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Vascular endothelial S1PR2 aggravates cardiac ischemia/reperfusion injury through triggering mitochondrial dysfunctions and endothelial pyroptosis via RHO/ROCK1/DRP1/NLRP3 pathway [heart]

ABSTRACT: Vascular endothelial S1PR2 aggravates cardiac ischemia/reperfusion injury through triggering mitochondrial dysfunctions and endothelial pyroptosis via RHO/ROCK1/DRP1/NLRP3 pathway [heart]

PROVIDER: PRJNA1030930 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26463701.fastq.gz	Fastqsanger.gz
	SRR26463702.fastq.gz	Fastqsanger.gz
	SRR26463703.fastq.gz	Fastqsanger.gz
	SRR26463704.fastq.gz	Fastqsanger.gz

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Project description:Purpose:to verify Drp1-mediated biological pathways under physiological and ischemia conditions.Methods:C57BL/6 mice and Drp1 knockdown mice were used for ischemia treatment. Right femoral arteries were catheterized with polyethylene catheters for bleeding 50% of total blood volume (≈7% of weight). The ischemia time started to calculate after the model was established. A laparotomy was then carried out to obtain superior mesenteric artery tissues (SMAs) for transcriptome analysis. Series-Cluster analysis was performed to identify the global trends of mitochondrial DEGs after Drp1 knockdown. Gene ontology (GO) analysis was performed to facilitate elucidating the biological process (BP), molecular function (MF) and cellular component (CC) of unique genes in the significant or representative profiles. Results:In addition to its traditional roles in GTPase regulation and mitochondrial fission, Drp1 may also regulate actin cytoskeleton and the movement of microtubules. Besides, Drp1 may participate in the regulation of morphology and functions of other organelles, including endoplasmic reticulum, peroxisome, phagolysosome, etc. As for general organ functions, Drp1 may regulate vascular constriction and dilation. These consequences indicated the important role of Drp1 in ischemia-induced cellular regulation. Conclusions: Drp1 deficiency proves the important role of Drp1 in ischemia-induced biomedical processes through multiple potential fission-independent manners. Methods:C57BL/6 mice and Drp1 knockdown mice were used for ischemia treatment. Right femoral arteries were catheterized with polyethylene catheters for bleeding 50% of total blood volume (≈7% of weight). The ischemia time started to calculate after the model was established. A laparotomy was then carried out to obtain superior mesenteric artery tissues (SMAs) for transcriptome analysis. Series-Cluster analysis was performed to identify the global trends of mitochondrial DEGs after Drp1 knockdown. Gene ontology (GO) analysis was performed to facilitate elucidating the biological process (BP), molecular function (MF) and cellular component (CC) of unique genes in the significant or representative profiles. Results:In addition to its traditional roles in GTPase regulation and mitochondrial fission, Drp1 may also regulate actin cytoskeleton and the movement of microtubules. Besides, Drp1 may participate in the regulation of morphology and functions of other organelles, including endoplasmic reticulum, peroxisome, phagolysosome, etc. As for general organ functions, Drp1 may regulate vascular constriction and dilation. These consequences indicated the important role of Drp1 in ischemia-induced cellular regulation. Conclusions: Drp1 deficiency proves the important role of Drp1 in ischemia-induced biomedical processes through multiple potential fission-independent manners.

Project description:Rho-associated kinase (ROCK) and zipper-interacting protein kinase (ZIPK) have been implicated in diverse physiological functions, including smooth muscle contraction, cell proliferation, cell adhesion, apoptosis, cell migration and inflammation. Many aspects of regulation via ROCK and ZIPK, however, remain unclear. In this study, we utilized an siRNA approach to knock down ROCK1 and ZIPK in cultured human arterial smooth muscle cells. Microarray analysis was performed, using a whole-transcript expression chip, to identify changes in gene expression profiles induced by ROCK1 and ZIPK knockdown. ROCK1 knockdown affected the expression of 553 genes (355 down-regulated and 198 up-regulated), while ZIPK knockdown affected the expression of 390 genes (219 down-regulated and 171 up-regulated). A high incidence of up- and down-regulation of transcription regulator genes was observed in both ROCK1 and ZIPK knockdowns. Other markedly affected groups included transporters, kinases, peptidases, transmembrane and G protein-coupled receptors, growth factors, phosphatases and ion channels. Three microRNAs (mir-145, mir-199 and mir-622) were up-regulated by ROCK1 knockdown, whereas ZIPK knockdown had no effect on microRNA expression. 76 differentially expressed genes were common to ROCK1 and ZIPK knockdown, of which 41 were down-regulated and 26 up-regulated by both treatments, while the other 9 genes were differentially up/down-regulated. Ingenuity Pathway Analysis identified five pathways shared between the two knockdowns, which are mainly involved in cell cycle regulation. Marked differences in the effects of ROCK1 and ZIPK knockdown on the genes involved in cell cycle regulation suggested that ROCK1 and ZIPK regulate the cell cycle by different mechanisms. ROCK1, but not ZIPK knockdown significantly reduced the viability of vascular SMC. ROCK1 knockdown also affected several cytokine signaling pathways with up-regulation of 5 and down-regulation of 4 cytokine genes, in contrast to ZIPK knockdown, which affected the expression of only two cytokine genes (both down-regulated). IL-6 gene expression and secretion of IL-6 protein were up-regulated by ROCK1 knockdown, whereas ZIPK knockdown reduced IL-6 mRNA expression and IL-6 protein secretion and ROCK1 protein expression, suggesting that ROCK1 may inhibit IL-6 secretion. IL-1β mRNA and protein levels were increased in response to ROCK1 knockdown. Finally, ROCK1 but not ZIPK knockdown inhibited proliferation of vascular smooth muscle cells. We conclude that ROCK1 and ZIPK have diverse, but predominantly distinct regulatory functions in vascular smooth muscle cells.

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Vascular endothelial S1PR2 aggravates cardiac ischemia/reperfusion injury through triggering mitochondrial dysfunctions and endothelial pyroptosis via RHO/ROCK1/DRP1/NLRP3 pathway [heart]

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