Therapeutic Potential of Sunitinib in Ameliorating Endothelial Dysfunction in Type 2 Diabetic Rats

Ali Mahdi; Tong Jiao; Yahor Tratsiakovich; Bernhard Wernly; Jiangning Yang; Claes Göran Östenson; A. H.Jan Danser; John Pernow; Zhichao Zhou

doi:10.1159/000520728

Therapeutic Potential of Sunitinib in Ameliorating Endothelial Dysfunction in Type 2 Diabetic Rats

Ali Mahdi, Tong Jiao, Yahor Tratsiakovich, Bernhard Wernly, Jiangning Yang, Claes Göran Östenson, A. H.Jan Danser, John Pernow, Zhichao Zhou^*

^*Corresponding author for this work

Internal Medicine

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Introduction: Sunitinib, a multi-targeted tyrosine kinase receptor inhibitor used to treat renal-cell carcinoma and gastrointestinal stromal tumor, was recently shown to have a beneficial effect on metabolism in type 2 diabetes (T2D). Endothelial dysfunction is a key factor behind macro- and microvascular complications in T2D. The effect of sunitinib on endothelial function in T2D remains, however, unclear. We therefore tested the hypothesis that sunitinib ameliorates endothelial dysfunction in T2D. Methods: Sunitinib (2 mg/kg/day, by gavage) was administered to T2D Goto-Kakizaki (GK) rats for 6 weeks, while water was given to GK and Wistar rats as controls. Hemodynamic, inflammatory, and metabolic parameters as well as endothelial function were measured. Results: Systolic, mean arterial blood pressures, plasma tumor necrosis factor α levels, kidney weight to body weight (BW) ratio, and glucose levels were higher, while BW was lower in GK rats than in Wistar rats. Six-week treatment with sunitinib in GK rats did not affect these parameters but suppressed the increase in glucose levels. Endothelium-dependent relaxations were reduced in both aortas and mesenteric arteries isolated from GK as compared to Wistar rats, which was markedly reversed in both types of arteries from GK rats treated with sunitinib. Conclusions: This study demonstrates that sunitinib has a glucose-lowering effect and ameliorates endothelial dysfunction in both conduit and resistance arteries of GK rats.

Original language	English
Pages (from-to)	160-166
Number of pages	7
Journal	Pharmacology
Volume	107
Issue number	3
DOIs	https://doi.org/10.1159/000520728
Publication status	Published - 1 Mar 2022

Bibliographical note

Funding Information:
This study was supported by the Swedish Heart and Lung Foundation (20190341 and 20200326 to Z.Z. and 20190266 to J.P.), the Loo and Hans Ostermans Foundation (2018-01213 and 2020-01209 to Z.Z.), the Karolinska Institute Grant (2018-01837 and 2020-01473) (to Z.Z.), the Lars Hiertas Minne Foundation (FO2018-0156 to Z.Z.), the Eva and Oscar Ahréns Foundation (2021-1233 to Z.Z.), the Swedish Research Council (2020-01372 to J.P.), the Diabetes Research Wellness Foundation (720-1519-16 and 363-PG to J.P.), the Stockholm County Council ALF (20190031 to J.P.), and the EFSD/Sanofi European Diabetes Research Programme in Macrovascular Complications (to J.P.).

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title = "Therapeutic Potential of Sunitinib in Ameliorating Endothelial Dysfunction in Type 2 Diabetic Rats",

abstract = "Introduction: Sunitinib, a multi-targeted tyrosine kinase receptor inhibitor used to treat renal-cell carcinoma and gastrointestinal stromal tumor, was recently shown to have a beneficial effect on metabolism in type 2 diabetes (T2D). Endothelial dysfunction is a key factor behind macro- and microvascular complications in T2D. The effect of sunitinib on endothelial function in T2D remains, however, unclear. We therefore tested the hypothesis that sunitinib ameliorates endothelial dysfunction in T2D. Methods: Sunitinib (2 mg/kg/day, by gavage) was administered to T2D Goto-Kakizaki (GK) rats for 6 weeks, while water was given to GK and Wistar rats as controls. Hemodynamic, inflammatory, and metabolic parameters as well as endothelial function were measured. Results: Systolic, mean arterial blood pressures, plasma tumor necrosis factor α levels, kidney weight to body weight (BW) ratio, and glucose levels were higher, while BW was lower in GK rats than in Wistar rats. Six-week treatment with sunitinib in GK rats did not affect these parameters but suppressed the increase in glucose levels. Endothelium-dependent relaxations were reduced in both aortas and mesenteric arteries isolated from GK as compared to Wistar rats, which was markedly reversed in both types of arteries from GK rats treated with sunitinib. Conclusions: This study demonstrates that sunitinib has a glucose-lowering effect and ameliorates endothelial dysfunction in both conduit and resistance arteries of GK rats.",

author = "Ali Mahdi and Tong Jiao and Yahor Tratsiakovich and Bernhard Wernly and Jiangning Yang and {\"O}stenson, {Claes G{\"o}ran} and Danser, {A. H.Jan} and John Pernow and Zhichao Zhou",

