis, including MCP-1 and Bim. • CyPA–FoxO1 signaling pathway stimulated the apoptosis of human umbilical vein ECs in vitro. [ABSTRACT FROM AUTHOR]

Abstract Aims Obesity is associated with increased cardiovascular morbidity and mortality. It is accompanied by augmented O-linked β- N -acetylglucosamine (O-GlcNAc) modification of proteins via increasing hexosamine biosynthetic pathway (HBP) flux. However, the changes and regulation of the O-GlcNAc levels induced by obesity are unclear. Main methods High fat diet (HFD) model was induced obesity in mice with or without the cholinergic drug pyridostigmine (PYR, 3 mg/kg/d) for 22 weeks and in vitro human umbilical vein endothelial cells (HUVECs) was treated with high glucose (HG, 30 mM) with or without acetylcholine (ACh). Key findings PYR significantly reduced body weight, blood glucose, and O-GlcNAcylation levels and attenuated vascular endothelial cells detachment in HFD-fed mice. HG addition induced endoplasmic reticulum (ER) stress and increased O-GlcNAcylation levels and apoptosis in HUVECs in a time-dependent manner. Additionally, HG decreased levels of phosphorylated AMP-activated protein kinase (AMPK). Interestingly, ACh significantly blocked damage to HUVECs induced by HG. Furthermore, the effects of ACh on HG-induced ER stress, O-GlcNAcylation, and apoptosis were prevented by treating HUVECs with 4-diphenylacetoxy- N -methylpiperidine methiodide (4-DAMP, a selective M3 AChR antagonist) or compound C (Comp C, an AMPK inhibitor). Treatment with 5-aminoimidazole-4-carboxamide ribose (AICAR, an AMPK activator), 4-phenyl butyric acid (4-PBA, an ER stress inhibitor), and 6-diazo-5-oxonorleucine (DON, a GFAT antagonist) reproduced a similar effect with ACh. Significance Activation of cholinergic signaling ameliorated endothelium damage, reduced levels of ER stress, O-GlcNAcylation, and apoptosis in mice and HUVECs under obese conditions, which may function through M3 AChR-AMPK signaling. [ABSTRACT FROM AUTHOR]

Background and aims Previous experiments suggest that both increased endothelial cell apoptosis and endothelial surface glycocalyx shedding could play a role in the endothelial dysfunction and inflammation of athero-prone regions of the vasculature. We sought to elucidate the possibly synergistic mechanisms by which endothelial cell apoptosis and glycocalyx shedding promote atherogenesis. Methods 4- to 6-week old male C57Bl/6 apolipoprotein E knockout ( ApoE −/− ) mice were fed a Western diet for 10 weeks and developed plaques in their brachiocephalic arteries. Results Glycocalyx coverage and thickness were significantly reduced over the plaque region compared to the non-plaque region (coverage plaque: 71 ± 23%, non-plaque: 97 ± 3%, p = 0.02; thickness plaque: 0.85 ± 0.15 μm, non-plaque: 1.2 ± 0.21 μm, p = 0.006). Values in the non-plaque region were not different from those found in wild type mice fed a normal diet (coverage WT: 92 ± 3%, p = 0.7 vs . non-plaque ApoE −/− , thickness WT: 1.1 ± 0.06 μm, p = 0.2 vs. non-plaque ApoE −/− ). Endothelial cell apoptosis was significantly increased in ApoE −/− mice compared to wild type mice ( ApoE −/− :64.3 ± 33.0, WT: 1.1 ± 0.5 TUNEL-pos/cm, p = 2 × 10 −7 ). The number of apoptotic endothelial cells per unit length was 2 times higher in the plaque region than in the non-plaque region of the same vessel ( p = 3 × 10 −5 ). Increased expression of matrix metalloproteinase 9 co-localized with glycocalyx shedding and plaque buildup. Conclusions Our results suggest that, in concert with endothelial apoptosis that increases lipid permeability, glycocalyx shedding initiated by inflammation facilitates monocyte adhesion and macrophage infiltration that promote lipid retention and the development of atherosclerotic plaques. [ABSTRACT FROM AUTHOR]

