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Reducing NOX2-derived reactive oxygen species enhances endothelial cell migration and vascular repair in the context of endothelium-specific insulin resistance

Session Endothelial cells

Speaker Noman Ali

Event : ESC Congress 2016

  • Topic : basic science
  • Sub-topic : Basic Science - Vascular Biology and Physiology
  • Session type : Rapid Fire Abstracts

Authors : N Ali (Leeds,GB), N Yuldasheva (Leeds,GB), A Sengupta (Leeds,GB), P Patel (Leeds,GB), J Smith (Leeds,GB), A Walker (Leeds,GB), A Skromna (Leeds,GB), N Makava (Leeds,GB), S Galloway (Leeds,GB), A Aziz (Birmingham,GB), B Mercer (Leeds,GB), S Wheatcroft (Leeds,GB), M Kearney (Leeds,GB), R Cubbon (Leeds,GB)

N. Ali1 , N. Yuldasheva1 , A. Sengupta2 , P. Patel1 , J. Smith1 , A. Walker1 , A. Skromna1 , N. Makava1 , S. Galloway1 , A. Aziz3 , B. Mercer2 , S. Wheatcroft1 , M. Kearney1 , R. Cubbon1 , 1University of Leeds, DCDR - Leeds - United Kingdom , 2Leeds General Infirmary - Leeds - United Kingdom , 3Birmingham City Hospital - Birmingham - United Kingdom ,

European Heart Journal ( 2016 ) 37 ( Abstract Supplement ), 831

Background/Introduction: Insulin resistance is independently associated with cardiovascular risk, and oxidative stress is recognised as a potential contributor to this relationship. We have previously shown that endothelium-specific insulin resistance causes endothelial dysfunction via increased vascular NADPH oxidase 2 (NOX2) derived reactive oxygen species (ROS) generation. Oxidative stress may also promote vascular disease by impairing endogenous vascular repair.

Purpose: We hypothesised that reducing NOX2-derived ROS in the context of endothelial specific insulin resistance could improve vascular repair.

Methods: Mice expressing a kinase dead human insulin receptor transgene in the endothelium (ESMIRO) were bred with mice deficient in NOX2, in order to produce double-cross ESMIRO x NOX2y/- (ExN) offspring. Metabolic phenotype was assessed with glucose and insulin tolerance tests. In vivo assessment of vascular repair was undertaken using Evans' blue staining 5-days after femoral artery wire injury, whilst in vitro assessment of endothelial cell (EC) migration was defined in scratch wound assays of cultured pulmonary endothelial cells (PECs). PEC proliferation was defined by EdU incorporation. To complement murine studies, we silenced insulin receptor expression by 50% in human umbilical vein endothelial cells (HUVECs) using lentiviral shRNA transduction (scrambled shRNA serving as control). Pharmacological NOX2 inhibition using the specific NOX2 inhibitor GP91-ds tat (or scrambled peptide control) was then used in HUVEC scratch wound assays. HUVEC proliferation was assessed by EdU incorporation. Data are expressed as mean [standard error] and compared using appropriate t-tests; *=p<0.05.

Results: No significant differences were seen between ExN and ESMIRO in glucose or insulin tolerance. ExN mice demonstrated significantly improved vascular regeneration following injury compared to ESMIRO (62% [4%] vs. 46% [3%]*), coupled to significantly enhanced EC migration (extent of wound closure 50.3% [5%] vs. 31.3% [5]*), but unchanged proliferation. Use of the pharmacological NOX2 inhibitor GP91-ds tat in insulin resistant HUVECs also produced a significant improvement in EC migration (extent of wound closure 83.5% [3.8] vs. 74.0% [3.7]*), but did not alter proliferation.

Conclusion: Reducing NOX2-derived ROS can augment vascular repair in the setting of endothelial specific insulin resistance, possibly via enhanced EC migration. These findings support a possible role for NOX2 inhibitors to promote recovery from vascular injury in the setting of insulin resistance.

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