Hypermethioninemia Leads to Fatal Bleeding and Increased Mortality in a Transgenic I278T Mouse Model of Homocystinuria
Abstract
:1. Introduction
2. Experimental Section
2.1. Chemicals and Test Compound
2.2. Animals and Study Design
2.3. Plasma Collection and Analysis
2.4. Flow-Mediated Vasodilation (FMD)
2.5. Carotid Artery Chemical Injury Thrombosis Model
2.6. Necropsy and Histopathology
2.7. RNA-Seq Analysis
2.8. Quantification of FXI in Plasma
2.9. Statistical Analysis
3. Results
3.1. Higher Met Intake Leads to Increased Mortality of I278T Mice
3.2. Higher Met Intake Leads to Arrested Growth of I278T Mice
3.3. I278T Mice on the HMD Diet Develop Severe Hypermethioninemia
3.4. High Met Intake Caused Fatal Intestinal Hemorrhage and Organ Failure in I278T Mice
3.5. Normal and High Met Intakes Result in Endothelial Dysfunction, but Fail to Produce a Prothrombotic Phenotype in I278T Model of HCU
3.6. Substantially Decreased Plasma FXI Concentration Could Explain Internal Bleeding and Premature Death of I278T Mice on HMD Diet
4. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Group 1 | Genotype | Diet | Injections | Number of Mice (Males/Females) |
---|---|---|---|---|
1 | +/+ (WT) | REG | PBS | 18 (9M & 9F) |
2 | -/- (I278T) | MRD&Bet | PBS | 22 (10M & 12F) |
3 | -/- (I278T) | REG | PBS | 26 (15M & 11F) |
4 | -/- (I278T) | HMD | PBS | 18 (8M & 10F) |
5 | -/- (I278T) | MRD&Bet | OT-58 | 17 (8M & 9F) |
6 | -/- (I278T) | REG | OT-58 | 18 (10M & 8F) |
7 | -/- (I278T) | HMD | OT-58 | 17 (8M & 9F) |
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Park, I.; Johnson, L.K.; Cox, A.; Branchford, B.R.; Paola, J.D.; Bublil, E.M.; Majtan, T. Hypermethioninemia Leads to Fatal Bleeding and Increased Mortality in a Transgenic I278T Mouse Model of Homocystinuria. Biomedicines 2020, 8, 244. https://doi.org/10.3390/biomedicines8080244
Park I, Johnson LK, Cox A, Branchford BR, Paola JD, Bublil EM, Majtan T. Hypermethioninemia Leads to Fatal Bleeding and Increased Mortality in a Transgenic I278T Mouse Model of Homocystinuria. Biomedicines. 2020; 8(8):244. https://doi.org/10.3390/biomedicines8080244
Chicago/Turabian StylePark, Insun, Linda K. Johnson, Allaura Cox, Brian R. Branchford, Jorge Di Paola, Erez M. Bublil, and Tomas Majtan. 2020. "Hypermethioninemia Leads to Fatal Bleeding and Increased Mortality in a Transgenic I278T Mouse Model of Homocystinuria" Biomedicines 8, no. 8: 244. https://doi.org/10.3390/biomedicines8080244