Summary of Study ST003222
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001883. The data can be accessed directly via it's Project DOI: 10.21228/M89X4H This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Study ID | ST003222 |
| Study Title | A small molecule macrophage migration inhibitory factor agonist ameliorates age-related myocardial intolerance to ischemia-reperfusion insults via metabolic regulation - Part 1 |
| Study Summary | Microphage migration inhibitory factor (MIF) is an innate cytokine that regulates both inflammatory and homeostatic responses. MIF is expressed by cardiomyocytes, where it exerts a protective action against ischemia-reperfusion (I/R) injury by activating AMP-activated protein kinase (AMPK). This effect is attenuated in the senescent heart due to an intrinsic, age-related reduction in MIF expression. We hypothesized that treating the aged heart with the small molecule MIF agonist (MIF20) can reinforce protective MIF signaling in cardiomyocytes, leading to a beneficial effect against I/R stress. The administration of MIF20 at the onset of reperfusion was found to not only decrease myocardial infarct size but also preserves systolic function in the aged heart. Protection from I/R injury was reduced in mice with cardiomyocyte-specific Mif deletion, consistent with the mechanism of action of MIF20 to allosterically increase MIF affinity for its cognate receptor CD74. We further found MIF20 to contribute to the maintenance of mitochondrial fitness and to preserve the contractile properties of aged cardiomyocytes under hypoxia/reoxygenation. MIF20 augments protective metabolic responses by reducing the NADH/NAD ratio, leading to a decrease in the accumulation of reactive oxygen species (ROS) in the aged myocardium under I/R stress. We also identify alterations in the expression levels of the downstream effectors PDK4 and LCAD, which participate in the remodeling of the cardiac metabolic profile. Data from this study demonstrates that pharmacologic augmentation of MIF signaling provides beneficial homeostatic actions on senescent myocardium under I/R stress. This experimental is part of case 4535 showing the Lipidomics experimental data. |
| Institute | University of Mississippi Medical Center |
| Last Name | Li |
| First Name | Ji |
| Address | 2500 N State St, Jackson, MS 39216-4505 |
| jli3@umc.edu | |
| Phone | 6018158995 |
| Submit Date | 2023-12-14 |
| Analysis Type Detail | LC-MS |
| Release Date | 2024-06-18 |
| Release Version | 1 |
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Project:
| Project ID: | PR001883 |
| Project DOI: | doi: 10.21228/M89X4H |
| Project Title: | A small molecule macrophage migration inhibitory factor agonist ameliorates age-related myocardial intolerance to ischemia-reperfusion insults via metabolic regulation |
| Project Summary: | Macrophage migration inhibitory factor (MIF) is an innate cytokine that regulates both inflammatory and homeostatic responses. MIF is expressed by cardiomyocytes, where it exerts a protective action against ischemia-reperfusion (I/R) injury by activating AMP-activated protein kinase (AMPK). This effect is attenuated in the senescent heart due to an intrinsic, age-related reduction in MIF expression. We hypothesized that treating the aged heart with the small molecule MIF agonist (MIF20) can reinforce protective MIF signaling in cardiomyocytes, leading to a beneficial effect against I/R stress. The administration of MIF20 at the onset of reperfusion was found to not only decrease myocardial infarct size but also preserves systolic function in the aged heart. Protection from I/R injury was reduced in mice with cardiomyocyte-specific Mif deletion, consistent with the mechanism of action of MIF20 to allosterically increase MIF affinity for its cognate receptor CD74. We further found MIF20 to contribute to the maintenance of mitochondrial fitness and to preserve the contractile properties of aged cardiomyocytes under hypoxia/reoxygenation. MIF20 augments protective metabolic responses by reducing the NADH/NAD ratio, leading to a decrease in the accumulation of reactive oxygen species (ROS) in the aged myocardium under I/R stress. We also identify alterations in the expression levels of the downstream effectors PDK4 and LCAD, which participate in the remodeling of the cardiac metabolic profile. Data from this study demonstrates that pharmacologic augmentation of MIF signaling provides beneficial homeostatic actions on senescent myocardium under I/R stress. |
