Mechanoregulation of p38 activity enhances endoplasmic reticulum stress‐mediated inflammation by arterial endothelium

Abstract

Endothelial up‐regulation of VCAM‐1 at susceptible sites in arteries modulates the recruitment efficiency of inflammatory monocytes that initiates atherosclerotic lesion formation. We reported that hydrodynamic shear stress (SS) mechanoregulates inflammation in human aortic endothelial cells through endoplasmic reticulum (ER) stress via activation of the transcription factor x‐box binding protein 1 (XBP1). Here, a microfluidic flow channel that produces a linear gradient of SS along a continuous monolayer of endothelium was used to delve the mechanisms underlying transcriptional regulation of TNF‐α‐stimulated VCAM‐1 expression. High‐resolution immunofluorescence imaging enabled continuous detection of platelet endothelial cell adhesion molecule 1 (PECAM‐1)‐dependent, outside‐in signaling as a function of SS magnitude. Differential expression of VCAM‐1 and intercellular adhesion molecule 1 (ICAM‐1) was regulated by the spatiotemporal activation of MAPKs, ER stress markers, and transcription factors, which was dependent on the mechanosensing of SS through PECAM‐1 and PI3K. Inhibition of p38 specifically abrogated the rise to peak VCAM‐1 at low SS (2 dyn/cm2), whereas inhibition of ERK1/2 attenuated peak ICAM‐1 at high SS (12 dyn/cm2). A shear stress‐regulated temporal rise in p38 phosphorylation activated the nuclear translocation of XBP1, which together with the transcription factor IFN regulatory factor 1, promoted maximum VCAM‐1 expression. These data reveal a mechanism by which SS sensitizes the endothelium to a cytokine‐induced ER stress response to spatially regulate inflammation promoting atherosclerosis.—Bailey, K. A., Moreno, E., Haj, F. G., Simon, S. I., Passerini, A. G. Mechanoregulation of p38 activity enhances endoplasmic reticulum stress‐mediated inflammation by arterial endothelium. FASEB J. 33, 12888–12899 (2019). http://www.fasebj.org

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

“…Bailey et al found that SS mechanoregulates the inflammatory response of human aortic ECs through activating the transcription factor XBP1 via ER stress, during which a temporal, SS-regulated rise in p38 phosphorylation activates XBP1 nuclear translocation and promotes the highest expression of vascular cell adhesion protein 1 (VCAM-1). In summary, a possible mechanism is that SS sensitizes the ECs to cytokine-induced ER stress, thereby modulating inflammation that promotes atherosclerosis [ 30 , 31 ]. In addition, SS induces human aortic EC apoptosis, the mechanism of which involves ER stress mediated by the interleukin-1 receptor-associated kinase 2 (IRAK2)/CHOP signaling pathway [ 32 ].…”

p38 promoted retinal micro-angiogenesis through up-regulated RUNX1 expression in diabetic retinopathy

“…The mitogen-activated protein kinase (MAPK)/p38 signaling pathway is well known to exert a crucial role in balancing cell survival and cell death [9][10][11]. Inhibition of the MAPK/p38 signaling pathway is known to suppress cell apoptosis and the expression of pro-inflammatory cytokines in related cells [12,13].…”

Dexmedetomidine alleviates LPS‑induced acute lung injury via regulation of the p38/HO‑1 pathway

“…p38 has attracted increased attention in inflammation, and p38 kinase plays a central role in inflammatory responses ( 29 – 31 ). Moreover, inhibition of p38 activation has been demonstrated to suppress LPS-induced inflammation ( 29 , 33 – 35 ).…”

“…The activation of the Nrf2/HO-1 signaling pathway also inhibits the activation of NLRP3 inflammasome, thus reducing IL-1β expression and exerting anti-inflammatory and cytoprotective effects ( 27 , 28 ). p38 kinase, which is a member of the mitogen-activated protein kinase (MAPK) family, plays a central role in inflammatory responses in a variety of disease models, such as Parkinson's disease, cancer and inflammatory disease ( 29 – 31 ), and has been the subject of basic research and drug discovery ( 32 ). Furthermore, inhibition of p38 activation has been revealed to suppress LPS-induced inflammation in different situations, such as in LPS-induced inflammation in IPEC-J2 cells, bronchial epithelial cells, macrophages and rats ( 29 , 33 – 35 ).…”