Loss of smooth muscle CYB5R3 amplifies angiotensin II–induced hypertension by increasing sGC heme oxidation

Durgin, Brittany G; Hahn, Scott; Schmidt, Heidi M.; Miller, Marcia A.; Hafeez, Neha; Mathar, Ilka; Freitag, Daniel F.; Sandner, Peter; Straub, Adam C.

doi:10.1172/jci.insight.129183

Cited by 40 publications

(40 citation statements)

References 52 publications

(88 reference statements)

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“…CCL20 [188], CRH (corticotropin releasing hormone) [189], SPP1 [190], LDLR (low density lipoprotein receptor) [191], RORA (RAR related orphan receptor A) [192], LYZ (lysozyme) [193], PTPRN2 [194], DAPK2 [195], OIP5 [196], PON3 [197], NR4A3 [198], VCAN (versican) [199], CNTNAP2 [200], IL1RAP [201], GLI2 [202], CDH13 [203], AEBP1 [204], BGN (biglycan) [205], LOX (lysyl oxidase) [206], IL1RL1 [207] and LUM (lumican) [208] were found to be involved in advancement of obesity, but these genes might be key for development of T2DM. C4BPA [209], KYNU (kynureninase) [210], ORM1 [211], ARSA (arylsulfatase A) [212], CYB5R3 [213], MAT1A [214], SDC4 [215], ASL (argininosuccinate lyase) [216], SLC4A4 [217], EPHB6 [218], SPARCL1 [219], THBS2 [220], EFNB2 [221] and CD248 [222] were revealed to be associated with hypertension, but these genes might be involved in progression of T2DM. GSDMD (gasdermin D) [223], UNC5B [224] and PDGFB (platelet derived growth factor subunit B) [225] have been reported significantly expressed in diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of potential key genes and mechanisms in type 2 diabetes mellitus

Vastrad¹,

Vastrad²

2021

Preprint

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Type 2 diabetes mellitus (T2DM) is etiologically related to metabolic disorder. The aim of our study was to screen out candidate genes of T2DM and to elucidate the underlying molecular mechanisms by bioinformatics methods. Expression profiling by high throughput sequencing data of GSE154126 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between T2DM and normal control were identified. And then, functional enrichment analyses of gene ontology (GO) and REACTOME pathway analysis was performed. Protein protein interaction (PPI) network and module analyses were performed based on the DEGs. Additionally, potential miRNAs of hub genes were predicted by miRNet database. Transcription factors (TFs) of hub genes were detected by NetworkAnalyst database. Further, validations were performed by receiver operating characteristic curve (ROC) analysis and real time polymerase chain reaction (RT PCR). In total, 925 DEGs were identified in T2DM, including 447 up regulated genes and 478 down-regulated genes. Functional enrichment analysis results showed that up regulated DEGs were significantly enriched in defense response, neutrophil degranulation, cell adhesion and extracellular matrix organization. The top 10 hub genes, JUN, VCAM1, RELA, U2AF2, ADRB2, FN1, CDK1, TK1, A2M and ACTA2 were identified from the PPI network, modules, miRNA hub gene regulatory network and TF hub gene regulatory network. Furthermore, ROC analysis and RT PCR revealed that JUN, VCAM1, RELA, U2AF2, ADRB2, FN1, CDK1, TK1, A2M and ACTA2 might serve as biomarkers in T2DM. Bioinformatics analysis is a useful tool to explore the molecular mechanism and pathogenesis of T2DM. The identified hub genes may participate in the onset and advancement of T2DM and serve as therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of potential key genes and mechanisms in type 2 diabetes mellitus

