Rac1 Pharmacological Inhibition Rescues Human Endothelial Dysfunction

Abstract

BackgroundEndothelial dysfunction contributes significantly to the development of vascular diseases. However, a therapy able to reduce this derangement still needs to be identified. We evaluated the effects of pharmacological inhibition of Rac1, a small GTPase protein promoting oxidative stress, in human endothelial dysfunction.Methods and ResultsWe performed vascular reactivity studies to test the effects of NSC23766, a Rac1 inhibitor, on endothelium‐dependent vasorelaxation of saphenous vein segments collected from 85 subjects who had undergone surgery for venous insufficiency and from 11 patients who had undergone peripheral vascular surgery. The endothelium‐dependent vasorelaxation of the varicose segments of saphenous veins collected from patients with venous insufficiency was markedly impaired and was also significantly lower than that observed in control nonvaricose vein tracts from the same veins. Rac1 activity, reactive oxygen species levels, and reduced nicotine adenine dinucleotide phosphate (NADPH) oxidase activity were significantly increased in varicose veins, and NSC23766 was able to significantly improve endothelium‐dependent vasorelaxation of dysfunctional saphenous vein portions in a nitric oxide–dependent manner. These effects were paralleled by a significant reduction of NADPH oxidase activity and activation of endothelial nitric oxide synthase. Finally, we further corroborated this data by demonstrating that Rac1 inhibition significantly improves venous endothelial function and reduces NADPH oxidase activity in saphenous vein grafts harvested from patients with vascular diseases undergoing peripheral bypass surgery.ConclusionsRac1 pharmacological inhibition rescues endothelial function and reduces oxidative stress in dysfunctional veins. Rac1 inhibition may represent a potential therapeutic intervention to reduce human endothelial dysfunction and subsequently vascular diseases in various clinical settings.

Rac1 Modulates Endothelial Function and Platelet Aggregation in Diabetes Mellitus

“…Although previous studies have suggested a reduction in eNOS expression after Rac1 inhibition,36 the modulation of Rac1 activity by NSC23766 in our study was not related to changes in its expression in both mouse vessels and human endothelial cells. Moreover, we were recently able to demonstrate that Rac1 inhibition by NSC23766 exerts a beneficial effect also in human vessels, ameliorating endothelial dysfunction 16. These results pointed out the important role of Rac1 as a therapeutic target to improve vascular homeostasis.…”

“…Moreover, we were recently able to demonstrate that Rac1 inhibition by NSC23766 exerts a beneficial effect also in human vessels, ameliorating endothelial dysfunction. 16 These results pointed out the important role of Rac1 as a therapeutic target to improve vascular homeostasis. Levay et al 27 have demonstrated an effect of NSC23766 as nonselective competitive antagonist of muscarinic acetylcholine receptors in neonatal rat cardiomyocytes.…”

“…NSC23766 has been shown to inhibit Rac1 activity by interfering with its binding domain involved in the determination of Rac1's specificity to a subset of guanine nucleotide exchange factors that catalyze the exchange of GDP to GTP to maintain Rac1 in its active, GTP‐bound, form 14, 15. Recently, we have shown the beneficial effects of Rac1 inhibition through NSC23766 on endothelial dysfunction in human vessels 16. However, the mechanisms by which NSC23766 exerts its protective role on endothelial function in hyperglycemia are still partially unknown.…”

“…14,15 Recently, we have shown the beneficial effects of Rac1 inhibition through NSC23766 on endothelial dysfunction in human vessels. 16 However, the mechanisms by which NSC23766 exerts its protective role on endothelial function in hyperglycemia are still partially unknown.…”

Qiliqiangxin attenuates hypoxia‐induced injury in primary rat cardiac microvascular endothelial cells via promoting HIF‐1α‐dependent glycolysis

“…2 Hypoxia-induced CMECs injury is considered as an initiating process and pathological basis of various cardiovascular diseases, 3 and protecting CMECs from hypoxia insult might thus be an important therapeutic strategy for treating various cardiovascular diseases. 4 Hypoxia can insult various endothelial cell biological activities such as cell growth, survival, migration and energy metabolism, which may lead to angiogenesis impairment, redundant reactive oxygen species (ROS) generation, mitochondrial dysfunction and energy metabolism disturbance to some extent.…”