| Institute: | University of Mississippi Medical Center |
| Last Name: | Li |
| First Name: | Ji |
| Address: | 2500 N State St, Jackson, MS 39216-4505 |
| Email: | jli3@umc.edu |
| Phone: | 6018158995 |
Subject:
| Subject ID: | SU003341 |
| Subject Type: | Mammal |
| Subject Species: | Mus musculus |
| Taxonomy ID: | 10090 |
Factors:
Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)
| mb_sample_id | local_sample_id | Sample source | Age | Genotype | Treatment |
|---|---|---|---|---|---|
| SA352093 | AWT-IR_1 | Heart | Aged | WT | I/R |
| SA352094 | AWT-IR_2 | Heart | Aged | WT | I/R |
| SA352095 | AWT-IR_3 | Heart | Aged | WT | I/R |
| SA352096 | AWT-IRMIF20_1 | Heart | Aged | WT | I/R+MIF20 |
| SA352097 | AWT-IRMIF20_2 | Heart | Aged | WT | I/R+MIF20 |
| SA352098 | AWT-IRMIF20_3 | Heart | Aged | WT | I/R+MIF20 |
| SA352099 | AWT-Sham_1 | Heart | Aged | WT | Sham |
| SA352100 | AWT-Sham_2 | Heart | Aged | WT | Sham |
| SA352101 | AWT-Sham_3 | Heart | Aged | WT | Sham |
| SA352102 | AWT-ShamMIF20_2 | Heart | Aged | WT | Sham+MIF20 |
| SA352103 | AWT-ShamMIF20_3 | Heart | Aged | WT | Sham+MIF20 |
| SA352104 | AWT-ShamMIF20_1 | Heart | Aged | WT | Sham+MIF20 |
| SA352105 | cMIFKO-IR_1 | Heart | NA | KO-MIF | I/R |
| SA352106 | cMIFKO-IR_2 | Heart | NA | KO-MIF | I/R |
| SA352107 | cMIFKO-IR_3 | Heart | NA | KO-MIF | I/R |
| SA352108 | cMIFKO-IRMIF20_2 | Heart | NA | KO-MIF | I/R+MIF20 |
| SA352109 | cMIFKO-IRMIF20_3 | Heart | NA | KO-MIF | I/R+MIF20 |
| SA352110 | cMIFKO-IRMIF20_1 | Heart | NA | KO-MIF | I/R+MIF20 |
| SA352111 | cMIFKO-Sham_1 | Heart | NA | KO-MIF | Sham |
| SA352112 | cMIFKO-Sham_3 | Heart | NA | KO-MIF | Sham |
| SA352113 | cMIFKO-Sham_2 | Heart | NA | KO-MIF | Sham |
| SA352114 | cMIFKO-ShamMIF20_2 | Heart | NA | KO-MIF | Sham+MIF20 |
| SA352115 | cMIFKO-ShamMIF20_3 | Heart | NA | KO-MIF | Sham+MIF20 |
| SA352116 | cMIFKO-ShamMIF20_1 | Heart | NA | KO-MIF | Sham+MIF20 |
| SA352117 | MIFff-IR_1 | Heart | NA | MIF | I/R |
| SA352118 | MIFff-IR_2 | Heart | NA | MIF | I/R |
| SA352119 | MIFff-IR_3 | Heart | NA | MIF | I/R |
| SA352120 | MIFff-IRMIF20_3 | Heart | NA | MIF | I/R+MIF20 |
| SA352121 | MIFff-IRMIF20_2 | Heart | NA | MIF | I/R+MIF20 |
| SA352122 | MIFff-IRMIF20_1 | Heart | NA | MIF | I/R+MIF20 |
| SA352123 | MIFff-Sham_1 | Heart | NA | MIF | Sham |
| SA352124 | MIFff-Sham_2 | Heart | NA | MIF | Sham |
| SA352125 | MIFff-Sham_3 | Heart | NA | MIF | Sham |
| SA352126 | MIFff-ShamMIF20_1 | Heart | NA | MIF | Sham+MIF20 |
| SA352127 | MIFff-ShamMIF20_2 | Heart | NA | MIF | Sham+MIF20 |
| SA352128 | MIFff-ShamMIF20_3 | Heart | NA | MIF | Sham+MIF20 |
| SA352129 | YWT-IR_3 | Heart | young | WT | I/R |
| SA352130 | YWT-IR_1 | Heart | young | WT | I/R |
| SA352131 | YWT-IR_2 | Heart | young | WT | I/R |
| SA352132 | YWT-IRMIF20_1 | Heart | young | WT | I/R+MIF20 |
| SA352133 | YWT-IRMIF20_2 | Heart | young | WT | I/R+MIF20 |
| SA352134 | YWT-IRMIF20_3 | Heart | young | WT | I/R+MIF20 |
| SA352135 | YWT-Sham_2 | Heart | young | WT | Sham |
| SA352136 | YWT-Sham_1 | Heart | young | WT | Sham |
| SA352137 | YWT-Sham_3 | Heart | young | WT | Sham |
| SA352138 | YWT-ShamMIF20_3 | Heart | young | WT | Sham+MIF20 |
| SA352139 | YWT-ShamMIF20_2 | Heart | young | WT | Sham+MIF20 |
| SA352140 | YWT-ShamMIF20_1 | Heart | young | WT | Sham+MIF20 |
| Showing results 1 to 48 of 48 |
Collection:
| Collection ID: | CO003334 |
| Collection Summary: | The sample collection method was: All mice groups underwent anesthesia with 2%-3% isoflurane and 100% O2. The mouse hearts were excised and rinsed in ice-cold PBS. Both atriums were removed; only the left ventricular myocardium, including the infarct area, was collected and was quickly frozen by using liquid nitrogen. Samples were preserved below -80 °C and were sent out for metabolomic and lipidomic analysis. |
| Sample Type: | Heart |
