Proteome Dynamics Reveals Pro-inflammatory Remodeling Of Plasma Proteome In A Mouse Model Of Nafld
antiinflammatory properties; Atherosclerosis; Biochemistry & Molecular Biology; fatty liver-disease; gene-expression; HDL; heavy water; high-density-lipoprotein; mass-spectrometry; NAFLD; oxidized phospholipids; ppar-alpha; proteome dynamics; proteomics; rapid method; shotgun; statistical-model
Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease. Because the liver is the major source of circulatory proteins, it is not surprising that hepatic disease could lead to alterations in the plasma proteome, which are therein implicated in atherosclerosis. The current study used low-density lipoprotein receptor-deficient (LDLR-/-) mice to examine the impact of Western diet (WD)-induced NAFLD on plasma proteome homeostasis. Using a (H2O)-H-2-metabolic labeling method, we found that a WD led to a proinflammatory distribution of circulatory proteins analyzed in apoB-depleted plasma, which was attributed to an increased production. The fractional turnover rates of short-lived proteins that are implicated in stress-response, lipid metabolism, and transport functions were significantly increased with WD (P < 0.05). Pathway analyses revealed that alterations in plasma proteome dynamics were related to the suppression of hepatic PPAR alpha, which was confirmed based on reduced gene and protein expression of PPAR alpha in mice fed a WD. These changes were associated with similar to 4-fold increase (P < 0.0001) in the proinflammatory property of apoB-depleted plasma. In conclusion, the proteome dynamics method reveals proinflammatory remodeling of the plasma proteome relevant to liver disease. The approach used herein may provide a useful metric of in vivo liver function and better enable studies of novel therapies surrounding NAFLD and other diseases.
Li L; Bebek G; Previs S F; Smith J D; Sadygov R G; McCullough A J; Willard B; Kasumov T
Journal of Proteome Research
2016
2016-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1021/acs.jproteome.6b00601" target="_blank" rel="noreferrer noopener">10.1021/acs.jproteome.6b00601</a>
Complexes of the Outer Mitochondrial Membrane Protein MitoNEET with Resveratrol-3-Sulfate
activators; binding; Biochemistry & Molecular Biology; cluster; crystal-structure; grapes; identification; iron-sulfur proteins; life-span; mass-spectrometry; thiazolidinedione
Binding of the thiazolidinedione antidiabetic drug pioglitazone led to the discovery of a novel outer mitochondrial membrane protein of unknown function called mitoNEET. The protein is homodimeric and contains a uniquely ligated two iron-two sulfur cluster in each of its two cytosolic domains. Electrospray ionization mass spectrometry was employed to characterize solutions of the soluble cytosolic domain (amino acids 32-108) of the protein. Ions characteristic of dimers containing the cofactors were readily detected under native conditions. mitoNEET responded to exposure to solutions at low pH by dissociation to give monomers that retained the cofactor, followed by dissociation of the cofactor in a concerted fashion. mitoNEET formed complexes with resveratrol-3-sulfate, one of the primary metabolites of the natural product resveratrol. Resveratrol itself showed no tendency to interact with mitoNEET. The formation of complexes was evident in both electrospray ionization mass spectrometry and isothermal titration calorimetry measurements. Up to eight molecules of the compound associated with the dimeric form of the protein in a sequential fashion. Dissociation constants determined by micorcalorimetry were in the range 5-16 mu M for the various binding sites. The only other known naturally occurring binding partner for mitoNEET at present is NADPH. It is very interesting that the iron-sulfur cluster containing protein interacts with two potentially redox active substances at the surface of mitochondria. These findings provide a new direction for research into two poorly understood, yet biomedically relevant, species.
