The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Alleviates Endothelial Dysfunction Following In Vitro Vascular Ischemia/Reperfusion Injury in Rats
Abstract
:1. Introduction
2. Results
2.1. Aortic Vasoreactivity Following Vascular IRI
2.1.1. Effect of CANA on Endothelial Function after Vascular IRI
2.1.2. Effects of CANA on Smooth Muscle Relaxation after Vascular IRI
2.1.3. Effects of CANA on Contractility after Vascular IRI
2.2. Effects of CANA on Aortic Gene Expression Following Vascular IRI
2.3. Aortic Gene Expression Explored by Machine Learning Algorithms
2.4. Effects of CANA on Aortic Intercellular Adhesion Molecule (ICAM)-1, Platelet Endothelial Cell Adhesion Molecule (PECAM)-1, Nitrotyrosine, and Caspase-3 Immunoreactivity after Vascular IRI
3. Discussion
3.1. Mechanisms Underlying Protective Effects of CANA against IRI in Vasculature
3.2. Study Limitations
4. Materials and Methods
4.1. Animals
4.2. Rat Model of Vascular IRI
4.2.1. Preparation of Aortic Rings
4.2.2. Conservation of Aortic Rings and Experimental Groups
4.2.3. Ex Vivo Organ Baths Functional Experiments
4.3. Gene Expression Analysis
4.4. Machine Learning Algorithms
4.5. Immunohistochemical Staining for ICAM-1, PECAM-1, Nitrotyrosine, and Caspase-3
4.6. Canagliflozin
4.7. Data Analysis and Statistics
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Control | IR | IR + CANA | |
---|---|---|---|
PE (% of KCl) | 2.6 ± 0.2 | 2.5 ± 0.1 | 1.9 ± 0.1 *,# |
pD2 to PE | 6.77 ± 0.07 | 7.20 ± 0.14 * | 6.84 ± 0.06 # |
KCl (g) | 4.6 ± 0.2 | 1.2 ± 0.1 * | 2.1 ± 0.1 *,# |
Rmax to ACh (%) | 75.2 ± 2.3 | 31.7 ± 3.2 * | 51.9 ± 2.5 *,# |
pD2 to ACh | 7.35 ± 0.08 | 6.28 ± 0.15 * | 6.86 ± 0.09 *,# |
Rmax to SNP (%) | 99.4 ± 0.2 | 99.0 ± 0.6 | 100.0 ± 0.0 |
pD2 to SNP | 8.65 ± 0.06 | 7.97 ± 0.07 * | 8.49 ± 0.09 # |
IR vs. Control | IR + CANA vs. Control | IR + CANA vs. IR | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Symbol | p-Value | Regulation | Comments | Symbol | p-Value | Regulation | Comments | Symbol | p-Value | Regulation | Comments |
Aifm1 | 0.527 | 1.06 | Aifm1 | 0.277 | 1.09 | Aifm1 | 0.764 | 1.03 | |||
Apaf1 | 0.716 | 1.03 | Apaf1 | 0.361 | 1.06 | Apaf1 | 0.67 | 1.04 | |||
Bad | 0.059 | −1.17 | Bad | 0.894 | −1.01 | Bad | 0.05 | 1.16 | |||
Bak1 | 0.374 | −1.1 | Bak1 | 0.532 | −1.07 | Bak1 | 0.545 | 1.03 | |||
Bax | 0.023 | 1.1 | Bax | 0.168 | 1.06 | Bax | 0.259 | −1.04 | |||
Bcl2 | 0.123 | 1.06 | Bcl2 | 0.791 | −1.00 | Bcl2 | 0.071 | −1.06 | |||
Bcl2L1 | 0.321 | 1.09 | Bcl2L1 | 0.453 | 1.08 | Bcl2L1 | 0.919 | −1.01 | |||
