Sunitinib Improves Endothelial Function in Type 2 Diabetic Rats
Authors: Zhou Zhichao , Mahdi Ali , Tratsiakovich Yahor , Jiao Tong , Yang Jiangning , Östenson Claes‐Göran , Danser A.H. Jan , Pernow John 
Published: June 2021

IntroductionPatients with various types of cancers have been treated with the tyrosine kinase inhibitor sunitinib. Recent clinical and experimental evidence have shown that sunitinib has potential in the treatment of type 2 diabetes (T2D) by inhibiting β cell loss and reducing glucose level. Endothelial dysfunction is a key factor behind macro‐ and microvascular complications in T2D. The beneficial effect of sunitinib on endothelial dysfunction in T2D remains unexplored, however. We therefore tested the hypothesis that long‐term treatment with low dose of sunitinib improves endothelial function in T2D.MethodsGoto Kakizaki (GK) rats at age of 10–12 weeks, a model that spontaneously develops T2D, were treated with either vehicle or sunitinib (2 mg/kg/day, by gavage) for 6 weeks. Age‐matched Wistar rats were used as controls. Blood glucose levels were measured at start and at the end of the treatment. Since sunitinib may increase blood pressure as a side effect, blood pressure was determined at the end of treatment by catheterization of carotid arteries in animals under anesthesia. Both conduit (aortas, AO) and resistance arteries (mesenteric arteries, MA) were isolated for determination of endothelium‐dependent relaxation (EDR) with acetylcholine (10−9–10−5 M) and endothelium‐independent relaxation (EIR) with sodium nitroprusside (10−5 M) using Wire Myographs.ResultsBoth systolic (SBP) and mean arterial blood pressures (MAP) were significantly higher in GK rats as compared to Controls (SBP/MAP: 154±4.5/133±5.3 mmHg in GK vs. 122±8.4/102±8.3 mmHg in Control; P<0.05). Blood pressure in GK rats was not affected by sunitinib treatment (SBP/MAP: 153±6.4/130±5.4 mmHg). Moreover, blood glucose level was higher in both GK+vehicle and GK+sunitinib groups than in Controls (7.7±0.9 mM in GK+vehicle and 8.0±0.7 mM in GK+sunitinib vs. 4.0±0.4 mM in Controls; P<0.05) at start of treatment. During treatment blood glucose level increased only in the GK+vehicle group (from 7.7±0.9 to 10±0.7 mM; P<0.01). Of note, EDR was reduced in both aortas and mesenteric arteries isolated from GK+vehicle group compared to Controls (AO/MA: −logEC50: 7.1±0.23/6.7±0.12 in GK vs. 8.4±0.14/7.2±0.08 in Controls; P<0.01). Interestingly, the impairment in EDR was markedly reversed in both types of arteries from GK rats treated with sunitinib (AO/MA: −logEC50: 7.6±0.09/7.7±0.07; P<0.001 in AO, P<0.05 in MA vs. GK+vehicle). EIR was comparable in both arterial preparations among the three groups.ConclusionsSunitinib reverses endothelial dysfunction in both conduit and resistance arteries of GK rats. Sunitinib blunts the increase in blood glucose level in GK rats. Sunitinib may act as an effective therapeutic tool for the treatment of endothelial dysfunction in T2D.Support or Funding Informationthe Loo and Hans Ostermans Foundation, the Sigurt and Elsa Goljes Memorial Foundation and the Swedish Heart and Lung Foundation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.