Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function

Heo, Kyung‐Sun; Le, Nhat Tu; Cushman, Hannah J.; Giancursio, Carolyn; Chang, Eugene; Woo, Chang Hoon; Sullivan, Mark A.; Taunton, Jack; Yeh, Edward T.H.; Fujiwara, Keigi; Abe, Jun

doi:10.1172/jci76453

Cited by 87 publications

(114 citation statements)

References 31 publications

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“…It has been reported that p90RSK overexpression was observed in athero-prone area, where is disturbed flow area and p90RSK expression was colocalized with VCAM-1 expression in endothelium of mouse aorta suggesting that p90RSK plays an inflammatory regulator (5,11,24). To investigate the effect of LPS on endothelial cells-exposed by laminar shear stress, LPSinjected mouse aorta was co-stained with VE-Cad as EC marker and p90RSK in Fig.…”

Section: Discussionmentioning

confidence: 93%

“…2A and B). Previously, we reported that EC transduced with adenovirus containing dominant negative p90RSK (K94A/K447A, Ad-DN-RSK), but in those transduced with Ad-LacZ, abolished atherogenic flowinduced proinflammatory adhesion molecule expression (5). It suggests that p90RSK kinase activation plays a crucial role in regulating EC inflammation.…”

Section: Discussionmentioning

confidence: 94%

“…Endothelial dysfunction is characterized by atherosclerosis with early events including vasoregulation, activation of inflammatory processes, and damaged barrier function due to endothelial cell (EC) death (4,5). Hemodynamic shear stress affects vascular atherosclerotic lesion and was associated with EC inflammation and apoptosis via regulating ERK5 and p53-mediated signaling pathway (5,11).…”

Section: Introductionmentioning

confidence: 99%

“…Hemodynamic shear stress affects vascular atherosclerotic lesion and was associated with EC inflammation and apoptosis via regulating ERK5 and p53-mediated signaling pathway (5,11).…”

Section: Introductionmentioning

confidence: 99%

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LPS-stimulated Macrophage Activation Affects Endothelial Dysfunction

2018

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Intestinal microbiota is involved in the atherosclerotic process by development of an atheromatous core with foam cells in carotid arteries. It has reported that lipopolysaccharide (LPS) from Escherichia coli localizes in human atherosclerotic plaque and causes inflammation via interaction with toll like receptor 4. However, there is no evidence that whether LPS-activated macrophages regulate endothelial cell (EC) function. We evaluated whether LPS-activated macrophage acts as one of the stimulants activating EC and its underlying signaling pathways. Using Western blotting and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), we confirmed that intraperitoneal injection with LPS increases iNOS protein and inflammatory cytokine, TNF-α and IL-6 mRNA expressions. To determine whether LPS-mediated macrophage inflammatory condition affects EC activation and inflammation, human umbilical vein endothelial cells (HUVECs) were incubated with isolated peritoneal macrophages from LPS-injected mice. Interestingly, p90RSK Serine 380 phosphorylation and protein expression were significantly increased by macrophage treatment in EC. Messenger RNA levels of vascular cell adhesion molecule 1 and p90RSK was increased, but endothelial nitric oxide synthase was decreased. In addition, NF-κB promoter activity, which plays an important role in the pathogenesis of inflammation, was strongly enhanced by the macrophage treatment in EC. We further evaluated the effects of LPS on EC function in the mouse aorta using en face staining. In agreement with in vitro result, p90RSK expression was strongly increased in the steady laminar flow region of the mouse aorta in mice injected with LPS. Together, our study demonstrates that p90RSK might be a one of the major therapeutic candidates for the prevention of vascular diseases mediated by LPS.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

“…Hemodynamic shear stress affects vascular atherosclerotic lesion and was associated with EC inflammation and apoptosis via regulating ERK5 and p53-mediated signaling pathway (5,11).…”

Section: Introductionmentioning

confidence: 99%

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LPS-stimulated Macrophage Activation Affects Endothelial Dysfunction

2018

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“…Turbulent blood flow, a crucial determinant of atherosclerosis, activates RSK in vitro and in vivo, and RSK signaling crucially governs flow-induced endothelial cell activation, controls nitric oxide bioavailability and promotes atherosclerotic plaque formation (Heo et al, 2015). In addition, increased RSK activity can be observed in blood vessels belonging to diabetic mice, and inhibiting RSK increases endothelial nitric oxide synthase (eNOS, also known as NOS3) expression and restores vasodilation by acetylcholine (Le et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Oxidized LDL induces FAK-dependent RSK signaling to drive NF-κB activation and VCAM-1 expression

Yurdagul

Sulzmaier

Chen

et al. 2016

Journal of Cell Science

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Oxidized low-density lipoprotein (oxLDL) accumulates early in atherosclerosis and promotes endothelial nuclear factor κB (NF-κB) activation, proinflammatory gene expression and monocyte adhesion. Like for other atherogenic factors, oxLDL-induced proinflammatory responses requires integrin-dependent focal adhesion kinase (FAK, also known as PTK2) signaling; however, the mechanism by which FAK mediates oxLDL-dependent NF-κB signaling has yet to be revealed. We now show that oxLDL induces NF-κB activation and VCAM-1 expression through FAK-dependent IκB kinase β (IKKβ, also known as IKBKB) activation. We further identify FAK-dependent activation of p90 ribosomal S6 kinase family proteins (RSK) as a crucial mediator of oxLDL-dependent IKKβ and NF-κB signaling, as inhibiting RSK blocks oxLDL-induced IKKβ and NF-κB activation, VCAM-1 expression and monocyte adhesion. Finally, transgenic mice containing a kinase-dead mutation in FAK specifically in the endothelial cells show reduced RSK activity, decreased VCAM-1 expression and reduced macrophage accumulation in regions of early atherosclerosis. Taken together, our data elucidates a new mechanism whereby oxLDL-induced endothelial FAK signaling drives an ERK-RSK pathway to activate IKKβ and NF-κB signaling and proinflammatory gene expression.

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SUMO‐specific proteases: SENPs in oxidative stress‐related signaling and diseases

Jiao,

Zhang,

Yang

2024

BioFactors

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Oxidative stress is employed to depict a series of responses detrimental to normal cellular functions resulting from an imbalance between intracellular oxidants, mainly reactive oxygen species and antioxidant defenses. Oxidative stress often contributes to the development of various diseases, including cancer, cardiovascular diseases, and neurodegenerative diseases. In this process, the relationship between small ubiquitin‐like modifier (SUMO) and oxidative stress has garnered significant attention, with its posttranslational modification (PTM) frequently serving as a marker of oxidative stress status. Sentrin/SUMO‐specific proteases (SENPs), affected by alternative splicing, PTMs such as phosphorylation and ubiquitination, and various protein interactions, are crucial molecules in the SUMO process. The human SENP family has six members (SENP1–3, SENP5–7), which are classified into two categories based on sequence similarity, substrate specificity, and subcellular location. They have two core functions in the human body: first, by cleaving the precursor SUMO and exposing the C‐terminal glycine, they initiate the SUMO process; second, they can specifically recognize and dissociate SUMO proteins bound to substrates, a process known as deSUMOylation. However, the connection between deSUMOylation and oxidative stress remains a relatively unexplored area despite their strong association with oxidative diseases such as cancer and cardiovascular disease. This article aims to illustrate the significant contribution of SENPs to the oxidative stress pathway through deSUMOylation by reviewing their structure and classification, their roles in oxidative stress, and the changes in their expression and activity in several typical oxidative stress‐related diseases.

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Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function

Cited by 87 publications

References 31 publications

LPS-stimulated Macrophage Activation Affects Endothelial Dysfunction

LPS-stimulated Macrophage Activation Affects Endothelial Dysfunction

Oxidized LDL induces FAK-dependent RSK signaling to drive NF-κB activation and VCAM-1 expression

SUMO‐specific proteases: SENPs in oxidative stress‐related signaling and diseases

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