Bid | 0.068 | 1.83 | Bid | 0.252 | 1.41 | Bid | 0.041 | −1.29 | |||
Casp1 | 0.018 | −1.28 | Casp1 | 0.061 | −1.27 | Casp1 | 0.945 | 1.01 | |||
Casp12 | 0.055 | 1.18 | Casp12 | 0.229 | 1.11 | Casp12 | 0.241 | −1.07 | |||
Casp3 | 0.256 | 1.1 | Casp3 | 0.247 | 1.11 | Casp3 | 0.91 | 1.01 | |||
Casp4 | 0.146 | 1.18 | Casp4 | 0.156 | 1.19 | Casp4 | 0.814 | 1.01 | |||
Casp6 | 0.276 | 1.17 | Casp6 | 0.863 | −1.03 | Casp6 | 0.191 | −1.21 | |||
Casp7 | 0.607 | 1.06 | Casp7 | 0.026 | 1.26 | Casp7 | 0.128 | 1.19 | |||
Casp8 | 0.461 | 1.08 | Casp8 | 0.059 | 1.20 | Casp8 | 0.266 | 1.1 | |||
Casp9 | 0.74 | −1.03 | Casp9 | 0.44 | 1.07 | Casp9 | 0.272 | 1.1 | |||
Cat | 0.767 | 1.14 | B | Cat | 0.818 | −1.10 | B | Cat | 0.581 | −1.25 | B |
Ccl11 | 0.171 | 1.64 | Ccl11 | 0.841 | 1.07 | Ccl11 | 0.246 | −1.52 | |||
Ccl12 | 0 | 8.55 | Ccl12 | 0 | 10.09 | Ccl12 | 0.658 | 1.18 | |||
Ccl2 | 0 | 24.21 | Ccl2 | 0 | 21.75 | Ccl2 | 0.53 | −1.11 | |||
Ccl20 | 0.787 | −1.01 | C | Ccl20 | 0.137 | −1.08 | C | Ccl20 | 0.089 | −1.06 | C |
Ccl3 | 0.003 | 71.33 | Ccl3 | 0.003 | 75.18 | Ccl3 | 0.73 | 1.05 | |||
Ccl4 | 0 | 34.85 | Ccl4 | 0 | 36.45 | Ccl4 | 0.806 | 1.05 | |||
Ccl5 | 0.011 | −2.81 | Ccl5 | 0.012 | −2.82 | Ccl5 | 0.985 | −1 | |||
Ccr1 | 0.153 | −4.21 | Ccr1 | 0.028 | −1.65 | Ccr1 | 0.326 | 2.55 | |||
Ccr2 | 0.461 | −1.18 | Ccr2 | 0.776 | −1.05 | Ccr2 | 0.556 | 1.12 | |||
Ccs | 0.113 | −1.22 | Ccs | 0.163 | −1.1 | Ccs | 0.349 | 1.11 | |||
Cd40 | 0.004 | 2.13 | Cd40 | 0.04 | 1.6 | Cd40 | 0.206 | −1.34 | |||
cd40lg | 0.281 | −1.56 | B | cd40lg | 0.882 | −1.07 | B | cd40lg | 0.428 | 1.46 | B |
Cflar | 0.894 | 1.01 | Cflar | 0.675 | 1.02 | Cflar | 0.885 | 1.01 | |||
CxCr4 | 0 | 4.47 | CxCr4 | 0 | 3.37 | CxCr4 | 0.144 | −1.32 | |||
Cyba | 0.092 | 1.07 | Cyba | 0.281 | 1.1 | Cyba | 0.706 | 1.03 | |||
cycs | 0.825 | 1.02 | cycs | 0.972 | 1 | cycs | 0.807 | −1.01 | |||
Duox1 | 0.998 | −1 | B | Duox1 | 0.666 | −1.1 | B | Duox1 | 0.798 | −1.09 | B |
Edn1 | 0.002 | 2.44 | Edn1 | 0.017 | 2.06 | Edn1 | 0.556 | −1.19 | |||
Epx | 0.746 | 1.06 | Epx | 0.587 | 1.1 | Epx | 0.806 | 1.04 | |||
Fadd | 0.954 | −1 | Fadd | 0.955 | −1 | Fadd | 0.978 | 1 | |||
Fas | 0.973 | −1.01 | B | Fas | 0.081 | −1.87 | B | Fas | 0.06 | −1.85 | B |
Faslg | 0.926 | 1.02 | Faslg | 0.932 | −1.02 | Faslg | 0.877 | −1.05 | |||
Flt1 | 0.143 | −1.22 | Flt1 | 0.242 | −1.09 | Flt1 | 0.352 | 1.12 | |||
Fos | 0 | 51.6 | Fos | 0 | 54.88 | Fos | 0.348 | 1.06 | |||
Gpx1 | 0.738 | 1.02 | Gpx1 | 0.065 | 1.11 | Gpx1 | 0.054 | 1.09 | |||
Gpx2 | 0.279 | 2.01 | B | Gpx2 | 0.144 | 2.12 | B | Gpx2 | 0.922 | 1.06 | B |
