Abstract:Diabetic cardiovascular diseases are characterized by progressive hyperglycemia, which results in excessive production of oxidative stress and pro-inflammatory cytokines. Cystic fibrosis (CF) is characterized by chronic inflammation due to mutations in CF transmembrane conductance regulator (CFTR). However, little information is available about the role of CFTR in hyperglycemia‑induced endothelial cell oxidative stress and inflammation. In the present study, a high glucose‑treatment was applied in human umbili… Show more
“…In type 2 diabetic mice, stimulation of PAR-2 can upregulate TNF-α expression [35]. MAPK and NF-kappa B signalling pathway are associated with the inflammation progress in endothelial cells [36]. Therefore, we examined the expression of TLR4 and TNF-α and MAPK and NF-kappa B signalling pathway-associated protein when PAR-2 on mouse brain microvascular endothelial cell was stimulated by tryptase.…”
BackgroundMast cells (MCs), the ‘first responders’ in brain injury, are able to disrupt the blood–brain barrier (BBB), but the underlying mechanism is not well understood. Tryptase is the most abundant MC secretory product. Protease-activated receptor 2 (PAR-2) has been identified as a specific receptor for tryptase, which is abundantly expressed in brain microvascular endothelial cells. The BBB comprises brain microvascular endothelial cells that display specialised molecular properties essential for BBB function and integrity. Therefore, the purpose of the present study was to investigate the effects of tryptase on mouse brain microvascular endothelial cell line bEnd3 and its potential mechanisms of action.MethodsInduction of mouse brain microvascular endothelial cell activation by tryptase was examined. Then, mouse brain microvascular endothelial cells were pretreated with a PAR-2 antagonist and stimulated with tryptase. Cellular activation, proinflammatory cytokine production, expression of PAR-2, Toll-like receptors (TLRs) and mitogen-activated protein kinases (MAPK), nuclear factor kappa B (NF-kappa B) phosphorylation were assessed.ResultsTryptase upregulated the production of VCAM-1, MMPs (MMP9 and MMP2), TLR4 and TNF-α and downregulated the expression of the tight junction proteins occludin and claudin-5 in mouse brain microvascular endothelial cell. Among the MAPK and NF-kappa B pathway, ERK and NF-kappa B were activated by tryptase. All of these effects could be eliminated by the PAR-2 inhibitor.ConclusionBased on our findings, we conclude that tryptase can trigger brain microvascular endothelial cell activation and proinflammatory mediator release. These findings may further clarify the involvement and mechanism of tryptase in BBB disruption.
“…In type 2 diabetic mice, stimulation of PAR-2 can upregulate TNF-α expression [35]. MAPK and NF-kappa B signalling pathway are associated with the inflammation progress in endothelial cells [36]. Therefore, we examined the expression of TLR4 and TNF-α and MAPK and NF-kappa B signalling pathway-associated protein when PAR-2 on mouse brain microvascular endothelial cell was stimulated by tryptase.…”
BackgroundMast cells (MCs), the ‘first responders’ in brain injury, are able to disrupt the blood–brain barrier (BBB), but the underlying mechanism is not well understood. Tryptase is the most abundant MC secretory product. Protease-activated receptor 2 (PAR-2) has been identified as a specific receptor for tryptase, which is abundantly expressed in brain microvascular endothelial cells. The BBB comprises brain microvascular endothelial cells that display specialised molecular properties essential for BBB function and integrity. Therefore, the purpose of the present study was to investigate the effects of tryptase on mouse brain microvascular endothelial cell line bEnd3 and its potential mechanisms of action.MethodsInduction of mouse brain microvascular endothelial cell activation by tryptase was examined. Then, mouse brain microvascular endothelial cells were pretreated with a PAR-2 antagonist and stimulated with tryptase. Cellular activation, proinflammatory cytokine production, expression of PAR-2, Toll-like receptors (TLRs) and mitogen-activated protein kinases (MAPK), nuclear factor kappa B (NF-kappa B) phosphorylation were assessed.ResultsTryptase upregulated the production of VCAM-1, MMPs (MMP9 and MMP2), TLR4 and TNF-α and downregulated the expression of the tight junction proteins occludin and claudin-5 in mouse brain microvascular endothelial cell. Among the MAPK and NF-kappa B pathway, ERK and NF-kappa B were activated by tryptase. All of these effects could be eliminated by the PAR-2 inhibitor.ConclusionBased on our findings, we conclude that tryptase can trigger brain microvascular endothelial cell activation and proinflammatory mediator release. These findings may further clarify the involvement and mechanism of tryptase in BBB disruption.