Treatment:
| Treatment ID: | TR003350 |
| Treatment Summary: | YWT: young wild type; Sham: no treatment; MIF20: treatment with MIF20; AWT: aged wild type; MIFff: with MIF; cMIFKO: knock out MIF; I/R: "ischemia-reperfusion"; For I/R, the myocardium underwent 45 minutes long ischemic condition, then followed by 24 hours long reperfusion. MIF20 was administered 5 minutes before the onset of reperfusion by I.V. injection via the jugular vein. MIF20 was administered until the MIF20 concentration in blood reached 8nM. Procedure is : We injected 100 uL of MIF20 solution (160 nM) into a mouse by I.V. Consider the total blood volume of a mouse is about 2 mL. Therefore, the MIF20 solution was diluted 20 times, reaching 8 nM in blood. |
Sample Preparation:
| Sampleprep ID: | SP003348 |
| Sampleprep Summary: | The lipidomic sample preparation method was: The samples were thawed on ice. Approximately 10 mg of each sample was weighed and homogenized by ball-mill in 1mL of extraction solution (MTBE:Methanol = 3:1, V/V) with internal standards. The mixture was vortexed for 15 min. Next, the mixture was added with 200 µL of water and vortexed for 1 min and incubating at 4 °C for 10 min. After centrifugation at 12000 rpm for 10 min (4 °C), 200 µL of the upper phase was collected for complete solvent drying under 20 °C. The residue was reconstituted using 200 µL of reconstitution solution (ACN:IPA = 1:1, V/V), followed by vortex for 3 min and centrifugation at 12000 rpm for 3 min. A 120 µL of the final supernatant was used for LC-MS analysis. The data acquisition instruments consisted of Ultra Performance Liquid Chromatography (UPLC) (Nex-era LC-40) and tandem mass spectrometry (MS/MS) (Triple Quad 6500+). |
Combined analysis:
| Analysis ID | AN005283 |
|---|---|
| Analysis type | MS |
| Chromatography type | Reversed phase |
| Chromatography system | Nexera LC-40 |
| Column | Thermo Accucore C30 (150 x 2.1mm,2.6um) |
| MS Type | ESI |
| MS instrument type | Triple quadrupole |
| MS instrument name | ABI Sciex 6500+ |
| Ion Mode | UNSPECIFIED |
| Units | lipid content in the sample (nmol/g) |
Chromatography:
| Chromatography ID: | CH003996 |
| Chromatography Summary: | Solvent A: acetonitrile /water (60/40, V/V) (0.1% formic acid added, 10 mmol/L ammonium formate) Solvent B: acetonitrile / Isopropyl alcohol (10/90, V/V) (0.1% formic acid added, 10 mmol/L ammonium formate) |
| Instrument Name: | Nexera LC-40 |
| Column Name: | Thermo Accucore C30 (150 x 2.1mm,2.6um) |
| Column Temperature: | 45 |
| Flow Gradient: | A:B; 80:20(V/V) at 0 min, 70:30(V/V) at 2 min, 40:60(V/V) at 4 min , 15:85(V/V) at 9 min, 10:90(V/V) at 14 min, 5:95(V/V) at 15.5 min, 5:95(V/V) at 17.3 min, 80:20(V/V) at 17.5 min, 80:20(V/V) at 20 min |
| Flow Rate: | 0.35ml/min |
| Solvent A: | 60% acetonitrile:40% water; 0.1% formic acid; 10 mmol/L ammonium formate |
| Solvent B: | 10% acetonitrile:90% isopropyl alcohol; 0.1% formic acid added; 10 mmol/L ammonium formate |
| Chromatography Type: | Reversed phase |
MS:
| MS ID: | MS005013 |
| Analysis ID: | AN005283 |
| Instrument Name: | ABI Sciex 6500+ |
| Instrument Type: | Triple quadrupole |
| MS Type: | ESI |
| MS Comments: | LIT and triple quadrupole (QQQ) scans were acquired on a triple quadrupole-linear ion trap mass spectrometer (QTRAP), QTRAP® 6500+ LC-MS/MS System, equipped with an ESI Turbo Ion-Spray interface, operating in positive and negative ion mode and controlled by Analyst 1.6.3 software (Sciex). The ESI source operation parameters were as follows: ion source, turbo spray; source temperature 500 ℃; ion spray voltage (IS) 5500 V(Positive),-4500 V(Neagtive); Ion source gas 1 (GS1), gas 2 (GS2), curtain gas (CUR) were set at 45, 55, and 35 psi, respectively. Instrument tuning and mass calibration were performed with 10 and 100 μmol/L polypropylene glycol solutions in QQQ and LIT modes, respectively. QQQ scans were acquired as MRM experiments with collision gas (nitrogen) set to 5 psi. DP and CE for individual MRM transitions was done with further DP and CE optimization. A specific set of MRM transitions were monitored for each period according to the lipids eluted within this period. |
| Ion Mode: | UNSPECIFIED |
