Matrix metalloproteinase-7 in platelet-activated macrophages accounts for cardiac remodeling in uremic mice

Yang, Yang; Wang, Chao; Song, Minghui; Li, Changchun; Chen, Meihan; Zhou, Jie; Mei, Changlin

doi:10.1007/s00395-020-0789-z

Cited by 26 publications

(22 citation statements)

References 54 publications

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“…APLP1 can be processed by gamma secretase but, unlike the homologs APP and APLP2, it was suggested that cleavage of APLP1 could occur without ectodomain shedding ( Schauenburg et al., 2018 ), potentially sequestering the protein intracellularly. MMP7 also exhibited a significant decrease over the time course and was shown to be a target of platelet activation ( Yang et al., 2020 ) and platelet-derived CXCL4 ( Erbel et al., 2015 ). These data demonstrate that many of the strongest changes in plasma proteins in whole blood ex vivo relate to platelet biology.…”

Section: Resultsmentioning

confidence: 99%

Multimodal analysis for human ex vivo studies shows extensive molecular changes from delays in blood processing

et al. 2021

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Multimodal analysis for human ex vivo studies shows extensive molecular changes from delays in blood processing 1) Flow Cytometry 2) Single-Cell RNAseq 3) Plasma Proteomics PBMC Time to Blood Processing (hours) PBMC Plasma Plasma Minimal Change Over 18 hours Extensive Change After 4 hours Extensive Change After 4 hours 2 4 6 Highlights Studies of human blood cells and plasma are highly sensitive to process variability Time variability distorts biology in cutting-edge single-cell and multiplex assays Longitudinal, multimodal, and aligned data enable data qualification and exploration Dataset holds potential novel, multi-modal biological correlations and hypotheses

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Section: Resultsmentioning

confidence: 99%

Multimodal analysis for human ex vivo studies shows extensive molecular changes from delays in blood processing

et al. 2021

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“…Following 6 h of incubation in Optimem®, the medium was removed and replaced with 5% FBS in DMEM/M199. Changes in FUNDC1 and Atf6 protein and/or transcript levels were assessed 48 h post-transfection [ 48 ].…”

Section: Methodsmentioning

confidence: 99%

Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury

et al. 2021

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Mitochondrial dysfunction is a fundamental challenge in septic cardiomyopathy. Mitophagy and the mitochondrial unfolded protein response (UPR mt ) are the predominant stress-responsive and protective mechanisms involved in repairing damaged mitochondria. Although mitochondrial homeostasis requires the coordinated actions of mitophagy and UPR mt , their molecular basis and interactive actions are poorly understood in sepsis-induced myocardial injury. Our investigations showed that lipopolysaccharide (LPS)-induced sepsis contributed to cardiac dysfunction and mitochondrial damage. Although both mitophagy and UPR mt were slightly activated by LPS in cardiomyocytes, their endogenous activation failed to prevent sepsis-mediated myocardial injury. However, administration of urolithin A, an inducer of mitophagy, obviously reduced sepsis-mediated cardiac depression by normalizing mitochondrial function. Interestingly, this beneficial action was undetectable in cardiomyocyte-specific FUNDC1 knockout (FUNDC1 CKO ) mice. Notably, supplementation with a mitophagy inducer had no impact on UPR mt , whereas genetic ablation of FUNDC1 significantly upregulated the expression of genes related to UPR mt in LPS-treated hearts. In contrast, enhancement of endogenous UPR mt through oligomycin administration reduced sepsis-mediated mitochondrial injury and myocardial dysfunction; this cardioprotective effect was imperceptible in FUNDC1 CKO mice. Lastly, once UPR mt was inhibited, mitophagy-mediated protection of mitochondria and cardiomyocytes was partly blunted. Taken together, it is plausible that endogenous UPR mt and mitophagy are slightly activated by myocardial stress and they work together to sustain mitochondrial performance and cardiac function. Endogenous UPR mt , a downstream signal of mitophagy, played a compensatory role in maintaining mitochondrial homeostasis in the case of mitophagy inhibition. Although UPR mt activation had no negative impact on mitophagy, UPR mt inhibition compromised the partial cardioprotective actions of mitophagy. This study shows how mitophagy modulates UPR mt to attenuate inflammation-related myocardial injury and suggests the potential application of mitophagy and UPR mt targeting in the treatment of myocardial stress.

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“…APLP1 can be processed by gamma-secretase but, unlike the homologs APP and APLP2, it was suggested that cleavage of APLP1 could occur without ectodomain shedding (Schauenburg et al, 2018), potentially sequestering the protein intracellularly. MMP7 also exhibited a significant decrease over the time course and was shown to be a target of platelet activation (Yang et al, 2020) and platelet-derived CXCL4 (Erbel et al, 2015). These data demonstrate that many of the strongest changes in plasma proteins in whole blood ex vivo relate to platelet biology.…”

Section: Resultsmentioning

confidence: 99%

Multimodal Analysis for Human ex vivo Studies Shows Extensive Molecular Changes from Delays in Blood Processing

Savage

Gutschow

Chiang

et al. 2020

Preprint

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Multi-omic profiling of human peripheral blood is increasingly utilized to identify biomarkers and pathophysiologic mechanisms of disease. The importance of these platforms in clinical and translational studies led us to investigate the impact of delayed blood processing on the numbers and state of peripheral blood mononuclear cells (PBMC) and on the plasma proteome. Similar to previous studies, we show minimal effects of delayed processing on the numbers and general phenotype of PBMCs up to 18 hours. In contrast, profound changes in the single-cell transcriptome and composition of the plasma proteome become evident as early as 6 hours after blood draw. These reflect patterns of cellular activation across diverse cell types that lead to progressive distancing of the gene expression state and plasma proteome from native in vivo biology. Differences accumulating during an overnight rest (18 hours) could confound relevant biologic variance related to many underlying disease states.

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Matrix metalloproteinase-7 in platelet-activated macrophages accounts for cardiac remodeling in uremic mice

Cited by 26 publications

References 54 publications

Multimodal analysis for human ex vivo studies shows extensive molecular changes from delays in blood processing

Multimodal analysis for human ex vivo studies shows extensive molecular changes from delays in blood processing

Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury

Multimodal Analysis for Human ex vivo Studies Shows Extensive Molecular Changes from Delays in Blood Processing

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