Caveolae Depletion Contributes to Vasorelaxant Effects of Chenodeoxycholic Acid

Abstract

Background/Aims: High concentration of bile acids (BAs) induces hydrophobicity-dependent vasorelaxtant effects with hydrophobic BAs showing greater responses than hydrophilic BAs, of which the underlying mechanisms are still unclear. Caveolae are invaginations on membranes of endothelial cells (ECs) entraping endothelial nitric oxide synthase (eNOS) to prevent its activation, which plays a critical role in regulation of vascular function. The purpose of the present study was to investigate the role of caveolae in vasorelaxant effects of BAs. Methods: Chenodeoxycholic acid (CDCA) and cholic acid (CA) were used to represent hydrophobic and hydrophilic BA, respectively. Vascular responses of abdominal aorta were measured by isometric force recording. Morphology of caveolae was examined by transmission electron microscopy. Protein expression of total eNOS (t-eNOS) or phosphorylated eNOS (p-eNOS) was determined by Western blot. Nitric oxide (NO) content was observed by fluorometric assay. Results: We demonstrated that CDCA as well as Methyl-β-cyclodextrin (MCD), a commonly used reagent for cholesterol depletion, reduced potassium chloride (KCl)- or phenylephrine (PE)-elicited vasoconstriction (P < 0.05), and enhanced acetylcholine (Ach)-elicited vasodilatation (P < 0.05) in endothelium-intact abdominal aorta but not in endothelium-denuded or CA-treated vessels. CDCA and MCD, but not CA significantly disrupted caveolae structure on ECs of abdominal aorta which was recovered by cholesterol incubation (P < 0.05). Protein expression of t-eNOS was significantly decreased (P < 0.05), and that of p-eNOS together with NO content was significantly increased in CDCA- and MCD- but not CA-treated vessels (P < 0.05) as compared with vehicle. The effect was reversed by either endothelium-denudation or cholesterol replenishment. Moreover, with cholesterol incubation, no significant differences were found in vascular responses among CDCA-, CA- or vehicle-treated vessels. Conclusion: These results indicate that CDCA diminishes caveolae on ECs of abdominal aorta promoting eNOS phosphorylation and NO production which contributes to its vasorelaxtant effect.

Detection of Vasodilators From Herbal Components by a Transcriptome-Based Functional Gene Module Reference Approach

“…Among them, ferulic acid, borneol, and daidzin had strong relaxant effects [Emax (% Phe) > 80%, Table 1 ], which is in accordance with previous findings (Suzuki et al, 2007; Deng et al, 2012; Silva-Filho et al, 2012; Zhao et al, 2014; Zhou et al, 2017; Santos et al, 2019). Magnolol, artemisinin, and chenodeoxycholic acid elicited a moderate relaxation [Emax (% Phe) > 50%, Table 1 ], also consistent with the reports of the previous studies (Teng et al, 1990; Li et al, 2005; Seok et al, 2012; Wang et al, 2017). In addition, our work first reported the vasorelaxant effects of four herbal compounds, liquiritin, ginsenoside Rc, bacopaside I, and ginsenoside Rb2, although the effect is low (Emax (% Phe) < 30%, Table 1 ).…”

Revealing the Angiopathy of Lacrimal Gland Lesion in Type 2 Diabetes

“…However, whether ambroxol could improve diabetic vasculopathy remains unclear. CDCA was reported to promote eNOS phosphorylation and NO production that contributes to its vasorelaxant effect (Wang et al, 2017 ). Babu PV reported that genistein can improve diabetes-caused vascular inflammation by suppressing diabetes-induced adhesion of monocytes to endothelial cells and endothelial secretion of adhesion molecules (Babu et al, 2012 ).…”

Substance P Hinders Bile Acid-Induced Hepatocellular Injury by Modulating Oxidative Stress and Inflammation

“…Constant BA stimulation promotes cell apoptosis, which results from oxidative stress with increased reactive oxygen species (ROS) generation [8]. Moreover, BA-damaged hepatocytes produce high levels of inflammatory cytokines, including interleukin (IL)-1β, IL-8, and tumor necrosis factor-α [9][10][11][12][13].…”