Dataset Information

Proteomic surveys of the mouse heart unveil cardiovascular responses to nitric oxide/cGMP signaling deficiencies.

ABSTRACT: Nitric oxide (NO) is an important signaling molecule in the cardiovascular system. Reduced bioavailability of NO results in debilitated signaling, which contributes to the pathogenesis of cardiometabolic disorders. However, the alterations in signaling under NO deficiency remain mostly unknown. To gain an appreciation of the signaling landscapes during NO deficiency we combined genetics and proteomics to quantify changes in the heart proteome, phosphoproteome, and S-nitrosocysteine proteome in mice lacking each of the nitric oxide synthases, NOS1, NOS2, and NOS3, mice lacking all three enzymes (tNOS), or the alpha 1-regulatory subunit of the soluble guanylate cyclase (sGCα1). Modest changes, less than 1% in the proteome and 4% in the phosphoproteome were quantified in single NOS gene or sGCα1 deletion mouse hearts indicating sufficient biological compensation. In contrast, the absence of a single NOS gene reduced the number of S-nitrosylated proteins by 80%, 57%, and 35% in NOS3, NOS1, and NOS2 null mice respectively. The profound deficit of S-nitrosylated proteins in the NOS3 null mice was localized in metabolic pathways, which may explain the metabolic dysregulation that develops in these mice. A 21% remodeling of the proteome and 9% of the phosphoproteome was quantified in the tNOS null mice. We quantified changes in the levels and regulation of integral kinases indicating an adaptive rewiring of signaling to secure essential functions such as contraction and metabolism in the tNOS null mice. The data revealed the emergence of enhanced mitogen-activated-kinases Mapk3/Mapk1 signaling documented by increased phosphorylation of these two kinases and their downstream targets in the sGCα1 and tNOS null mice. These data highlight that adaptive compensation of signaling prevents overt phenotypes during NO signaling deficits, whereas maladaptive signaling via Mapk3/Mapk1 may promote cardiac dysfunction and pathological cardiomyopathy that progressively develops in the tNOS null mice.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Hossein Fazelinia

LAB HEAD: Harry Ischiropoulos, PhD

PROVIDER: PXD060084 | Pride | 2025-04-29

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	20221025_095331_HI1701_wp_dDIA.sne	Other
	20231012_153920_HI1701i_mergedSL.sne	Other
	x220903_HI1701_WP_01.raw	Raw
	x220903_HI1701_WP_02.raw	Raw
	x220903_HI1701_WP_03.raw	Raw

Items per page:

1 - 5 of 64

Similar Datasets

Project description:This a model from the article: Vascular and perivascular nitric oxide release and transport: biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3). Chen K, Popel AS Free Radic Biol Med. 2007 Mar 15;42(6):811-22. 17320763 , Abstract: Nitric oxide (NO) derived from nitric oxide synthase (NOS) is an important paracrine effector that maintains vascular tone. The release of NO mediated by NOS isozymes under various O(2) conditions critically determines the NO bioavailability in tissues. Because of experimental difficulties, there has been no direct information on how enzymatic NO production and distribution change around arterioles under various oxygen conditions. In this study, we used computational models based on the analysis of biochemical pathways of enzymatic NO synthesis and the availability of NOS isozymes to quantify the NO production by neuronal NOS (NOS1) and endothelial NOS (NOS3). We compared the catalytic activities of NOS1 and NOS3 and their sensitivities to the concentration of substrate O(2). Based on the NO release rates predicted from kinetic models, the geometric distribution of NO sources, and mass balance analysis, we predicted the NO concentration profiles around an arteriole under various O(2) conditions. The results indicated that NOS1-catalyzed NO production was significantly more sensitive to ambient O(2) concentration than that catalyzed by NOS3. Also, the high sensitivity of NOS1 catalytic activity to O(2) was associated with significantly reduced NO production and therefore NO concentrations, upon hypoxia. Moreover, the major source determining the distribution of NO was NOS1, which was abundantly expressed in the nerve fibers and mast cells close to arterioles, rather than NOS3, which was expressed in the endothelium. Finally, the perivascular NO concentration predicted by the models under conditions of normoxia was paradoxically at least an order of magnitude lower than a number of experimental measurements, suggesting a higher abundance of NOS1 or NOS3 and/or the existence of other enzymatic or nonenzymatic sources of NO in the microvasculature. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Chen K, Popel AS (2007) - version02 The original CellML model was created by: Lloyd, Catherine, May c.lloyd@aukland.ac.nz The University of Auckland The Bioengineering Institute This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Project description:Trypomastigotes from Trypanosoma cruzi adhere to the extracellular matrix (ECM) in order to invade mammalian host cells. Incubation of trypomastigotes with ECM leads to a decrease of nitric oxide synthase (NOS) activity and associated post-translational modifications (PTMs). Herein, resin-assisted enrichment of thiols combined with mass spectrometry were employed to map site-specific S-nitrosylated (SNO) proteins from T. cruzi trypomastigotes incubated (MTy) or not (Ty) with ECM. We confirmed the reduction of S-nitrosylation upon incubation with ECM, associated to a rewiring of the subcellular distribution and intracellular signaling pathways of the SNO proteins between MTy and Ty conditions. Forty (~10.7%) and 248 (~66.4%) SNO-peptides were uniquely identified in MTy and Ty, respectively, in addition to 85 peptides (~22.7%) quantified in both conditions. S-nitrosylated proteins were enriched in a wide range of cellular components, including surface membranes and vesicles, and are involved in ribosome, transport, carbohydrate and lipid metabolisms. Of note, we described for the first time nytrosylation of histones H2B and H3 on Cys64 and Cys126, respectively, which is was more abundant in MTy. Additionally, sequence alignment shows that H3 (Cys126) histone is also present in T.b.brucei, but not in L. major, while H2B (Cys64) is absent in both parasites and other higher eukaryotes. Protein-protein interaction networks analyzed by STRING revealed ribosomal proteins, proteins involved in carbon and fatty acid metabolism to be among the enriched protein complexes. Among the SNO ribosomal proteins, 90% were identified and quantified uniquely or upregulated in the Ty fraction. Enzymes involved in oxidoreductase, kinases and phosphatases were identified as nitrosylated and phosphorylated in the same conditions suggesting a crosstalk between these modifications linked to regulation of energy metabolism of T. cruzi in the presence of ECM. Although enzymatic activity of NOS was described in T. cruzi, its identification is elusive. In silico mapping of putative nitric oxide synthase (NOS) gene(s) based on domain architecture identified four putative T. cruzi proteins expressing a putative C-terminal NOS domain: two putative P450 reductases, a putative FMN/FAD containing oxidoreductase and a putative oxidoreductase-protein. Our results provide the first site-specific characterization of S-nitrosylated proteins in T. cruzi linked to the roles of NO in reprogramming parasite cells to invade mammalian hosts.

Dataset Information

Proteomic surveys of the mouse heart unveil cardiovascular responses to nitric oxide/cGMP signaling deficiencies.

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets