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Endoplasmic Reticulum Stress and Mitochondrial Function in Airway Smooth Muscle.

ABSTRACT: Inflammatory airway diseases such as asthma affect more than 300 million people world-wide. Inflammation triggers pathophysiology via such as tumor necrosis factor ? (TNF?) and interleukins (e.g., IL-13). Hypercontraction of airway smooth muscle (ASM) and ASM cell proliferation are major contributors to the exaggerated airway narrowing that occurs during agonist stimulation. An emergent theme in this context is the role of inflammation-induced endoplasmic reticulum (ER) stress and altered mitochondrial function including an increase in the formation of reactive oxygen species (ROS). This may establish a vicious cycle as excess ROS generation leads to further ER stress. Yet, it is unclear whether inflammation-induced ROS is the major mechanism leading to ER stress or the consequence of ER stress. In various diseases, inflammation leads to an increase in mitochondrial fission (fragmentation), associated with reduced levels of mitochondrial fusion proteins, such as mitofusin 2 (Mfn2). Mitochondrial fragmentation may be a homeostatic response since it is generally coupled with mitochondrial biogenesis and mitochondrial volume density thereby reducing demand on individual mitochondrion. ER stress is triggered by the accumulation of unfolded proteins, which induces a homeostatic response to alter protein balance via effects on protein synthesis and degradation. In addition, the ER stress response promotes protein folding via increased expression of molecular chaperone proteins. Reduced Mfn2 and altered mitochondrial dynamics may not only be downstream to ER stress but also upstream such that a reduction in Mfn2 triggers further ER stress. In this review, we summarize the current understanding of the link between inflammation-induced ER stress and mitochondrial function and the role played in the pathophysiology of inflammatory airway diseases.

SUBMITTER: Delmotte P

PROVIDER: S-EPMC6974519 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Endoplasmic Reticulum Stress and Mitochondrial Function in Airway Smooth Muscle.

Delmotte Philippe P Sieck Gary C GC

Frontiers in cell and developmental biology 20200115

Inflammatory airway diseases such as asthma affect more than 300 million people world-wide. Inflammation triggers pathophysiology via such as tumor necrosis factor α (TNFα) and interleukins (e.g., IL-13). Hypercontraction of airway smooth muscle (ASM) and ASM cell proliferation are major contributors to the exaggerated airway narrowing that occurs during agonist stimulation. An emergent theme in this context is the role of inflammation-induced endoplasmic reticulum (ER) stress and altered mitoch ...[more]

PMID: 32010691

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Project description:Accumulation of damaged or misfolded proteins resulted from oxidative protein modification induces endoplasmic reticulum (ER) stress by activating the pathways of unfolded protein response. In pathologic hemolytic conditions, extracellular free hemoglobin is submitted to rapid oxidation causing heme release. Resident cells of atherosclerotic lesions, after intraplaque hemorrhage, are exposed to heme leading to oxidative injury. Therefore, we raised the question whether heme can also provoke ER stress. Smooth muscle cells are one of the key players of atherogenesis; thus, human aortic smooth muscle cells (HAoSMCs) were selected as a model cell to reveal the possible link between heme and ER stress. Using immunoblotting, quantitative polymerase chain reaction and immunocytochemistry, we quantitated the markers of ER stress. These were: phosphorylated eIF2α, Activating transcription factor-4 (ATF4), DNA-damage-inducible transcript 3 (also known as C/EBP homology protein, termed CHOP), X-box binding protein-1 (XBP1), Activating transcription factor-6 (ATF6), GRP78 (glucose-regulated protein, 78kDa) and heme responsive genes heme oxygenase-1 and ferritin. In addition, immunohistochemistry was performed on human carotid artery specimens from patients who had undergone carotid endarterectomy. We demonstrate that heme increases the phosphorylation of eiF2α in HAoSMCs and the expression of ATF4. Heme also enhances the splicing of XBP1 and the proteolytic cleavage of ATF6. Consequently, there is up-regulation of target genes increasing both mRNA and protein levels of CHOP and GRP78. However, TGFβ and collagen type I decreased. When the heme binding proteins, alpha-1-microglobulin (A1M) and hemopexin (Hpx) are present in cell media, the ER stress provoked by heme is inhibited. ER stress pathways are also retarded by the antioxidant N-acetyl cysteine (NAC) indicating that reactive oxygen species are involved in heme-induced ER stress. Consistent with these findings, elevated expression of the ER stress marker GRP78 and CHOP were observed in smooth muscle cells of complicated lesions with hemorrhage compared to either atheromas or healthy arteries. In conclusion, heme triggers ER stress in a time- and dose-dependent manner in HAoSMCs. A1M and Hpx as well as NAC effectively hamper heme-induced ER stress, supporting their use as a potential therapeutic approach to reverse such a deleterious effects of heme toxicity.

Dataset Information

Endoplasmic Reticulum Stress and Mitochondrial Function in Airway Smooth Muscle.

Publications

Endoplasmic Reticulum Stress and Mitochondrial Function in Airway Smooth Muscle.

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