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Pharmacological inhibition of Axl affects smooth muscle cell functions under oxidative stress.
Vascul Pharmacol. 2010 Sep-Oct; 53(3-4):185-92.VP

Abstract

We previously demonstrated that reactive oxygen species (ROS) activate Axl, a receptor tyrosine kinase, resulting in increased survival of rat aortic smooth muscle cells (RASMs). Our experiments in Axl knockout mice showed significant reduction in vascular pathologies. We hypothesize that selective pharmacological inhibitors of Axl could prove beneficial in treating vascular diseases associated with oxidative stress. We investigated a role for two novel compounds specific for Axl (R428 and R572) on ligand independent activation of Axl mediated cell survival and migration. Stimulation of RASMs with H(2)O(2) for 5 min significantly increased Akt phosphorylation (p-Akt). Inhibition at 50% (IC(50)) of p-Akt was calculated at lower concentrations in R428 (100 nM) and R572 (10 nM) compared to Fc-Axl (2 microg/mL). Flow cytometry staining with Annexin V showed a 2-fold increase in apoptosis with R428 and R572 compared to Fc-Axl after H(2)O(2), which was validated by concomitant increases in cleaved caspase-3. Pretreatment with R428 and R572 decreased cell migration by approximately 50% in response to 20% serum (similar to that after Fc-Axl). R428 and R572 decreased intracellular production of ROS in comparison to Fc-Axl. In conclusion, R428 and R572 are more potent inhibitors of ligand independent mediated Axl signaling compared to Fc-Axl in RASMs under oxidative stress.

Authors+Show Affiliations

Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20643227

Citation

Smolock, E M., and V A. Korshunov. "Pharmacological Inhibition of Axl Affects Smooth Muscle Cell Functions Under Oxidative Stress." Vascular Pharmacology, vol. 53, no. 3-4, 2010, pp. 185-92.
Smolock EM, Korshunov VA. Pharmacological inhibition of Axl affects smooth muscle cell functions under oxidative stress. Vascul Pharmacol. 2010;53(3-4):185-92.
Smolock, E. M., & Korshunov, V. A. (2010). Pharmacological inhibition of Axl affects smooth muscle cell functions under oxidative stress. Vascular Pharmacology, 53(3-4), 185-92. https://doi.org/10.1016/j.vph.2010.07.002
Smolock EM, Korshunov VA. Pharmacological Inhibition of Axl Affects Smooth Muscle Cell Functions Under Oxidative Stress. Vascul Pharmacol. 2010 Sep-Oct;53(3-4):185-92. PubMed PMID: 20643227.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological inhibition of Axl affects smooth muscle cell functions under oxidative stress. AU - Smolock,E M, AU - Korshunov,V A, Y1 - 2010/07/16/ PY - 2010/04/16/received PY - 2010/06/17/revised PY - 2010/07/13/accepted PY - 2010/7/21/entrez PY - 2010/7/21/pubmed PY - 2010/12/30/medline SP - 185 EP - 92 JF - Vascular pharmacology JO - Vascul. Pharmacol. VL - 53 IS - 3-4 N2 - We previously demonstrated that reactive oxygen species (ROS) activate Axl, a receptor tyrosine kinase, resulting in increased survival of rat aortic smooth muscle cells (RASMs). Our experiments in Axl knockout mice showed significant reduction in vascular pathologies. We hypothesize that selective pharmacological inhibitors of Axl could prove beneficial in treating vascular diseases associated with oxidative stress. We investigated a role for two novel compounds specific for Axl (R428 and R572) on ligand independent activation of Axl mediated cell survival and migration. Stimulation of RASMs with H(2)O(2) for 5 min significantly increased Akt phosphorylation (p-Akt). Inhibition at 50% (IC(50)) of p-Akt was calculated at lower concentrations in R428 (100 nM) and R572 (10 nM) compared to Fc-Axl (2 microg/mL). Flow cytometry staining with Annexin V showed a 2-fold increase in apoptosis with R428 and R572 compared to Fc-Axl after H(2)O(2), which was validated by concomitant increases in cleaved caspase-3. Pretreatment with R428 and R572 decreased cell migration by approximately 50% in response to 20% serum (similar to that after Fc-Axl). R428 and R572 decreased intracellular production of ROS in comparison to Fc-Axl. In conclusion, R428 and R572 are more potent inhibitors of ligand independent mediated Axl signaling compared to Fc-Axl in RASMs under oxidative stress. SN - 1879-3649 UR - https://www.unboundmedicine.com/medline/citation/20643227/Pharmacological_inhibition_of_Axl_affects_smooth_muscle_cell_functions_under_oxidative_stress_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1537-1891(10)00109-6 DB - PRIME DP - Unbound Medicine ER -