Insulin Resistance and Pellino-1 Mediated Decrease in the Activities of Vasodilator Signaling Contributes to...

Area of Science:

• Pharmacology
• Cardiovascular Research
• Endocrinology

Background:

• Tyrosine kinase inhibitors (TKIs) can induce hypertension, potentially leading to cardiovascular complications.
• The precise mechanisms underlying TKI-induced hypertension remain incompletely understood.
• Sunitinib is a widely used TKI with known hypertensive effects.

Purpose of the Study:

• To elucidate the mechanisms by which sunitinib induces hypertension and vascular dysfunction.
• To investigate the role of insulin resistance and the AKT/eNOS/NO signaling pathway in sunitinib-induced hypertension.

Main Methods:

• Male Sprague-Dawley rats were administered sunitinib or a placebo.
• Blood pressure, metabolic parameters, and serum markers were analyzed.
• Vascular function was assessed using wire myography.
• Western blot analysis was performed on mesenteric artery tissues and cells.
• Insulin sensitivity was evaluated through insulin tolerance and glucose tolerance tests.

Main Results:

• Sunitinib administration significantly increased blood pressure and induced metabolic abnormalities, including hypoglycemia and hyperinsulinemia.
• Insulin resistance was observed in sunitinib-treated rats.
• Endothelium-dependent relaxation of mesenteric arteries was impaired by sunitinib.
• Sunitinib decreased the expression of phosphorylated IRS-1, Pellino-1, AKT, and eNOS, and reduced nitric oxide levels.
• Knocking down Pellino-1 partially restored sunitinib-induced decreases in phosphorylated AKT and eNOS.

Conclusions:

• Sunitinib induces hypertension and vascular dysfunction linked to insulin resistance.
• The mechanism involves Pellino-1-mediated inhibition of the AKT/eNOS/NO signaling pathway.
• These findings offer insights for managing sunitinib-induced side effects.