Vastrad¹,

Vastrad²

2021

Preprint

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“…Cyb5r3 , the principal reductase in mitochondria, is also significantly upregulated due to I/R injury, and can be restored by H 2 S. Cyb5r3 is also a heme reductase and recycles oxidized heme (Fe3+) back to its reduced form (Fe2+) [ 41 ]. Upregulation of Blvra and Cyb5r3 levels following I/R injury is likely to confer self-protection against oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Proteomics Reveals the Potential Protective Mechanism of Hydrogen Sulfide on Retinal Ganglion Cells in an Ischemia/Reperfusion Injury Animal Model

et al. 2020

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Glaucoma is the leading cause of irreversible blindness and is characterized by progressive retinal ganglion cell (RGC) degeneration. Hydrogen sulfide (H2S) is a potent neurotransmitter and has been proven to protect RGCs against glaucomatous injury in vitro and in vivo. This study is to provide an overall insight of H2S’s role in glaucoma pathophysiology. Ischemia-reperfusion injury (I/R) was induced in Sprague-Dawley rats (n = 12) by elevating intraocular pressure to 55 mmHg for 60 min. Six of the animals received intravitreal injection of H2S precursor prior to the procedure and the retina was harvested 24 h later. Contralateral eyes were assigned as control. RGCs were quantified and compared within the groups. Retinal proteins were analyzed via label-free mass spectrometry based quantitative proteomics approach. The pathways of the differentially expressed proteins were identified by ingenuity pathway analysis (IPA). H2S significantly improved RGC survival against I/R in vivo (p < 0.001). In total 1115 proteins were identified, 18 key proteins were significantly differentially expressed due to I/R and restored by H2S. Another 11 proteins were differentially expressed following H2S. IPA revealed a significant H2S-mediated activation of pathways related to mitochondrial function, iron homeostasis and vasodilation. This study provides first evidence of the complex role that H2S plays in protecting RGC against I/R.

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“…However, recently and also presented on the last cGMP meeting in 2017, it was shown that vascular SMC express a reductase (CYB5R3) turning back oxidized sGC into the native form (Shah et al 2018). More recently, it has been demonstrated that knock out of CYB5R3 in vascular SMC is linked to a hypertensive phenotype by reducing NOmediated sGC stimulation (Durgin et al 2019). Besides sGC, other signaling molecules in the NO and NP pathway may be very sensitive to oxidative stress, too.…”

Section: Pgc Structure and Functionmentioning

confidence: 99%

cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development

Friebe

Sandner

Schmidtko

2019

Naunyn-Schmiedeberg's Arch Pharmacol

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Cyclic guanosine monophosphate (cGMP) is a unique second messenger molecule formed in different cell types and tissues. cGMP targets a variety of downstream effector molecules and, thus, elicits a very broad variety of cellular effects. Its production is triggered by stimulation of either soluble guanylyl cyclase (sGC) or particulate guanylyl cyclase (pGC); both enzymes exist in different isoforms. cGMP-induced effects are regulated by endogenous receptor ligands such as nitric oxide (NO) and natriuretic peptides (NPs). Depending on the distribution of sGC and pGC and the formation of ligands, this pathway regulates not only the cardiovascular system but also the kidney, lung, liver, and brain function; in addition, the cGMP pathway is involved in the pathogenesis of fibrosis, inflammation, or neurodegeneration and may also play a role in infectious diseases such as malaria. Moreover, new pharmacological approaches are being developed which target sGC-and pGC-dependent pathways for the treatment of various diseases. Therefore, it is of key interest to understand this pathway from scratch, beginning with the molecular basis of cGMP generation, the structure and function of both guanylyl cyclases and cGMP downstream targets; research efforts also focus on the subsequent signaling cascades, their potential crosstalk, and also the translational and, ultimately, the clinical implications of cGMP modulation. This review tries to summarize the contributions to the "9th International cGMP Conference on cGMP Generators, Effectors and Therapeutic Implications" held in Mainz in 2019. Presented data will be discussed and extended also in light of recent landmark findings and ongoing activities in the field of preclinical and clinical cGMP research.

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Loss of smooth muscle CYB5R3 amplifies angiotensin II–induced hypertension by increasing sGC heme oxidation

Cited by 40 publications

References 52 publications

Bioinformatics analysis of potential key genes and mechanisms in type 2 diabetes mellitus

Bioinformatics analysis of potential key genes and mechanisms in type 2 diabetes mellitus

Proteomics Reveals the Potential Protective Mechanism of Hydrogen Sulfide on Retinal Ganglion Cells in an Ischemia/Reperfusion Injury Animal Model

cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development

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