The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Directly Enhances the Contractile Recovery of Mouse Hearts at a Concentration Equivalent to that Achieved with Standard Dosing in Humans
Abstract
:1. Introduction
2. Results
2.1. When Perfused at A Concentration Equivalent to Human Cmax, Linagliptin Enhances the Contractile Recovery of Mouse Hearts after Ischemia Reperfusion
2.2. Linagliptin Enhances the Contractile Recovery of The Hearts of Aged, Diabetic High Fat Diet-Fed Mice
2.3. Linagliptin Induces Phosphorylation of the Cardiomyocyte Ca2+ Handling Protein Phospholamban
2.4. Linagliptin Directly Induces Intracellular Signaling in Endothelial Cells and Indirectly Induces Intracellular Signaling in Cardiomyocytes
3. Discussion
4. Materials and Methods
4.1. Isolated Heart Perfusion Study 1
4.2. Isolated Heart Perfusion Study 2
4.3. Cell Culture
4.4. Immunoblotting
4.5. Immunohistochemistry
4.6. RNA Sequencing
4.7. Statistics
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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LVDP (cmH2O) | dP/dtmax (cmH2O × ms−1) | dP/dtmin (cmH2O × ms−1) | Heart Rate (bpm) | ||||||
---|---|---|---|---|---|---|---|---|---|
n | Baseline | R40 | Baseline | R40 | Baseline | R40 | Baseline | R40 | |
Vehicle | 19 | 94 ± 32 | 21 ± 16 | 3493 ± 1527 | 1268 ± 904 | −2821 ± 979 | −1127 ± 746 | 278 ± 86 | 348 ± 89 |
Linagliptin | 23 | 95 ± 35 | 42 ± 32 a | 3957 ± 1957 | 2426 ± 2025 | −2762 ± 1080 | −1782 ± 1207 | 306 ± 77 | 377 ± 90 |
Sitagliptin | 23 | 84 ± 29 | 21 ± 16 b | 4058 ± 2317 | 1667 ± 1188 | −2706 ± 1063 | −1335 ± 840 | 277 ± 95 | 340 ± 89 |
Alogliptin | 22 | 88 ± 43 | 20 ± 18 b | 4134 ± 2722 | 1492 ± 1077 | −2930 ± 1486 | −1289 ± 908 | 294 ± 97 | 331 ± 87 |
Saxagliptin | 20 | 90 ± 36 | 23 ± 18 c | 3898 ± 2522 | 1765 ± 1632 | −2765 ± 1158 | −1297 ± 894 | 300 ± 109 | 332 ± 121 |
LVDP (cmH2O) | dP/dtmax (cmH2O × ms−1) | dP/dtmin (cmH2O × ms−1) | Heart Rate (bpm) | ||||||
---|---|---|---|---|---|---|---|---|---|
n | Baseline | R40 | Baseline | R40 | Baseline | R40 | Baseline | R40 | |
Age-matched control + Vehicle | 17 | 101 ± 30 | 25 ± 19 | 3777 ± 1913 | 1274 ± 1011 | −2600 ± 960 | −1295 ± 1240 | 275 ± 101 | 337 ± 98 |
DM-HFD + Vehicle | 15 | 90 ± 27 | 21 ± 14 | 3433 ± 1021 | 1266 ± 796 | −2541 ± 604 | −1152 ± 692 | 295 ± 83 | 293 ± 139 |
DM-HFD + Linagliptin | 18 | 103 ± 22 | 38 ± 16 ab | 3951 ± 1856 | 1920 ± 1295 | −2763 ± 946 | −1639 ± 1521 | 288 ± 87 | 327 ± 86 |
DM-HFD + Sitagliptin | 14 | 81 ± 39 | 14 ± 11 c | 3139 ± 1894 | 1065 ± 870 | −2156 ± 1143 | −913 ± 760 | 311 ± 91 | 320 ± 108 |
DM-HFD + Alogliptin | 17 | 83 ± 28 | 20 ± 19 d | 3422 ± 2024 | 1212 ± 949 | −2483 ± 1361 | −1313 ± 1475 | 297 ± 114 | 362 ± 148 |
DM-HFD + Saxagliptin | 15 | 81 ± 15 | 15 ± 11 c | 3219 ± 1620 | 1156 ± 1099 | −2251 ± 993 | −957 ± 842 | 278 ± 94 | 321 ± 135 |
DM-HFD + 5-hydroxy saxagliptin | 15 | 69 ± 54 | 14 ± 11 ac | 2578 ± 2275 | 805 ± 871 | −1744 ± 1393 aef | −672 ± 732 | 237 ± 73 | 317 ± 106 |
DM-HFD + GLP-1 | 18 | 96 ± 39 | 21 ± 17 e | 3929 ± 1486 | 1400 ± 937 | −2981 ± 839 gh | −1287 ± 758 | 311 ± 93 | 346 ± 91 |
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Batchu, S.N.; Yerra, V.G.; Liu, Y.; Advani, S.L.; Klein, T.; Advani, A. The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Directly Enhances the Contractile Recovery of Mouse Hearts at a Concentration Equivalent to that Achieved with Standard Dosing in Humans. Int. J. Mol. Sci. 2020, 21, 5756. https://doi.org/10.3390/ijms21165756
Batchu SN, Yerra VG, Liu Y, Advani SL, Klein T, Advani A. The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Directly Enhances the Contractile Recovery of Mouse Hearts at a Concentration Equivalent to that Achieved with Standard Dosing in Humans. International Journal of Molecular Sciences. 2020; 21(16):5756. https://doi.org/10.3390/ijms21165756
Chicago/Turabian StyleBatchu, Sri Nagarjun, Veera Ganesh Yerra, Youan Liu, Suzanne L. Advani, Thomas Klein, and Andrew Advani. 2020. "The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Directly Enhances the Contractile Recovery of Mouse Hearts at a Concentration Equivalent to that Achieved with Standard Dosing in Humans" International Journal of Molecular Sciences 21, no. 16: 5756. https://doi.org/10.3390/ijms21165756