Gpx3 | 0.696 | 1.05 | Gpx3 | 0.909 | 1.01 | Gpx3 | 0.678 | −1.04 | |||
Gpx4 | 0.697 | 1.02 | Gpx4 | 0.748 | 1.01 | Gpx4 | 0.897 | −1 | |||
Gpx5 | 0.428 | −1.09 | B | Gpx5 | 0.198 | −1.17 | B | Gpx5 | 0.089 | −1.06 | C |
Gpx6 | 0.787 | −1.01 | C | Gpx6 | 0.137 | −1.08 | C | Gpx6 | 0.089 | −1.06 | C |
Gpx7 | 0.647 | 1.03 | Gpx7 | 0.286 | 1.08 | Gpx7 | 0.453 | 1.05 | |||
Gstk1 | 0.305 | 1.11 | Gstk1 | 0.453 | 1.07 | Gstk1 | 0.655 | −1.04 | |||
Hspa1a | 0 | 4.63 | A | Hspa1a | 0 | 5.65 | A | Hspa1a | 0.376 | 1.22 | |
Icam1 | 0 | 4.34 | Icam1 | 0 | 3.66 | Icam1 | 0.233 | −1.19 | |||
Il10 | 0 | 35.06 | A | Il10 | 0 | 38.69 | A | Il10 | 0.63 | −1.1 | |
Il18 | 0.817 | 1.03 | Il18 | 0.316 | −1.16 | Il18 | 0.306 | −1.2 | |||
Il1a | 0 | 210.71 | A | Il1a | 0 | 138.48 | A | Il1a | 0.193 | −1.52 | |
Il1b | 0 | 28.95 | Il1b | 0 | 24.13 | Il1b | 0.386 | −1.2 | |||
Il6 | 0 | 95.21 | Il6 | 0 | 53.87 | Il6 | 0.086 | −1.77 | |||
Il7 | 0.238 | −1.38 | Il7 | 0.693 | 1.08 | Il7 | 0.099 | 1.48 | |||
Il9 | 0.381 | −1.22 | B | Il9 | 0.659 | −1.12 | B | Il9 | 0.591 | 1.09 | B |
Itgb2 | 0.028 | −1.44 | Itgb2 | 0.015 | −1.55 | Itgb2 | 0.668 | −1.08 | |||
Jun | 0.005 | 1.34 | Jun | 0.027 | 1.31 | Jun | 0.813 | −1.02 | |||
Ncf1 | 0.827 | 1.03 | Ncf1 | 0.136 | −1.12 | Ncf1 | 0.247 | −1.16 | |||
Nfkb1 | 0.046 | 1.11 | Nfkb1 | 0.074 | 1.11 | Nfkb1 | 0.96 | −1 | |||
Nos2 | 0.891 | −1.08 | B | Nos2 | 0.686 | 1.29 | B | Nos2 | 0.567 | 1.39 | B |
Nox4 | 0.023 | 1.35 | Nox4 | 0.372 | 1.11 | Nox4 | 0.14 | −1.21 | |||
Noxo1 | 0.127 | −1.9 | B | Noxo1 | 0.036 | −2.27 | B | Noxo1 | 0.674 | −1.2 | B |
Prdx1 | 0.239 | 1.12 | Prdx1 | 0.376 | 1.09 | Prdx1 | 0.178 | −1.03 | |||
Prdx2 | 0.01 | 1.23 | Prdx2 | 0.026 | 1.21 | Prdx2 | 0.593 | −1.02 | |||
Prdx3 | 0.099 | 1.19 | Prdx3 | 0.088 | 1.21 | Prdx3 | 0.841 | 1.01 | |||
Prdx4 | 0.179 | 1.09 | Prdx4 | 0.027 | 1.14 | Prdx4 | 0.49 | 1.05 | |||
Sele | 0 | 8.3 | A | Sele | 0 | 9.81 | A | Sele | 0.644 | 1.18 | |
Slc5a1 | 0.241 | −1.23 | B | Slc5a1 | 0.847 | −1.06 | B | Slc5a1 | 0.516 | 1.16 | B |
Sod1 | 0.352 | −1.09 | Sod1 | 0.948 | −1.01 | Sod1 | 0.234 | 1.09 | |||
Sod2 | 0.005 | 1.32 | Sod2 | 0.001 | 1.33 | Sod2 | 0.991 | 1 | |||
Sod3 | 0 | 1.24 | Sod3 | 0.002 | 1.36 | Sod3 | 0.217 | 1.1 | |||
Tgfb1 | 0.129 | 1.11 | Tgfb1 | 0.176 | 1.09 | Tgfb1 | 0.764 | −1.02 | |||
Tlr1 | 0.082 | −1.49 | Tlr1 | 0.183 | −1.27 | Tlr1 | 0.468 | 1.18 | |||
Tlr4 | 0.83 | 1.03 | Tlr4 | 0.284 | 1.19 | Tlr4 | 0.267 | 1.16 | |||
Tlr6 | 0.095 | −1.23 | Tlr6 | 0.131 | −1.16 | Tlr6 | 0.575 | 1.06 | |||
