Effect of N-arachidonoyl- l -serine on human cerebromicrovascular endothelium

Abstract

N-arachidonoyl-l-serine (ARA-S) is an endogenous lipid, chemically related to the endocannabinoid, N-arachidonoyl ethanolamine (i.e., anandamide) and with similar physiologic and pathophysiologic functions. Reports indicate that ARA-S possesses vasoactive and neuroprotective properties resembling those of cannabinoids. However, in contrast to cannabinoids, ARA-S binds weakly to its known classical receptors, CB1 and CB2, and is therefore considered to be a ‘cannabinoid-like’ substance. The originally described ARA-S induced-endothelial-dependent vasorelaxation was not abrogated by CB1, CB2 receptor antagonists or TRPV1 competitive inhibitor. The present report demonstrates that ARA-S enhances the fluorescence staining of both cannabinoid receptors (CB1 and CB2) in human brain endothelial cells (HBEC). This reaction is specific since it was reduced by respective selective receptor antagonist (SR141716A and SR141728A). ARA-S alone or in the presence of ET-1 was shown to alter the cytoskeleton (actin). Both ARA-S stimulated phosphorylation of various kinases (MAPK, Akt, JNK and c-JUN) and alteration of cytoskeleton are mediated via CB1, CB2 and TRPV1 receptors. The findings also showed the involvement of Rho/Rock and PI3/Akt/NO pathways in the ARA-S-induced phosphorylation of kinases and actin reorganization in HBEC. All of the above mentioned ARA-S-induced effects were reduced by the treatment with LY294002 (inhibitor of PI3/Akt kinase), except MAPK kinase. In addition, MAPK, JNK, c-JUN phosphorylation were inhibited by H1152 (inhibitor of Rho/ROCK kinase), except Akt kinase. Furthermore, PI3/Akt pathway was inhibited by pretreatment with l-NAME (inhibitor of NOS). The findings suggest that ARA-S is a modulator of Rho kinase and may play a critical role in the regulation of its activity and subsequent effects on the cytoskeleton and its role in supporting essential cell functions like vasodilation, proliferation and movement.

Lipidomics reveals altered biosynthetic pathways of glycerophospholipids and cell signaling as biomarkers of the polycystic ovary syndrome

“…According to our results, this pathway could be differentially regulated in PCOS patients and affected at long-term during the natural history of the disease and be involved in infertility and pregnancy loss, two main clinical consequences of this pathology [ 63 , 64 ]. An interesting additional observation derived from our study is that free fatty acids (FFAs) are not differential lipid species between PCOS women and healthy control, in contrast to several previous metabolomics and lipidomics studies where systematic increases in free fatty acid contents are described [ 44 , 45 , 50 , 51 , 53 , 54 , 65 ]. FFAs are important for physiological homeostasis, providing a major portion of mammalian bioenergetics needs.…”

N-Acyl Amino Acids (Elmiric Acids): Endogenous Signaling Molecules with Therapeutic Potential

“…Subsequent studies of NASer on human brain endothelial cells described effects of this N-acyl amino acid on the cytoskeleton (actins) and on the signal transduction pathways that are involved (Kino et al, 2016). Interestingly, data were reported indicating the involvement of three receptors, CB1, CB2, and TRPV1.…”

Anti-Microbial Activity of Phytocannabinoids and Endocannabinoids in the Light of Their Physiological and Pathophysiological Roles

“…N-Arachidonoyl-L-serine (AraS) is an endogenous bioactive lipid found both in the central nervous system (CNS) and in the periphery, with a similar structure and physiological functions as AEA [385,386] (Figure 3). It possesses vasoactive, pro-angiogenic, pro-neurogenic, and neuroprotective properties [386][387][388].…”