Modulation of Prostanoids Profile and Counter-Regulation of SDF-1α/CXCR4 and VIP/VPAC2 Expression by Sitagliptin in Non-Diabetic Rat Model of Hepatic Ischemia-Reperfusion Injury
Abstract
:1. Introduction
2. Results
2.1. A Rat Model of IR and Its Validation
2.2. Effect of IR Injury and Sitagliptin on Liver Profile of Eicosanoids
2.3. Effect of IR Injury and Sitagliptin on Liver Expression of CXCR4/SDF1
2.4. Effect of IR Injury and Sitagliptin on Liver Expression of PAC1, VPAC1, VPAC2/VIP
2.5. Effect of IR Injury and Sitagliptin on Liver Expression of GLP1R/GLP1
2.6. Relationship between Eicosanoids, DPP4 Ligands, and Their Receptors, and Mediators of Inflammation and Oxidative, Nitrosative, and Halogenative Stress (Univariate Analysis)
2.6.1. Eicosanoids
2.6.2. CXCR4/SDF1
2.6.3. PAC1, VPAC1, VPAC2/VIP
2.6.4. GLP1R/GLP1
2.7. Independent Predictors of Liver Eicosanoids and DPP4 Ligands and Their Receptors (Multivariate Analysis)
2.7.1. Independent Predictors of Liver Eicosanoids
2.7.2. Independent Predictors of Liver Expression of DPP4 Ligands and Their Receptors
3. Discussion
4. Materials and Methods
4.1. Experimental Setting
4.1.1. Animals
4.1.2. Chemicals
4.1.3. The IR Procedure
4.2. Analytical Methods
4.2.1. Metabolomic Analysis of Eicosanoids
Chemicals and Reagents
Sample Preparation
LC-MS Analysis
4.2.2. Immunoassays
4.2.3. Protein Determination
4.2.4. Transcriptional Analysis
4.2.5. Inflammatory Mediators and Markers of Oxidative, Nitrosative, and Halogenative Stress
4.3. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Metabolite | Median Prostanoid Concentration (pg/mg) (IQR) | p | |||
---|---|---|---|---|---|
Control, n = 9 | IR, n = 9 | SIR, n = 10 | Sitagliptin, n = 8 | ||
6-ketoPGF1α (PGI2) | 68.0 (72.5) 2,4 | 247.5 (70.5) 1,3 | 121.8 (48.3) 2,4 | 211 (141.5) 1,3 | 0.001 |
PGE2 | 154.7 (127) 2 | 263.3 (74.4) 1,3 | 184.7 (39) 2 | 225.4 (160) | 0.050 |
PGF2 | 58.7 (35.5) | 55.1 (17.7) | 57.4 (27.7) | 62.4 (25.8) | 0.962 |
PGD2 | 571 (849) 4 | 1142 (434) 4 | 1180 (493) 4 | 1555 (144) 1,2,3 | 0.002 |
15-deoxy-12,14-PGJ2 (PGD2) | 1.04 (1.47) 3,4 | 1.15 (1.87) 3,4 | 2.88 (2.48) 1,2 | 3.2 (1.23) 1,2 | 0.004 |
13,14-dihydro-PGE1 (PGE1) | 0.066 (0.11) 2 | 0.15 (0.12) 1,3 | 0.053 (0.06) 2 | 0.082 (0.10) | 0.043 |
TXB2 (TXA2) | 6.19 (4.42) | 3.6 (2.85) | 3.44 (5.0) | 4.61 (3.0) | 0.559 |
LTB4 (LTA4) | 41.9 (102) | 136.2 (66.9) | 90.6 (124.1) | 124.1 (102.5) | 0.495 |
6-ketoPGF1α (PGI2)/TXB2 (TXA2) | 15.7 (34.4) 2,4 | 75.2 (72.9) 1,3 | 21.6 (45.4) 2 | 46.3 (39.2) 1 | 0.015 |