Unresolved endoplasmic reticulum (ER) stress, with the subsequent persistent activation of the unfolded protein response (UPR) is a well-recognized mechanism of endothelial cell apoptosis with a major impact on the integrity of the endothelium during the course of cardiovascular diseases. As in other cell types, Ca 2 + influx into endothelial cells can promote ER stress and/or contribute to mechanisms associated with it. In previous work we showed that in human coronary artery endothelial cells (HCAECs) the Ca 2 + -permeable non-selective cation channel Transient Receptor Potential Canonical 3 (TRPC3) mediates constitutive Ca 2 + influx which is critical for operation of inflammatory signaling in these cells, through a mechanism that entails coupling of TRPC3 constitutive function to activation of Ca 2 + /calmodulin-dependent protein kinase II (CAMKII). TRPC3 has been linked to UPR signaling and apoptosis in cells other than endothelial, and CAMKII is a mediator of ER stress-induced apoptosis in various cell types, including endothelial cells. In the present work we used a pharmacological approach to examine whether in HCAECs TRPC3 and CAMKII also contribute to mechanisms of ER stress-induced apoptosis. The findings show for the first time that in HCAECs activation of the UPR and the subsequent ER stress-induced apoptosis exhibit a strong requirement for constitutive Ca 2 + influx and that TRPC3 contributes to this process. In addition, we obtained evidence indicating that, similar to its roles in non-endothelial cells, CAMKII participates in ER stress-induced apoptosis in HCAECs. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) are the novel class of transcripts involved in transcriptional, post-transcriptional, translational, and post-translational regulation of physiology and the pathology of diseases. Studies have evidenced that the impairment of endothelium is a critical event in the pathogenesis of atherosclerosis and its complications. Endothelial dysfunction is characterized by an imbalance in vasodilation and vasoconstriction, oxidative stress, proinflammatory factors, and nitric oxide bioavailability. Disruption of the endothelial barrier permeability, the first step in developing atherosclerotic lesions is a consequence of endothelial dysfunction. Though several factors interfere with the normal functioning of the endothelium, intrinsic epigenetic mechanisms governing endothelial function are regulated by lncRNAs and perturbations contribute to the pathogenesis of the disease. This review comprehensively addresses the biogenesis of lncRNA and molecular mechanisms underlying and regulation in endothelial function. An insight correlating lncRNAs and endothelial dysfunction-associated diseases can positively impact the development of novel biomarkers and therapeutic targets in endothelial dysfunction-associated diseases and treatment strategies. [Display omitted] • lncRNAs are emerging players in regulating endothelial homeostasis. • Few lncRNAs are functionally correlated with ED and its associated diseases. • Targeting these lncRNAs might help in developing new therapeutic strategies. • Understanding of lncRNAs facilitate the discovery of novel biomarkers for ED. [ABSTRACT FROM AUTHOR]

Cyclophilin A (CyPA), which is encoded by PPIA , is a ubiquitously expressed intracellular protein and is secreted in response to inflammatory stimuli. CyPA stimulates proinflammatory and apoptosis signaling pathways in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), promotes VSMC migration and proliferation, EC adhesion molecules expression, and inflammatory cell chemotaxis and apoptosis. Therefore, we sought to study the transcriptional regulation of CyPA, we hypothesized that transcription factor STAT3 regulated CyPA expression and activated vascular ECs in vitro in a CyPA-dependent manner. Using RT-qPCR, immunostaining, luciferase and ChIP assays, we found that STAT3 induced CyPA expression depended on its transcriptional activation by binding to a specific region containing the STAT3-responsive element (SRE) in the CyPA promoter. Moreover, with cell viability and apoptosis assays, we identified STAT3 stimulated CyPA-dependent apoptosis of human umbilical vein ECs in vitro. • STAT3 promoted CyPA expression in human umbilical vein ECs depended on its transcriptional activation. • STAT3 stimulated the transcriptional activity of the CyPA promoter in human umbilical vein ECs. • STAT3 bind to the specific region of CyPA promoter containing STAT3-response element in human umbilical vein ECs. • STAT3-CypA signaling pathway stimulated the apoptosis of human umbilical vein ECs in vitro. [ABSTRACT FROM AUTHOR]

Background: Targeting vascular endothelial growth factor is a common treatment strategy for neovascular eye disease, a leading cause of visual impairment and blindness. However, these approaches are limited or carry various complications. Therefore, there is an urgent need for the development of unique therapeutic approaches.Purpose: To investigate the anti-angiogenic effects of curcumolide and its mechanism of action.Methods /study Designs: In this study, we examine the effects of curcumolide on the process of vasculature formation, including cell proliferation, migration, tube formation and apoptosis in vitro using human umbilical vascular endothelial cells (HUVECs). We also assess the anti-angiogenic effects of curcumolide in vivo using a mouse model of oxygen induced retinopathy (OIR). The mechanism of anti-angiogenic effects was investigated by measuring the expression level of various signaling proteins and the molecular docking simulations.Results: Intravitreal injection of curcumolide reduced the formation of retinal neovascular tufts and VEGFR2 phosphorylation in the murine OIR model at concentrations administered without definite cellular and retinal toxicities. Curcumolide suppressed VEGF-induced HRMECs proliferation, migration and tube formation in a dose-dependent manner. Meanwhile, it promoted caspase-dependent apoptosis. Curcumolide also inhibited VEGF-induced phosphorylation of VEGFR-2 tyrosine kinase, and suppressed downstream protein kinases of VEGFR2, including Src, FAK, ERK, AKT, and mTOR in HRMECs. In silico study revealed that curcumolide bound with ATP-binding sites of the VEGFR2 kinase unit by the formation of a hydrogen bond and hydrophobic interactions.Conclusion: Curcumolide has anti-angiogenic activity in HUVECs and in a murine OIR model of ischemia-induced retinal neovascularization, and it might be a potential drug candidate for the treatment of proliferative diabetic retinopathy. [ABSTRACT FROM AUTHOR]