Tnf | 0 | 17.56 | Tnf | 0 | 14.7 | Tnf | 0.483 | −1.19 | |||
Tnfrsf12a | 0.947 | 1.01 | Tnfrsf12a | 0.609 | −1.1 | Tnfrsf12a | 0.462 | −1.12 | |||
Tollip | 0.06 | 1.1 | Tollip | 0.027 | 1.2 | Tollip | 0.204 | 1.1 | |||
Tp53 | 0.051 | 3.7 | B | Tp53 | 0.076 | 4.79 | B | Tp53 | 0.762 | 1.3 | B |
Txn1 | 0.202 | 1.05 | Txn1 | 0.386 | 1.03 | Txn1 | 0.437 | −1.02 | |||
Txnrd1 | 0 | 1.28 | Txnrd1 | 0 | 1.34 | Txnrd1 | 0.325 | 1.05 | |||
Txnrd2 | 0.428 | 1.04 | Txnrd2 | 0.773 | 1.02 | Txnrd2 | 0.772 | −1.02 | |||
Vcam1 | 0.011 | 1.73 | Vcam1 | 0.024 | 1.75 | Vcam1 | 0.934 | 1.01 | |||
Vegfc | 0.156 | 1.24 | Vegfc | 0.154 | 1.26 | Vegfc | 0.87 | 1.02 | |||
Xiap | 0.381 | 1.1 | Xiap | 0.14 | 1.21 | Xiap | 0.116 | 1.09 |
Name/Gene ID/Symbol | Gene Name/Description (for Rattus Norvegicus (=Wistar rat)) |
---|---|
Aifm1 | apoptosis inducing factor, mitochondria associated 1 |
Apaf1 | apoptotic peptidase activating factor 1 |
Bad | BCL2-associated agonist of cell death |
Bak1 | BCL2-antagonist/killer 1 |
Bax | BCL2 associated X, apoptosis regulator |
Bcl2 | BCL2, apoptosis regulator |
Bcl2L1 | Bcl2-like 1 |
Bid | BH3 interacting domain death agonist |
Casp1 | caspase 1 |
Casp12 | caspase 12 |
Casp3 | caspase 3 |
Casp4 | caspase 4 |
Casp6 | caspase 6 |
Casp7 | caspase 7 |
Casp8 | caspase 8 |
Casp9 | caspase 9 |
Cat | catalase |
Ccl11 | C-C motif chemokine ligand 11 |
Ccl12 | chemokine (C-C motif) ligand 12 |
Ccl2 | C-C motif chemokine ligand 2 |
Ccl20 | C-C motif chemokine ligand 20 |
Ccl3 | C-C motif chemokine ligand 3 |
Ccl4 | C-C motif chemokine ligand 4 |
Ccl5 | C-C motif chemokine ligand 5 |
Ccr1 | C-C motif chemokine receptor 1 |
Ccr2 | C-C motif chemokine receptor 2 |
Ccs | copper chaperone for superoxide dismutase |
Cd40 | CD40 molecule |
cd40lg | CD40 ligand |
Cflar | CASP8 and FADD-like apoptosis regulator |
CxCr4 | C-X-C motif chemokine receptor 4 |
Cyba | cytochrome b-245 alpha chain |
cycs | cytochrome c, somatic |
Duox1 | dual oxidase 1 |
Edn1 | endothelin 1 |
Epx | eosinophil peroxidase |
Fadd | Fas associated via death domain |
Fas | Fas cell surface death receptor |
Faslg | Fas ligand |
Flt1 | Fms related receptor tyrosine kinase 1 |
Fos | Fos proto-oncogene, AP-1 transcription factor subunit |
Gpx1 | glutathione peroxidase 1 |
Gpx2 | glutathione peroxidase 2 |
Gpx3 | glutathione peroxidase 3 |
Gpx4 | glutathione peroxidase 4 |
Gpx5 | glutathione peroxidase 5 |
Gpx6 | glutathione peroxidase 6 |
Gpx7 | glutathione peroxidase 7 |
Gstk1 | glutathione S-transferase kappa 1 |
Hspa1a | heat shock protein family A (Hsp70) member 1A |