Dependent Variable | Explanator Variables | Regression Coefficient (β), p | rp | VIF | R2; ANOVA |
---|---|---|---|---|---|
6-ketoPGF1α (PGI2) | (Constant) | 100.4 | R2 = 0.832; F = 19.1, p < 0.0001 | ||
13,14-dihydro-PGE1 | 321.3, p = 0.003 | 0.53 | 1.07 | ||
PGE2 | 0.26, p = 0.028 | 0.41 | 1.63 | ||
Cxcr4 (log) | 56.7, p = 0.022 | 0.42 | 1.32 | ||
3-NT | 1.56, p < 0.001 | 0.64 | 1.18 | ||
Nox4 (log) | −22.0, p = 0.055 | −0.36 | 1.64 | ||
VIP | −0.73, p = 0.025 | −0.42 | 1.39 | ||
IL-1β | 0.07, p = 0.002 | 0.55 | 1.21 | ||
PGE2 | (Constant) | 23.11 | R2 = 0.744; F = 30.0, p < 0.0001 | ||
6-ketoPGF1α (PGI2) | 0.33, p < 0.001 | 0.57 | 1.17 | ||
PGF2 | 1.57, p < 0.001 | 0.63 | 1.26 | ||
LTB4 | 0.33, p = 0.006 | 0.47 | 1.33 | ||
PGF2 | (Constant) | 3.10 | R2 = 0.613; F = 26.1, p < 0.0001 | ||
PGE2 | 0.18, p < 0.001 | 0.69 | 1.05 | ||
TXB2 (log) | 33.9, p = 0.002 | 0.52 | 1.05 | ||
PGD2 | (Constant) | 126.7 | R2 = 0.729; F = 20.8, p < 0.0001 | ||
15-deoxy-12,14-PGJ2 | 145.5, p < 0.001 | 0.59 | 1.10 | ||
PGE2 | 2.27, p = 0.007 | 0.46 | 1.40 | ||
SDF1α | 4.86, p = 0.026 | 0.39 | 1.50 | ||
Sitagliptin | 405, p = 0.005 | 0.48 | 1.19 | ||
15-deoxy-12,14-PGJ2 | (Constant) | 0.20 | R2 = 0.453; F = 13.7, p < 0.001 | ||
PGD2 | 0.002, p < 0.001 | 0.60 | 1.00 | ||
Sitagliptin | 1.25, p = 0.006 | 0.45 | 1.00 | ||
13,14-dihydro-PGE1 | (Constant) | 0.08 | R2 = 0.161; F = 6.54, p = 0.015 | ||
IR | 0.07, p = 0.015 | 0.40 | 1.00 | ||
TXB2 (log) | (Constant) | 0.24 | R2 = 0.279; F = 12.8, p = 0.001 | ||
PGF2 | 0.01, p = 0.001 | 0.53 | 1.00 | ||
LTB4 | (Constant) | −42.2 | R2 = 0.624; F = 17.7, p < 0.0001 | ||
15-deoxy-12,14-PGJ2 | 17.6, p = 0.002 | 0.50 | 1.02 | ||
PGE2 | 0.42, p = 0.001 | 0.53 | 1.40 | ||
SDF1α | 0.72, p = 0.027 | 0.38 | 1.42 |
Dependent Variable | Explanatory Variables | Regression Coefficient (β), p | rp | VIF | R2; ANOVA |
---|---|---|---|---|---|
CXCR4 | (Constant) | 48.1 | R2 = 0.390; F = 10.2, p < 0.001 | ||
6-ketoPGF1α (PGI2) | 0.07, p = 0.034 | 0.36 | 1.31 | ||
IR | 15.8, p = 0.027 | 0.38 | 1.31 | ||
Cxcr4 (log) | (Constant) | −0.11 | R2 = 0.376; F = 19.9, p < 0.0001 | ||
IR | 0.50, p < 0.001 | 0.61 | 1.00 | ||
Sdf1 (log) | (Constant) | 0.002 | R2 = 0.817; F = 46.1, p < 0.0001 | ||
Nox4 (log) | 0.16, p < 0.001 | 0.60 | 1.13 | ||
Vpac1 (log) | 0.40, p < 0.001 | 0.65 | 1.57 | ||
Nampt (log) | 0.62, p < 0.001 | 0.62 | 1.41 | ||
SDF1α | (Constant) | −12.8 | R2 = 0.436; F = 12.7, p < 0.001 | ||
LTB4 | 0.16, p = 0.028 | 0.37 | 1.54 | ||
PGD2 | 0.02, p = 0.030 | 0.37 | 1.54 | ||
Vpac1 (log) | (Constant) | 0.003 | R2 = 0.893; F = 85.8, p < 0.0001 | ||
