Abstract
Rutaecarpine (RUT) is a bioactive alkaloid isolated from the fruit of Evodia rutaecarpa that exerts a cellular protective effect. However, its protective effects on endothelial cells and its mechanism of action are still unclear. In this study, we demonstrated the effects of RUT on nitric oxide (NO) synthesis via endothelial nitric oxide synthase (eNOS) phosphorylation in endothelial cells and the underlying molecular mechanisms. RUT treatment promoted NO generation by increasing eNOS phosphorylation. Additionally, RUT induced an increase in intracellular Ca2+ concentration and phosphorylation of Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ), AMP-activated protein kinase (AMPK), and Ca2+/calmodulin-dependent kinase II (CaMKII). Inhibition of transient receptor potential vanilloid type 1 (TRPV1) attenuated RUT-induced intracellular Ca2+ concentration and phosphorylation of CaMKII, CaMKKβ, AMPK, and eNOS. Treatment with KN-62 (a CaMKII inhibitor), Compound C (an AMPK inhibitor), and STO-609 (a CaMKKβ inhibitor) suppressed RUT-induced eNOS phosphorylation and NO generation. Interestingly, RUT attenuated the expression of ICAM-1 and VCAM-1 induced by TNF-α and inhibited the inflammation-related NF-κB signaling pathway. Taken together, these results suggest that RUT promotes NO synthesis and eNOS phosphorylation via the Ca2+/CaMKII and CaM/CaMKKβ/AMPK signaling pathways through TRPV1. These findings provide evidence that RUT prevents endothelial dysfunction and benefit cardiovascular health.
Highlights
Endothelial activation maintains vascular homeostasis via the release of various vasoactive substances, including nitric oxide (NO) [1]
These results indicate that TRPV1 activation leads to the phosphorylation of calmodulin-dependent protein kinase kinase β (CaMKKβ), calmodulin-dependent kinase II (CaMKII), and AMPactivated protein kinase (AMPK), which is required for RUT-induced endothelial nitric oxide synthase (eNOS) phosphorylation and NO generation
These results indicate that TRPV1 activation leads to the that both CaMKII and CaMKKβ/AMPK signaling pathways are crucial upstream kinases phosphorylation of CaMKKβ, CaMKII, and AMPK, which is required for RUT-induced of RUT-induced eNOS phosphorylation and NO generation
Summary
Endothelial activation maintains vascular homeostasis via the release of various vasoactive substances, including nitric oxide (NO) [1]. NO, a biomolecule that plays a physiologically protective role, is synthesized by endothelial NO synthase (eNOS) from the amino acid L-arginine in endothelial cells [2]. In the endothelium, NO exhibits a vascular protective effect through various actions such as inhibition of the adhesion and migration of immune cells, as well as aggregation and thrombosis of platelets [3]. The production of NO through eNOS activation in vascular endothelium should be taken into consideration in studies regarding the treatment and prevention of vascular disease, including atherosclerosis. 2021, 22, 9407 should be taken into consideration in studies regarding the treatment and prevention of vascular disease, including atherosclerosis Sci. 2021, 22, 9407 should be taken into consideration in studies regarding the treatment and prevention of vascular disease, including atherosclerosis
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