Arif W; Xu S; Isailovic D; Geldenhuys W J; Carroll R T; Funk M O
Biochemistry
2011
2011-06
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1021/bi200546s" target="_blank" rel="noreferrer noopener">10.1021/bi200546s</a>
Novel role of aminopeptidase-A in angiotensin-(1-7) metabolism post myocardial infarction
ace2; Aminopeptidase A; angiotensin peptides; antihypertensive agents; carboxypeptidase; Cardiovascular System & Cardiology; enzyme; inhibitors; kidney; MALDI-imaging; mass-spectrometry; Myocardial infarction; Physiology; renal damage; renin-angiotensin system; spontaneously hypertensive-rats; system
Aminopeptidase-A (APA) is a less well-studied enzyme of the renin-angiotensin system. We propose that it is involved in cardiac angiotensin (ANG) metabolism and its pathologies. ANG-(1-7) can ameliorate remodeling after myocardial injury. The aims of this study are to 1) develop mass spectrometric (MS) approaches for the assessment of ANG processing by APA within the myocardium; and 2) investigate the role of APA in cardiac ANG-(1-7) metabolism after myocardial infarction (MI) using sensitive MS techniques. MI was induced in C57Bl/6 male mice by ligating the left anterior descending (LAD) artery. Frozen mouse heart sections (in situ assay) or myocardial homogenates (in vitro assay) were incubated with the endogenous APA substrate, ANG II. Results showed concentration-and time-dependent cardiac formation of ANG III from ANG II, which was inhibited by the specific APA inhibitor, 4-amino-4-phosphonobutyric acid. Myocardial APA activity was significantly increased 24 h after LAD ligation (0.82 +/- 0.02 vs. 0.32 +/- 0.02 rho mol.min(-1).mu g(-1), MI vs. sham, P < 0.01). Both MS enzyme assays identified the presence of a new peptide, ANG-(2-7), m/z 784, which accumulated in the MI (146.45 +/- 6.4 vs. 72.96 +/- 7.0%, MI vs. sham, P < 0.05). Use of recombinant APA enzyme revealed that APA is responsible for ANG-(2-7) formation from ANG-(1-7). APA exhibited similar substrate affinity for ANG-(1-7) compared with ANG II {K-m (ANG II) = 14.67 +/- 1.6 vs. K-m [ANG-(1-7)] = 6.07 +/- 1.12 mu mol/l, P < 0.05}. Results demonstrate a novel role of APA in ANG-(1-7) metabolism and suggest that the upregulation of APA, which occurs after MI, may deprive the heart of cardioprotective ANG-(1-7). Thus APA may serve as a potentially novel therapeutic target for management of tissue remodeling after MI.
Alghamri M S; Morris M; Meszaros J G; Elased K M; Grobe N
American Journal of Physiology-Heart and Circulatory Physiology
2014
2014-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1152/ajpheart.00911.2013" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00911.2013</a>
Dataset of effect of Wogonin, a natural flavonoid, on the viability and activation of NF-kappaB and MAPKs in IL-1beta-stimulated human OA chondrocytes.
MAPK; Mass-spectrometry; NF-kappaB; Nrf2; Osteoarthritis; Wogonin
This article contains data related to the article "Wogonin, a plant derived small molecule exerts potent anti-inflammatory and chondroprotective effects through activation of ROS/ERK/Nrf2 signaling pathways in human Osteoarthritis chondrocytes" (Khan et al. 2017) [1]. The data are related to effects of Wogonin on the viability and IL-1beta-stimulated activation of NF-kappaB and ERK1/2, JNK1/2 and p38 MAPKs in human OA chondrocytes. Gene expression data representing the chondrogenic phenotype and the efficiency of Nrf2 knockdown in monolayer culture of human OA chondrocytes were shown. Moreover, mass spectrometric calibration curve of Wogonin used to quantify the intracellular uptake were also presented. The data are presented in the form of figures and significance of these has been given in the research article (Khan et al. 2017) [1].
Khan Nazir M; Haseeb Abdul; Ansari Mohammad Y; Devarapalli Pratap; Haynie Sara; Haqqi Tariq M
Data in brief
2017
2017-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.dib.2017.03.054" target="_blank" rel="noreferrer noopener">10.1016/j.dib.2017.03.054</a>