ARHGAP18 Protects Against Thoracic Aortic Aneurysm Formation by Mitigating the Synthetic and Proinflammatory Smooth Muscle Cell Phenotype

Liu, Renjing; Lo, Lisa; Lay, Angelina J.; Zhao, Yang; Ting, Ka Ka; Robertson, E.; Sherrah, Andrew G.; Jarrah, Sorour; Li, Haibo; Zhou, Zhaoxiong; Hambly, Brett D.; Richmond, David; Jeremy, Richmond W.; Bannon, Paul G.; Vadas, MA; Gamble, Jennifer R.

doi:10.1161/circresaha.117.310692

Cited by 42 publications

(26 citation statements)

References 50 publications

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“…MEG-01 cells (ATCC) were cultured in Dulbecco's modified RPMI 1640 medium (Gibco) supplemented with 4.5% (vol/vol) lglutamine (Gibco) and 10% (vol/vol) FBS (Invitrogen). Primary mouse VSMCs were isolated from WT and mT/mG mouse aortas by enzymatic diges tion and cultured as described previously (42). VSMCs were cocultured with or without RPs or thrombinactivated platelets (APs).…”

Section: Discussionmentioning

confidence: 99%

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Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repair

Zeng¹,

Xia²,

Fan³

et al. 2019

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

“…Immunofluorescence. Cells and tissues were fixed and stained according to standard protocols (42). Primary antibodies included anti-rabbit PDGFRβ antibody (1:200, Santa Cruz Biotechnology Inc., catalog sc374573), anti-goat KLF4 antibody (1:200, R&D Sys tems, AF3158), and Alexa Fluor 594-conjugated antiACTA2 (1:200, Abcam, ab202510).…”

mentioning

confidence: 99%

Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repair

Zeng¹,

Xia²,

Fan³

et al. 2019

Journal of Clinical Investigation

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“…Why VSMCs are already ‘primed’ to express pro-IL-1β is not known but may be related to their de-differentiated, non-contractile phenotype in culture that is commonly observed in diseased blood vessels in vivo. Various mechanisms have been proposed for the basal, unstimulated cytokine release by senescent VSMCs, including altered signalling pathways and genomic instability [28] , [29] , [43] , [44] .…”

Section: Discussionmentioning

confidence: 99%

Calcium phosphate particles stimulate interleukin-1β release from human vascular smooth muscle cells: A role for spleen tyrosine kinase and exosome release

Dautova

Kapustin

Pappert

et al. 2018

Journal of Molecular and Cellular Cardiology

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AimsCalcium phosphate (CaP) particle deposits are found in several inflammatory diseases including atherosclerosis and osteoarthritis. CaP, and other forms of crystals and particles, can promote inflammasome formation in macrophages leading to caspase-1 activation and secretion of mature interleukin-1β (IL-1β). Given the close association of small CaP particles with vascular smooth muscle cells (VSMCs) in atherosclerotic fibrous caps, we aimed to determine if CaP particles affected pro-inflammatory signalling in human VSMCs.Methods and resultsUsing ELISA to measure IL-1β release from VSMCs, we demonstrated that CaP particles stimulated IL-1β release from proliferating and senescent human VSMCs, but with substantially greater IL-1β release from senescent cells; this required caspase-1 activity but not LPS-priming of cells. Potential inflammasome agonists including ATP, nigericin and monosodium urate crystals did not stimulate IL-1β release from VSMCs. Western blot analysis demonstrated that CaP particles induced rapid activation of spleen tyrosine kinase (SYK) (increased phospho-Y525/526). The SYK inhibitor R406 reduced IL-1β release and caspase-1 activation in CaP particle-treated VSMCs, indicating that SYK activation occurs upstream of and is required for caspase-1 activation. In addition, IL-1β and caspase-1 colocalised in intracellular endosome-like vesicles and we detected IL-1β in exosomes isolated from VSMC media. Furthermore, CaP particle treatment stimulated exosome secretion by VSMCs in a SYK-dependent manner, while the exosome-release inhibitor spiroepoxide reduced IL-1β release.ConclusionsCaP particles stimulate SYK and caspase-1 activation in VSMCs, leading to the release of IL-1β, at least in part via exosomes. These novel findings in human VSMCs highlight the pro-inflammatory and pro-calcific potential of microcalcification.

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“…Upon ANG II infusion, Arhgap18Ϫ/Ϫ mice develops TAA with a higher frequency, whereas the incidence of AAA was eliminated while ANG II-induced hypertension was unaltered. Arhgap18Ϫ/Ϫ deficient VSMCs demonstrate synthetic and inflammatory phenotype associated with reduction of Akt2 expression (601). Induction and activation of MMP2 and MMP9 has been described to contribute to AAA.…”

Section: Signal Intermediates Protecting Ang Ii-induced Taa And/or Tadmentioning

confidence: 99%

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

718

703

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The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (ATR) is believed to mediate most functions of ANG II in the system. ATR utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between ATR signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. ATR remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.

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ARHGAP18 Protects Against Thoracic Aortic Aneurysm Formation by Mitigating the Synthetic and Proinflammatory Smooth Muscle Cell Phenotype

Abstract: We have identified as a novel protective gene against TAA formation and define an additional target for the future development of treatments to limit TAA pathogenesis.

Cited by 42 publications

References 50 publications

Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repair

Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repair

Calcium phosphate particles stimulate interleukin-1β release from human vascular smooth muscle cells: A role for spleen tyrosine kinase and exosome release

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

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