Ursodeoxycholic Acid (UDCA) Exerts Anti-Atherogenic Effects by Inhibiting Endoplasmic Reticulum (ER) Stress Induced by Disturbed Flow

Chung, Jaewoo; Kim, Kyoung Hwa; Lee, Seok Cheol; An, Sook Hee; Kwon, Kihwan

doi:10.14348/molcells.2015.0094

Cited by 26 publications

(16 citation statements)

References 32 publications

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“…ER stress and the UPR in ECs can be mediated through the mechanosensitive pathway. Disturbed flow and low magnitude shear stress act through ER stress to promote vascular cell adhesion molecule 1 expression and monocyte adhesion to the endothelium, early events in atherosclerosis [46, 47]. In this study, we found that clinorotation for 48 h significantly upregulated ER stress markers PERK and ATF6, as well as GRP78 in HUVECs, consistent with a previous study in preosteoblast cells under clinorotation [13].…”

Section: Discussionsupporting

confidence: 91%

Autophagy protects HUVECs against ER stress-mediated apoptosis under simulated microgravity

Pan

Gao

et al. 2019

Apoptosis

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Astronauts exposed to a gravity-free environment experience cardiovascular deconditioning that causes post-spaceflight orthostatic intolerance and other pathological conditions. Endothelial dysfunction is an important factor responsible for this alteration. Our previous study showed enhanced autophagy in endothelial cells under simulated microgravity. The present study explored the cytoprotective role of autophagy under microgravity in human umbilical vein endothelial cells (HUVECs). We found that clinorotation for 48 h induced apoptosis and endoplasmic reticulum (ER) stress in HUVECs. ER stress and the unfolded protein response (UPR) partially contributed to apoptosis under clinorotation. Autophagy partially reduced ER stress and restored UPR signaling by autophagic clearance of ubiquitin-protein aggregates, thereby reducing apoptosis. In addition, the ER stress antagonist 4-phenylbutyric acid upregulated autophagy in HUVECs. Taken together, these findings indicate that autophagy plays a protective role against apoptosis under clinorotation by clearing protein aggregates and partially restoring the UPR.

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Section: Discussionsupporting

confidence: 91%

Autophagy protects HUVECs against ER stress-mediated apoptosis under simulated microgravity

Pan

Gao

et al. 2019

Apoptosis

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“…Evidence from nonatherosclerotic swine suggested that the ER stress markers IRE1, XBP1, and ATF6 are activated in ECs in atherosclerotic-susceptible areas of the aorta [ 27 ]. Recently, studies have found that disturbed blood flow with low shear stress (SS), a major atherogenic factor leading to EC dysfunction, can directly induce ER stress in ECs, thus exerting critical effects on the progression of atherosclerosis [ 28 ]. For in vitro cultured ECs, atherogenic SS preferentially upregulated the expression of the UPR regulator GRP78 through a p38- and integrin alpha2beta1-dependent mechanism before atheroprone lesion development, which reflects a potential atheroprotective and compensatory response to ER stress [ 29 ].…”

Section: Proatherogenic Effects Of Er Stress In Different Cell Typmentioning

confidence: 99%

“…It is worth noting that these effects can all be ameliorated by ursodeoxycholic acid (UDCA). In a disturbed flow-induced atherosclerosis mouse model, UDCA effectively reduced ER stress, evidenced by decreased expression of XBP1 and CHOP in ECs, and it inhibited the inflammatory response and apoptosis of ECs caused by disturbed flow, thus suppressing the formation of atherosclerotic plaques [ 28 ].…”

Section: Proatherogenic Effects Of Er Stress In Different Cell Typmentioning

confidence: 99%

“…Ursodeoxycholic acid (UDCA), a hydrophilic endogenous bile acid, is the precursor form of TUDCA before conjugation with taurine. In a mouse model of disturbed flow-induced atherosclerosis, UDCA was found to inhibit the formation of atherosclerotic plaques by inhibiting ER stress and attenuating inflammatory responses, as evidenced by decreased expression of XBP1 and CHOP and reduced adhesion molecule levels in ECs [ 28 ].…”

Section: Therapeutic Potential Of Regulating Er Stress Modulators mentioning

confidence: 99%

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Role of Endoplasmic Reticulum Stress in Atherosclerosis and Its Potential as a Therapeutic Target

Yang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Endoplasmic reticulum (ER) stress is closely associated with atherosclerosis and related cardiovascular diseases (CVDs). It occurs due to various pathological factors that interfere with ER homeostasis, resulting in the accumulation of unfolded or misfolded proteins in the ER lumen, thereby causing ER dysfunction. Here, we discuss the role of ER stress in different types of cells in atherosclerotic lesions. This discussion includes the activation of apoptotic and inflammatory pathways induced by prolonged ER stress, especially in advanced lesional macrophages and endothelial cells (ECs), as well as common atherosclerosis-related ER stressors in different lesional cells, which all contribute to the clinical progression of atherosclerosis. In view of the important role of ER stress and the unfolded protein response (UPR) signaling pathways in atherosclerosis and CVDs, targeting these processes to reduce ER stress may be a novel therapeutic strategy.

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“…Shear stress is specified in dyne per cm 2 , in which 1 dyne per cm 2 is 0.1 Pa or 0.1 N per m 2 . We used a unidirectional steady flow (shear stress of 20 dyne/cm 2 ) for LSS and a bidirectional disturbed flow (shear stress of ±5 dyne/cm 2 ) for oscillatory shear stress (OSS), as described previously 17,18 . In the crossover experiment between LSS and OSS, HUVECs were exposed to LSS or OSS for 24 h, followed by exposure to the other type of shear stress for 24 h.…”

Section: Methodsmentioning

confidence: 99%

Coxsackievirus and adenovirus receptor mediates the responses of endothelial cells to fluid shear stress

Chung

Kim

et al. 2019

Exp Mol Med

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Endothelial mechanotransduction by fluid shear stress (FSS) modulates endothelial function and vascular pathophysiology through mechanosensors on the cell membrane. The coxsackievirus and adenovirus receptor (CAR) is not only a viral receptor but also a component of tight junctions and plays an important role in tissue homeostasis. Here, we demonstrate the expression, regulatory mechanism, and role of CAR in vascular endothelial cells (ECs) under FSS conditions. Disturbed flow increased, whereas unidirectional laminar shear stress (LSS) decreased, CAR expression in ECs through the Krüppel-like factor 2 (KLF2)/activator protein 1 (AP-1) axis. Deletion of CAR reduced the expression of proinflammatory genes and endothelial inflammation induced by disturbed flow via the suppression of NF-κB activation. Consistently, disturbed flow-induced atherosclerosis was reduced in EC-specific CAR KO mice. CAR was found to be involved in endothelial mechanotransduction through the regulation of platelet endothelial cell adhesion molecule 1 (PECAM-1) phosphorylation. Our results demonstrate that endothelial CAR is regulated by FSS and that this regulated CAR acts as an important modulator of endothelial mechanotransduction by FSS.

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Ursodeoxycholic Acid (UDCA) Exerts Anti-Atherogenic Effects by Inhibiting Endoplasmic Reticulum (ER) Stress Induced by Disturbed Flow

Cited by 26 publications

References 32 publications

Autophagy protects HUVECs against ER stress-mediated apoptosis under simulated microgravity

Autophagy protects HUVECs against ER stress-mediated apoptosis under simulated microgravity

Role of Endoplasmic Reticulum Stress in Atherosclerosis and Its Potential as a Therapeutic Target

Coxsackievirus and adenovirus receptor mediates the responses of endothelial cells to fluid shear stress

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