Antiangiogenic
tyrosine kinases inhibitors induce
hypertension, which may increase the incidents of cardiovascular complications and limit their use. However, the mechanisms by which usage of TKIs results in
hypertension have not been fully understood. Here, we report the potential mechanisms of how
sunitinib, a widely used TKI, induces
hypertension. Male SD rats were randomly divided into control group and
sunitinib-administrated group. We show that
sunitinib administration for seven days caused a significant increase in artery blood pressure, along with glycerolipid metabolism abnormalities including decreased food intake and low
body weight,
hypoglycemia,
hyperinsulinemia.
Sunitinib administration also resulted in a significant increase in the levels of
insulin autoantibody (IAA), cyclic
adenosine monophosphate and
free fatty acid in serum; whereas,
sunitinib administration had no effects on serum
glucagon levels.
Sunitinib led to the decreased
insulin sensitivity as determined by
insulin tolerance test (ITT) and
glucose tolerance test (GTT), reflecting
insulin resistance occurred in
sunitinib-treated rats. The results obtained from wire myograph assay in the mesenteric arteries show that endothelium-dependent relaxation, but not endothelium-independent relaxation, was impaired by
sunitinib. Furthermore, western blot analysis revealed that the expressions levels of phosphorylated IRS-1, Pellino-1, AKT and eNOS were significantly attenuated by
sunitinib in rat mesenteric artery tissues and in the
sunitinib-treated primary cultured mesenteric artery endothelial cells. The levels of serum and
endothelium-derived nitric oxide were also significantly decreased by
sunitinib. Moreover,
sunitinib-induced decrease in the expression levels of phosphorylated AKT and eNOS was further reduced by knocking down of Pellino-1 in MAECs. Our results suggest that
sunitinib causes vascular dysfunction and
hypertension, which are associated with
insulin resistance- and Pellino-1-mediated inhibition of AKT/eNOS/NO signaling. Our results may provide a rational for preventing and/or treating
sunitinib-induced endothelial dysfunction and
hypertension.