Upregulation of CFTR Protects against Palmitate-Induced Endothelial Dysfunction by Enhancing Autophagic Flux

Chen, Hongqi; Chen, Wenliang; Yao, Yinlian; Ye, Naobei; Hou, Ning; Luo, Jia

doi:10.1155/2020/8345246

Cited by 7 publications

(5 citation statements)

References 58 publications

(65 reference statements)

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“…Oxidative stress due to overproduction of ROS acts as a key pathological mechanism in all stages of AS. While in normal physiology, ROS are important reactive molecules that regulate various cellular functions and processes, ROS-induced oxidative stress leads to vascular injury, inflammation, and foam cell formation. , Exposure to FFAs is well recognized as a trigger for overproduction of ROS, inflammatory response, and endothelial cell dysfunction . Recent research has suggested the use of various types of NSAIDs to inhibit oxidative stress in patients with AS .…”

Section: Discussionmentioning

confidence: 99%

“…25,26 Exposure to FFAs is well recognized as a trigger for overproduction of ROS, inflammatory response, and endothelial cell dysfunction. 27 Recent research has suggested the use of various types of NSAIDs to inhibit oxidative stress in patients with AS. 28 Here, we report that feprazone might protect against ROS-mediated vascular injury by inhibiting the generation of ROS induced by FFAs.…”

Section: Discussionmentioning

confidence: 99%

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Feprazone Prevents Free Fatty Acid (FFA)-Induced Endothelial Inflammation by Mitigating the Activation of the TLR4/MyD88/NF-κB Pathway

et al. 2021

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Increased levels of free fatty acid (FFA)-induced endothelial dysfunction play an important role in the initiation and development of atherosclerosis. Feprazone is a nonsteroidal anti-inflammatory compound. However, the beneficial effects of feprazone on FFA-induced endothelial dysfunction have not been reported before. In the current study, we found that treatment with feprazone ameliorated FFA-induced cell death of human aortic endothelial cells (HAECs) by restoring cell viability and reducing the release of lactate dehydrogenase (LDH). Importantly, we found that treatment with feprazone ameliorated FFA-induced oxidative stress by reducing the production of mitochondrial reactive oxygen species (ROS). In addition, feprazone prevented FFA-induced expression and secretion of proinflammatory cytokines and chemokines, such as chemokine ligand 5 (CCL5), interleukin-6 (IL-6), and interleukin-8 (IL-8). We also found that feprazone decreased the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). Interestingly, we found that feprazone reduced the expression of cell adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1). Our results also demonstrate that feprazone prevented FFA-induced activation of the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor kappa-B (NF-κB) signaling pathway. These findings suggest that feprazone might serve as a potential agent for the treatment of atherosclerosis by improving the endothelial function.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Feprazone Prevents Free Fatty Acid (FFA)-Induced Endothelial Inflammation by Mitigating the Activation of the TLR4/MyD88/NF-κB Pathway

et al. 2021

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“…Functional endothelial CFTR limits oxidative stress and contributes to the normal anti-inflammatory state of human umbilical vein endothelial cells (HUVEC) [ 72 ]. Studies on HUVEC suggest a role for CFTR in maintenance of endothelial cell homeostasis [ 73 ], while other studies suggest CFTR upregulation protects against palmitate-induced endothelial dysfunction by improving autophagic flux [ 74 ]. Although CFTR impairment downregulates endothelial cell proliferation, migration and autophagy, defective CFTR function leads to endothelial cell activation and a persisting pro-inflammatory endothelium state with increased leukocyte adhesion.…”

Section: The Role Of Cftr In In Nonepithelial Cellsmentioning

confidence: 99%

Cystic fibrosis transmembrane conductance regulator in COPD: a role in respiratory epithelium and beyond

et al. 2022

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The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel for transport of chloride and bicarbonate anions. Functional roles of CFTR have been identified in a broad range of cell types including epithelial, endothelial, immune, and structural cells. While CFTR has been investigated largely in the context of inborn dysfunction in cystic fibrosis (CF), recent evidence shows CFTR is also affected by acquired dysfunction in chronic obstructive pulmonary disease (COPD). In patients with COPD and smokers, CFTR impairment has been demonstrated in the upper and lower airways, sweat glands and intestines, suggesting both pulmonary and systemic defects. Cigarette smoke, a key factor in COPD development, is the major cause of acquired CFTR dysfunction. Inflammation, bacterial by-products, and reactive oxygen species can further impair CFTR expression and function. CFTR dysfunction could directly contribute to disease manifestation and progression of COPD including disturbed airway surface liquid homeostasis, airway mucus obstruction, pathogen colonisation and inflammation. Mucus plugging and neutrophilic inflammation contribute to tissue destruction, development of dysfunction at the level of the small airways and COPD progression. Acquired CFTR dysfunction in extra-pulmonary organs could add to common co-morbidities and the disease burden. This review explores how CFTR dysfunction may be acquired and its potential effects on patients with COPD, particularly those with chronic bronchitis. The development of CFTR potentiators and the probable benefits of CFTR potentiation to improve tissue homeostasis, reduce inflammation, improve host defence, and potentially reduce remodelling in the lungs will be discussed.

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“…NAD + reduces microvascular damage after cardiac I/R through restoring autophagic flux 171 . Forskolin protects against palmitate‐induced endothelial dysfunction by improving autophagic flux 76 . Thence, these observations implicated that targeting incomplete autophagy and reactivating autophagic flux may provide new mechanistic insights for potential therapeutic strategies for CVDs.…”

Section: Implications Of Incomplete Autophagy For Pharmacotherapymentioning

confidence: 99%

Incomplete autophagy: Trouble is a friend

Zhang

Cao

Qiu

et al. 2022

Medicinal Research Reviews

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Incomplete autophagy is an impaired self‐eating process of intracellular macromolecules and organelles in which accumulated autophagosomes do not fuse with lysosomes for degradation, resulting in the blockage of autophagic flux. In this review, we summarized the literature over the past decade describing incomplete autophagy, and found that different from the double‐edged sword effect of general autophagy on promoting cell survival or death, incomplete autophagy plays a crucial role in disrupting cellular homeostasis, and promotes only cell death. What matters is that incomplete autophagy is closely relevant to the pathogenesis and progression of various human diseases, which, meanwhile, intimately linking to the pharmacologic and toxicologic effects of several compounds. Here, we comprehensively reviewed the latest progress of incomplete autophagy on molecular mechanisms and signaling pathways. Moreover, implications of incomplete autophagy for pharmacotherapy are also discussed, which has great relevance for our understanding of the distinctive role of incomplete autophagy in cellular physiology and disease. Consequently, targeting incomplete autophagy may contribute to the development of novel generation therapeutic agents for diverse human diseases.

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Upregulation of CFTR Protects against Palmitate-Induced Endothelial Dysfunction by Enhancing Autophagic Flux

Cited by 7 publications

References 58 publications

Feprazone Prevents Free Fatty Acid (FFA)-Induced Endothelial Inflammation by Mitigating the Activation of the TLR4/MyD88/NF-κB Pathway

Feprazone Prevents Free Fatty Acid (FFA)-Induced Endothelial Inflammation by Mitigating the Activation of the TLR4/MyD88/NF-κB Pathway

Cystic fibrosis transmembrane conductance regulator in COPD: a role in respiratory epithelium and beyond

Incomplete autophagy: Trouble is a friend

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