Home
|
Inbox
|
Search
|
View Abstract
SU5416 Plus Hypoxia but Not Selective VEGFR2 Inhibition with Cabozantinib Plus Hypoxia Induces Pulmonary Hypertension in Rats: Potential Role of BMPR2 Signaling
Description
.abstract img { width:300px !important; height:auto; display:block; text-align:center; margin-top:10px } .abstract { overflow-x:scroll } .abstract table { width:100%; display:block; border:hidden; border-collapse: collapse; margin-top:10px } .abstract td, th { border-top: 1px solid #ddd; padding: 4px 8px; } .abstract tbody tr:nth-child(even) td { background-color: #efefef; } .abstract a { overflow-wrap: break-word; word-wrap: break-word; }
A7674 - SU5416 Plus Hypoxia but Not Selective VEGFR2 Inhibition with Cabozantinib Plus Hypoxia Induces Pulmonary Hypertension in Rats: Potential Role of BMPR2 Signaling
Author Block: R. Sitapara, C. Sugarragchaa, L. Zisman; Pulmokine Inc., Rensselaer, NY, United States.
Background: SU5416 plus chronic hypoxia is known to cause pronounced pulmonary arterial hypertension (PAH) with angio-obliterative lesions in rodents. This effect is assumed to be primarily through VEGF receptor (VEFGR) inhibition. SU5416 inhibits VEGFR2 with an IC50 of 1230nM (solubilized membrane assay) whereas Cabozantinib inhibits VEGFR2 with an IC50 of 0.035nM (invitro kinase assay). We, therefore, hypothesized that Cabozantinib plus hypoxia would induce severe pulmonary hypertension in rats.Methods: Male SD rats were given SU5416 (20mg/kg) or the highly selective VEGFR2 inhibitor Cabozantinib (20mg/kg) via SC injection or Alzet osmotic pump, and housed in a hypoxia chamber at FiO2 10% for 3 weeks. Right ventricular hemodynamics and RV hypertrophy ((RVH) (RV/ (LV+IVS))) were evaluated at 14 and 28d after the end of hypoxia exposure. SU5416 was screened for inhibitor activity against 468 human kinases using KINOMEscan™ Profiling (DiscoverX). Inhibitor binding constants (Kd) of SU5416 and Cabozantinib for BMPR2 were determined by KdELECT Assay. Results: Selective inhibition of VEGFR2 using Cabozantinib (SC injection) plus hypoxia did not induce severe PAH. Right ventricular systolic pressure (RVSP) measured at 14 and 28d post hypoxia was 36.8±2.3 mmHg and 36.2±3.4 mmHg respectively, compared to 27.5±1.5 mmHg in a normal control group. When Cabozantinib was given at a continuous rate of 17.8µg/hr using an Alzet osmotic pump for 14days while in hypoxia, RVSP was 40.0 ± 3.1 mm Hg at 14d and 27.9 ± 1.9 mm Hg 28d after removal from hypoxia. Consistent with its known effect, SU5416 plus hypoxia exposure induced severe PAH (RVSP of 61.9 ± 6.1 and 64.9 ± 8.4 mm Hg at 14d and 28d post removal from hypoxia, respectively). Cabozantinib via SC injection or Alzet osmotic pump induced less RVH at 14d post hypoxia compared to SU5416 (RV/(IVS+LV): 0.38±0.01 or 0.37±0.02 vs. 0.60±0.04). To understand potential off target effects of SU5416, a KINOMEscan™ Profile against 468 human kinases was performed, which revealed SU5416 to be an inhibitor of BMPR2. A KdELECT Assay was performed to compare the inhibitor binding constant (Kd) of SU5416 and Cabozantinib for BMPR2. SU5416 had a Kd of 2.1µM where was Cabozantinib failed to inhibit BMPR2 up to >10µM. Conclusion: Selective inhibition of VEGFR2 using Cabozantinib plus hypoxia did not induce severe PAH. Severe PAH due to SU5416 plus hypoxia may be due to combined VEGFR2 and BMPR2 inhibition.
Author Block: R. Sitapara, C. Sugarragchaa, L. Zisman; Pulmokine Inc., Rensselaer, NY, United States.
Background: SU5416 plus chronic hypoxia is known to cause pronounced pulmonary arterial hypertension (PAH) with angio-obliterative lesions in rodents. This effect is assumed to be primarily through VEGF receptor (VEFGR) inhibition. SU5416 inhibits VEGFR2 with an IC50 of 1230nM (solubilized membrane assay) whereas Cabozantinib inhibits VEGFR2 with an IC50 of 0.035nM (invitro kinase assay). We, therefore, hypothesized that Cabozantinib plus hypoxia would induce severe pulmonary hypertension in rats.Methods: Male SD rats were given SU5416 (20mg/kg) or the highly selective VEGFR2 inhibitor Cabozantinib (20mg/kg) via SC injection or Alzet osmotic pump, and housed in a hypoxia chamber at FiO2 10% for 3 weeks. Right ventricular hemodynamics and RV hypertrophy ((RVH) (RV/ (LV+IVS))) were evaluated at 14 and 28d after the end of hypoxia exposure. SU5416 was screened for inhibitor activity against 468 human kinases using KINOMEscan™ Profiling (DiscoverX). Inhibitor binding constants (Kd) of SU5416 and Cabozantinib for BMPR2 were determined by KdELECT Assay. Results: Selective inhibition of VEGFR2 using Cabozantinib (SC injection) plus hypoxia did not induce severe PAH. Right ventricular systolic pressure (RVSP) measured at 14 and 28d post hypoxia was 36.8±2.3 mmHg and 36.2±3.4 mmHg respectively, compared to 27.5±1.5 mmHg in a normal control group. When Cabozantinib was given at a continuous rate of 17.8µg/hr using an Alzet osmotic pump for 14days while in hypoxia, RVSP was 40.0 ± 3.1 mm Hg at 14d and 27.9 ± 1.9 mm Hg 28d after removal from hypoxia. Consistent with its known effect, SU5416 plus hypoxia exposure induced severe PAH (RVSP of 61.9 ± 6.1 and 64.9 ± 8.4 mm Hg at 14d and 28d post removal from hypoxia, respectively). Cabozantinib via SC injection or Alzet osmotic pump induced less RVH at 14d post hypoxia compared to SU5416 (RV/(IVS+LV): 0.38±0.01 or 0.37±0.02 vs. 0.60±0.04). To understand potential off target effects of SU5416, a KINOMEscan™ Profile against 468 human kinases was performed, which revealed SU5416 to be an inhibitor of BMPR2. A KdELECT Assay was performed to compare the inhibitor binding constant (Kd) of SU5416 and Cabozantinib for BMPR2. SU5416 had a Kd of 2.1µM where was Cabozantinib failed to inhibit BMPR2 up to >10µM. Conclusion: Selective inhibition of VEGFR2 using Cabozantinib plus hypoxia did not induce severe PAH. Severe PAH due to SU5416 plus hypoxia may be due to combined VEGFR2 and BMPR2 inhibition.
|
Home
|
Inbox
|
Search
|