Mdk (log) | 0.38, p < 0.001 | 0.82 | 1.27 | ||
Nox2 (log) | −0.18, p = 0.043 | −0.36 | 1.13 | ||
Sdf1 (log) | 0.62, p < 0.001 | 0.83 | 1.24 | ||
Vpac2 (log) | (Constant) | 0.17 | R2 = 0.231; F = 9.88, p = 0.004 | ||
IR | −0.78, p = 0.004 | −0.48 | 1.00 | ||
VIP | (Constant) | 200.0 | R2 = 0.388; F = 6.55, p = 0.002 | ||
PGE2 | −0.09, p = 0.073 | −0.32 | 1.13 | ||
3-BT | −1.95, p = 0.040 | −0.36 | 1.01 | ||
IR | −23.1, p = 0.021 | −0.40 | 1.12 | ||
Glp1r (log) | (Constant) | −0.02 | R2 = 0.829; F = 77.3, p < 0.0001 | ||
Nox1 (log) | 1.02, p < 0.001 | 0.89 | 1.10 | ||
Nox2 (log) | −0.67, p = 0.030 | −0.37 | 1.10 | ||
GLP1 | (Constant) | 49.9 | R2 = 0.315; F = 7.37, p = 0.002 | ||
IFNγ | −0.004, p =0.019 | −0.40 | 1.00 | ||
IR 1 | 14.4, p =0.006 | 0.47 | 1.00 |
Gene | Forward Sequence | Reverse Sequence |
---|---|---|
Gapdh | TGACTCTACCCACGG-CAAGTTCAA | ACGACATACTCAGCACCAG-CATCA |
Cxcr4 | GCTGGAGAGCGAGCATTG | TAGATGGTGGGCAGGAAGATCC |
Sdf1 | CTCAACACTCCAAACTGTGCCC | GTCCAGGTACTCTTGGATCCAC |
Pac1 | GGCTGTGCTGAGGCTCTATTTTG | AGGATGATGATGATGCCGATGA |
Vpac1 | GATGTGGGACAACCTCACCTG | TAACCATGAATGGGGGCAAAC |
Vpac2 | GGTGAGCAGCATCCACCCAG | TCACTAGTGCAGTTTTTGCTTA |
Glp1r | GGGTATCTGGCTGCATAAGGACAAC | AAGGATGGCTGAAGCGATGAC |
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Krzystek-Korpacka, M.; Fleszar, M.G.; Fortuna, P.; Gostomska-Pampuch, K.; Lewandowski, Ł.; Piasecki, T.; Kosyk, B.; Szeląg, A.; Trocha, M. Modulation of Prostanoids Profile and Counter-Regulation of SDF-1α/CXCR4 and VIP/VPAC2 Expression by Sitagliptin in Non-Diabetic Rat Model of Hepatic Ischemia-Reperfusion Injury. Int. J. Mol. Sci. 2021, 22, 13155. https://doi.org/10.3390/ijms222313155
Krzystek-Korpacka M, Fleszar MG, Fortuna P, Gostomska-Pampuch K, Lewandowski Ł, Piasecki T, Kosyk B, Szeląg A, Trocha M. Modulation of Prostanoids Profile and Counter-Regulation of SDF-1α/CXCR4 and VIP/VPAC2 Expression by Sitagliptin in Non-Diabetic Rat Model of Hepatic Ischemia-Reperfusion Injury. International Journal of Molecular Sciences. 2021; 22(23):13155. https://doi.org/10.3390/ijms222313155
Chicago/Turabian StyleKrzystek-Korpacka, Małgorzata, Mariusz G. Fleszar, Paulina Fortuna, Kinga Gostomska-Pampuch, Łukasz Lewandowski, Tomasz Piasecki, Bogna Kosyk, Adam Szeląg, and Małgorzata Trocha. 2021. "Modulation of Prostanoids Profile and Counter-Regulation of SDF-1α/CXCR4 and VIP/VPAC2 Expression by Sitagliptin in Non-Diabetic Rat Model of Hepatic Ischemia-Reperfusion Injury" International Journal of Molecular Sciences 22, no. 23: 13155. https://doi.org/10.3390/ijms222313155