“…Here, we further investigate if other ion channels participate in PA-induced endothelial dysfunction. CFTR is an ATP-gated Cl − channel, and downregulation of CFTR causes apoptosis via ROS and inflammation in renal cells, vascular smooth muscle cells, and other cell types [ 23 , 38 – 40 ]. In this study, we found that CFTR expression decreased in PA-insulted endothelial cells; Forskolin significantly inhibited PA-induced endothelial dysfunction showing as increasing cell viability, inhibiting cell apoptosis, reducing ROS generation, and restoring NO generation.…”
Section: Discussionmentioning
confidence: 99%
“…A large number of studies showed that CF patients had endothelial perturbation and microvascular dysfunction [ 15 – 20 ], suggesting that CFTR deficiency contributes to endothelial dysfunction. Besides, CFTR was showed to protect against endothelial apoptosis from oxidative stress and inflammation [ 21 – 23 ]. Recently, several researches demonstrated that CFTR regulated autophagy in the intestinal cancer cells, lipopolysaccharide-induced acute lung injury, and the immune response in CF [ 24 – 26 ].…”
Saturated free fatty acids (FFAs) elevate in metabolic symptom leading to endothelial dysfunction. Cystic fibrosis transmembrane regulator (CFTR) functionally expresses in endothelial cells. The role of CFTR in FFA-induced endothelial dysfunction remains unclear. This study is aimed at exploring the effects of CFTR on palmitate- (PA-) induced endothelial dysfunction and its underlying mechanisms. We found that PA-induced endothelial dysfunction is characterized by a decrease of cell viability, reduction of NO generation and mitochondrial membrane potential, impairment of the tube formation, but an increase of ROS generation and cell apoptosis. Simultaneously, PA decreased CFTR protein expression. CFTR agonist Forskolin upregulated CFTR protein expression and protected against PA-induced endothelial dysfunction, while CFTR knockdown exacerbated endothelial dysfunction induced by PA and blunted the protective effects of Forskolin. In addition, PA impaired autophagic flux, and autophagic flux inhibitors aggravated PA-induced endothelial apoptosis. CFTR upregulation significantly restored autophagic flux in PA-insulted endothelial cells, which was involved in increasing the protein expression of Atg16L, Atg12-Atg5 complex, cathepsin B, and cathepsin D. In contrast, CFTR knockdown significantly inhibited the effects of Forskolin on autophagic flux and the expression of the autophagy-regulated proteins. Our findings illustrate that CFTR upregulation protects against PA-induced endothelial dysfunction by improving autophagic flux and underlying mechanisms are involved in enhancing autophagic signaling mediated by the Atg16L-Atg12-Atg5 complex, cathepsin B, and cathepsin D. CFTR might serve as a novel drug target for endothelial protection in cardiovascular diseases with a characteristic of elevation of FFAs.
“…RelA/p65, c-Rel and RelB, plays a critical role in inflammatory process and metabolic disease [18]. It has been reported that high blood glucose, urinary albumin, angiotensin II could contribute to NF-kappaB activation [19,20]. Evidence have shown that NF-kappaB activation in endothelial cells exerted a vital role in DN.…”
ETBR deficiency may contribute to the progression of DN in a STZ model, but the underlying mechanism is not fully revealed. In this study, STZ-diabetic ETBR -/mice was characterized by increased serum creatinine, urinary albumin and ET-1 expression, and enhanced glomerulosclerosis compared with STZ-diabetic WT mice. HG conditioned media of ETBR -/endothelial cells promoted MC proliferation and upregulated ECM-related proteins, and ET-1 knockout in endothelial cells or inhibition of ET-1/ETAR in MC suppressed MC proliferation. ET-1 was over-expressed in ETBR -/endothelial cells and was regulated by NF-kapapB pathway. And ET-1/ETBR suppressed NF-kappaB via eNOS to modulate ET-1 in endothelial cells. Furthermore, ET-1/ETAR promoted RhoA/ROCK pathway in MC, and accelerated MC proliferation and ECM accumulation. In vivo experiments proved ETBR -/mice inhibited NF-kappaB pathway to ameliorate DN and eNOS -/mice had similar results. Hence, in HG-exposed ETBR -/endothelial cells, suppression of ET-1/ETBR activated NF-kappaB pathway via inhibiting eNOS to secrete large amount of ET-1. Due to the communication between endothelial cells and MCs, ET-1/ETAR in MC promoted RhoA/ROCK pathway to accelerate MC proliferation and ECM accumulation.Research 2005, 97(2):125-134.30. Lee T, Chung T, Lin S, Chang N: Endothelin receptor blockade ameliorates renal injury by inhibition of RhoA/Rho-kinase signalling in deoxycorticosterone acetate-salt hypertensive rats. J Hypertens 2014, 32(4):795-805.
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