The NuRD chromatin-remodeling complex enzyme CHD4 prevents hypoxia-induced endothelial Ripk3 transcription and murine embryonic vascular rupture

Colijn, Sarah; Gao, Siqi; Ingram, Kyle G.; Menendez, Matthew T.; Muthukumar, Vijay; Silasi‐Mansat, Robert; Chmielewska, Joanna; Hinsdale, Myron E.; Lupu, Florea; Griffin, Courtney T.

doi:10.1038/s41418-019-0376-8

Cited by 16 publications

(26 citation statements)

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“…It is possible that this inconsistency may be due to different background strains in the mice that were analyzed. The Ripk3 −/− mice used in the original study were derived from C57BL/6N embryonic stem cells (Newton et al, 2004), whereas our Ripk3 fl/fl mice were derived from C57BL/6J embryonic stem cells (Colijn et al, 2019). Lin et al reported that they performed their study on a C57BL/6J background; however, it is unclear for how many generations the original C57BL/6N strain was crossed onto the C57BL/6J strain.…”

Section: Discussionmentioning

confidence: 99%

“…It is also possible that differences between the Ripk3 −/− genetic model used by Lin et al and our Ripk3 fl/fl genetic model could contribute to the discrepancies between our studies. Specifically, whereas our Ripk3 fl/fl mouse model results in removal of exons one through nine of Ripk3 upon Cre-mediated recombination, only the first three exons of Ripk3 are targeted for deletion in the Ripk3 −/− mouse model (Colijn et al, 2019;Newton et al, 2004). Ripk3 has been reported to have two alternative splicing variants in addition to the full length form (Yang et al, 2005), and although part of the alternative spliced sequences include the first three exons and therefore may not be transcribed in the Ripk3 −/− mouse, this was not addressed in the design of the Ripk3 knockout locus.…”

Section: Discussionmentioning

confidence: 99%

“…We also sought to confirm that the Ripk3-floxed allelewhich results in removal of the first nine out of the ten exons of Ripk3 after Cre-mediated excision (Colijn et al, 2019) does not produce a transcribed version of exon 10. This exon encodes a functional domain that is involved in several kinase-independent processes (Moriwaki et al, 2017), which, if still translated, could confound our results.…”

Section: Ripk3 Deletion In Macrophages or Endothelial Cells Exacerbatmentioning

confidence: 99%

“…Apoe −/− mice on the C57BL/6J background (Piedrahita et al, 1992), SM22-Cre transgenic mice (Holtwick et al, 2002), LysM-Cre transgenic mice (Clausen et al, 1999), VE-Cadherin-Cre transgenic mice (Alva et al, 2006) and Ripk3-floxed (Ripk3 fl/fl ) mice on the C57BL/6J background (Colijn et al, 2019) have been described. Ripk3-knockout (Ripk3 Δ/Δ ) mice were generated by utilizing the germ-line excision phenomenon that occurs when Cre activity aberrantly turns on in the gonads of the breeders (Harno et al, 2013), thereby altering the Ripk3-floxed allele into a Ripk3-knockout allele.…”

Section: Mice (Mus Musculus)mentioning

confidence: 99%

“…As RIPK3 is a widely expressed proteinas reported by the Human Protein Atlas (Uhlén et al, 2015)there is potential for RIPK3 to have tissue-or cell-specific functions. To explore the cellspecific function of RIPK3 in the vasculature, and to confirm which cell typesif anyundergo necroptosis in atherosclerosis, we developed a conditional model of Ripk3 deletion that utilizes a Ripk3 locus integrated with loxP sites (Colijn et al, 2019). We conducted this study by using the Ripk3-floxed mice crossed with macrophage-, vascular smooth muscle cell-and endothelial cellspecific Cre recombinases on the Apoe −/− murine model of atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

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Cell-specific and athero-protective roles for RIPK3 in a murine model of atherosclerosis

Colijn

Muthukumar

Xie

et al. 2020

Disease Models &Amp; Mechanisms

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Receptor-interacting protein kinase 3 (RIPK3) was recently implicated in promoting atherosclerosis progression through a proposed role in macrophage necroptosis. However, RIPK3 has been connected to numerous other cellular pathways, which raises questions about its actual role in atherosclerosis. Furthermore, RIPK3 is expressed in a multitude of cell types, suggesting that it may be physiologically relevant to more than just macrophages in atherosclerosis. In this study, Ripk3 was deleted in macrophages, endothelial cells, vascular smooth muscle cells or globally on the Apoe −/− background using Cre-lox technology. To induce atherosclerosis progression, male and female mice were fed a Western diet for three months before tissue collection and analysis. Surprisingly, necroptosis markers were nearly undetectable in atherosclerotic aortas. Furthermore, en face lesion area was increased in macrophage-and endothelial-specific deletions of Ripk3 in the descending and abdominal regions of the aorta. Analysis of bone-marrow-derived macrophages and cultured endothelial cells revealed that Ripk3 deletion promotes expression of monocyte chemoattractant protein 1 (MCP-1) and E-selectin in these cell types, respectively. Western blot analysis showed upregulation of MCP-1 in aortas with Ripk3-deficient macrophages. Altogether, these data suggest that RIPK3 in macrophages and endothelial cells protects against atherosclerosis through a mechanism that likely does not involve necroptosis. This protection may be due to RIPK3-mediated suppression of proinflammatory MCP-1 expression in macrophages and E-selectin expression in endothelial cells. These findings suggest a novel and unexpected cell-type specific and athero-protective function for RIPK3. This article has an associated First Person interview with the first author of the paper.

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Section: Discussionmentioning

confidence: 99%