Icam1 | intercellular adhesion molecule 1 |
Il10 | interleukin 10 |
Il18 | interleukin 18 |
Il1a | interleukin 1 alpha |
Il1b | interleukin 1 beta |
Il6 | interleukin 6 |
Il7 | interleukin 7 |
Il9 | interleukin 9 |
Itgb2 | integrin subunit beta 2 |
Jun | Jun proto-oncogene, AP-1 transcription factor subunit |
Ncf1 | neutrophil cytosolic factor 1 |
Nfkb1 | nuclear factor kappa B subunit 1 |
Nos2 | nitric oxide synthase 2 |
Nox4 | NADPH oxidase 4 |
Noxo1 | NADPH oxidase organizer 1 |
Prdx1 | peroxiredoxin 1 |
Prdx2 | peroxiredoxin 2 |
Prdx3 | peroxiredoxin 3 |
Prdx4 | peroxiredoxin 4 |
Sele | selectin E |
Slc5a1 | solute carrier family 5 member 1 |
Sod1 | superoxide dismutase 1 |
Sod2 | superoxide dismutase 2 |
Sod3 | superoxide dismutase 3 |
Tgfb1 | transforming growth factor, beta 1 |
Tlr1 | toll-like receptor 1 |
Tlr4 | toll-like receptor 4 |
Tlr6 | toll-like receptor 6 |
Tnf | tumor necrosis factor |
Tnfrsf12a | TNF receptor superfamily member 12A |
Tollip | toll interacting protein |
Tp53 | tumor protein p53 |
Txn1 | thioredoxin 1 |
Txnrd1 | thioredoxin reductase 1 |
Txnrd2 | thioredoxin reductase 2 |
Vcam1 | vascular cell adhesion molecule 1 |
Vegfc | vascular endothelial growth factor C |
Xiap | X-linked inhibitor of apoptosis |
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Korkmaz-Icöz, S.; Kocer, C.; Sayour, A.A.; Kraft, P.; Benker, M.I.; Abulizi, S.; Georgevici, A.-I.; Brlecic, P.; Radovits, T.; Loganathan, S.; et al. The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Alleviates Endothelial Dysfunction Following In Vitro Vascular Ischemia/Reperfusion Injury in Rats. Int. J. Mol. Sci. 2021, 22, 7774. https://doi.org/10.3390/ijms22157774
Korkmaz-Icöz S, Kocer C, Sayour AA, Kraft P, Benker MI, Abulizi S, Georgevici A-I, Brlecic P, Radovits T, Loganathan S, et al. The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Alleviates Endothelial Dysfunction Following In Vitro Vascular Ischemia/Reperfusion Injury in Rats. International Journal of Molecular Sciences. 2021; 22(15):7774. https://doi.org/10.3390/ijms22157774
Chicago/Turabian StyleKorkmaz-Icöz, Sevil, Cenk Kocer, Alex A. Sayour, Patricia Kraft, Mona I. Benker, Sophia Abulizi, Adrian-Iustin Georgevici, Paige Brlecic, Tamás Radovits, Sivakkanan Loganathan, and et al. 2021. "The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Alleviates Endothelial Dysfunction Following In Vitro Vascular Ischemia/Reperfusion Injury in Rats" International Journal of Molecular Sciences 22, no. 15: 7774. https://doi.org/10.3390/ijms22157774