Shear stress activation of nuclear receptor PXR in endothelial detoxification

Abstract

Endothelial cells (ECs) are constantly exposed to xenobiotics and endobiotics or their metabolites, which perturb EC function, as well as to shear stress, which plays a crucial role in vascular homeostasis. Pregnane X receptor (PXR) is a nuclear receptor and a key regulator of the detoxification of xeno-and endobiotics. Here we show that laminar shear stress (LSS), the atheroprotective flow, activates PXR in ECs, whereas oscillatory shear stress, the atheroprone flow, suppresses PXR. LSS activation of PXR in cultured ECs led to the increased expression of a PXR target gene, multidrug resistance 1 (MDR1). An in vivo study using rats showed that the expression of MDR1 was significantly higher in the endothelium from the descending thoracic aorta, where flow is mostly laminar, than from the inner curvature of aortic arch, where flow is disturbed. Functionally, LSSactivated PXR protects ECs from apoptosis triggered by doxorubicin via the induction of MDR1 and other detoxification genes. PXR also suppressed the expression of proinflammatory adhesion molecules and monocyte adhesion in response to TNF-α and lipopolysaccharide. Overexpression of a constitutively active PXR in rat carotid arteries potently attenuated proinflammatory responses. In addition, cDNA microarray revealed a large number of the PXR-activated endothelial genes whose products are responsible for major steps of detoxification, including phase I and II metabolizing enzymes and transporters. These detoxification genes in ECs are induced by LSS in ECs in a PXR-dependent manner. In conclusion, our results indicate that PXR represents a flow-activated detoxification system to protect ECs against damage by xeno-and endobiotics.hemodynamics | endothelial homeostasis | nuclear hormone receptor | gene regulation

P-glycoprotein expression and localization in the rat uterus throughout gestation and labor

“…A number of studies have reported that Abcb1 gene expression can be regulated by various factors such as steroid hormones (Nuessler et al 1997, Nakayama et al 1999, cellular membrane stretch (Sardini et al 1994, Wang et al 2013, and inflammation (Salkeni et al 2009, Poller et al 2010, Gibson et al 2012. P4 is the major regulatory hormone of pregnancy, essential for the maintenance of pregnancy and uterine growth (Thijssen 2005).…”

Nuclear Receptors in Vascular Biology

“…Through PXR activation vascular tissue was able to convert the inactive pro-drug clopidogrel to its active metabolite [5]. A number of these findings were recently confirmed in vitro and in vivo [40] and extended to show that PXR activity is up-regulated in regions of laminar shear stress (athero-protected) but depressed with oscillatory shear stress (proatherogenic) in the mouse [40].…”

Roles of Xenobiotic Receptors in Vascular Pathophysiology

“…98 Recently, the IL-8 receptor (IL8R), also known sion of proinflammatory adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and endothelial leukocyte adhesion molecule-1 (ELAM-1, otherwise known as E-selectin) in response to tumor necrosis factor-α (TNF-α) and lipopolysaccharide (LPS) in ECs. 53 Overexpression of a constitutively active PXR in rat carotid arteries also potently attenuated proinflammatory responses. 53 PXR is also expressed in classical immunocytes including monocytes/macrophages and lymphocytes (both T and B cells) and inhibits inflammation.…”

“…17 The circulation can be a hostile milieu, with increased concentrations of xenobiotics and endobiotics resulting from drugs, chemical agents, smoking, air pollution, nutritional metabolites, and pathogenic microbes or their toxins. 53 These circulating endogenous and foreign chemicals can contribute to vascular dysfunction and the development of vascular disease. 54 Recent studies have demonstrated that PXR is not only expressed in the liver and intestine and its role in detoxification is not liver and intestine specific.…”