note = "Funding Information: This study was supported by the Swedish Heart and Lung Foundation (20190341 and 20200326 to Z.Z. and 20190266 to J.P.), the Loo and Hans Ostermans Foundation (2018-01213 and 2020-01209 to Z.Z.), the Karolinska Institute Grant (2018-01837 and 2020-01473) (to Z.Z.), the Lars Hiertas Minne Foundation (FO2018-0156 to Z.Z.), the Eva and Oscar Ahr{\'e}ns Foundation (2021-1233 to Z.Z.), the Swedish Research Council (2020-01372 to J.P.), the Diabetes Research Wellness Foundation (720-1519-16 and 363-PG to J.P.), the Stockholm County Council ALF (20190031 to J.P.), and the EFSD/Sanofi European Diabetes Research Programme in Macrovascular Complications (to J.P.). Publisher Copyright: {\textcopyright} 2021 ",

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T1 - Therapeutic Potential of Sunitinib in Ameliorating Endothelial Dysfunction in Type 2 Diabetic Rats

AU - Mahdi, Ali

AU - Jiao, Tong

AU - Tratsiakovich, Yahor

AU - Wernly, Bernhard

AU - Yang, Jiangning

AU - Östenson, Claes Göran

AU - Danser, A. H.Jan

AU - Pernow, John

AU - Zhou, Zhichao

N1 - Funding Information: This study was supported by the Swedish Heart and Lung Foundation (20190341 and 20200326 to Z.Z. and 20190266 to J.P.), the Loo and Hans Ostermans Foundation (2018-01213 and 2020-01209 to Z.Z.), the Karolinska Institute Grant (2018-01837 and 2020-01473) (to Z.Z.), the Lars Hiertas Minne Foundation (FO2018-0156 to Z.Z.), the Eva and Oscar Ahréns Foundation (2021-1233 to Z.Z.), the Swedish Research Council (2020-01372 to J.P.), the Diabetes Research Wellness Foundation (720-1519-16 and 363-PG to J.P.), the Stockholm County Council ALF (20190031 to J.P.), and the EFSD/Sanofi European Diabetes Research Programme in Macrovascular Complications (to J.P.). Publisher Copyright: © 2021

PY - 2022/3/1

Y1 - 2022/3/1

N2 - Introduction: Sunitinib, a multi-targeted tyrosine kinase receptor inhibitor used to treat renal-cell carcinoma and gastrointestinal stromal tumor, was recently shown to have a beneficial effect on metabolism in type 2 diabetes (T2D). Endothelial dysfunction is a key factor behind macro- and microvascular complications in T2D. The effect of sunitinib on endothelial function in T2D remains, however, unclear. We therefore tested the hypothesis that sunitinib ameliorates endothelial dysfunction in T2D. Methods: Sunitinib (2 mg/kg/day, by gavage) was administered to T2D Goto-Kakizaki (GK) rats for 6 weeks, while water was given to GK and Wistar rats as controls. Hemodynamic, inflammatory, and metabolic parameters as well as endothelial function were measured. Results: Systolic, mean arterial blood pressures, plasma tumor necrosis factor α levels, kidney weight to body weight (BW) ratio, and glucose levels were higher, while BW was lower in GK rats than in Wistar rats. Six-week treatment with sunitinib in GK rats did not affect these parameters but suppressed the increase in glucose levels. Endothelium-dependent relaxations were reduced in both aortas and mesenteric arteries isolated from GK as compared to Wistar rats, which was markedly reversed in both types of arteries from GK rats treated with sunitinib. Conclusions: This study demonstrates that sunitinib has a glucose-lowering effect and ameliorates endothelial dysfunction in both conduit and resistance arteries of GK rats.

AB - Introduction: Sunitinib, a multi-targeted tyrosine kinase receptor inhibitor used to treat renal-cell carcinoma and gastrointestinal stromal tumor, was recently shown to have a beneficial effect on metabolism in type 2 diabetes (T2D). Endothelial dysfunction is a key factor behind macro- and microvascular complications in T2D. The effect of sunitinib on endothelial function in T2D remains, however, unclear. We therefore tested the hypothesis that sunitinib ameliorates endothelial dysfunction in T2D. Methods: Sunitinib (2 mg/kg/day, by gavage) was administered to T2D Goto-Kakizaki (GK) rats for 6 weeks, while water was given to GK and Wistar rats as controls. Hemodynamic, inflammatory, and metabolic parameters as well as endothelial function were measured. Results: Systolic, mean arterial blood pressures, plasma tumor necrosis factor α levels, kidney weight to body weight (BW) ratio, and glucose levels were higher, while BW was lower in GK rats than in Wistar rats. Six-week treatment with sunitinib in GK rats did not affect these parameters but suppressed the increase in glucose levels. Endothelium-dependent relaxations were reduced in both aortas and mesenteric arteries isolated from GK as compared to Wistar rats, which was markedly reversed in both types of arteries from GK rats treated with sunitinib. Conclusions: This study demonstrates that sunitinib has a glucose-lowering effect and ameliorates endothelial dysfunction in both conduit and resistance arteries of GK rats.

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Therapeutic Potential of Sunitinib in Ameliorating Endothelial Dysfunction in Type 2 Diabetic Rats

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