Farnesoid X Receptor Activation Modulates Calcium Homeostasis in Rat Aortic Vascular Smooth Muscle Cells

Ran Zhang ； Liang Peng ； Haihong Ran ； Yongyan Fan ； Yu Zhao ； Feng Cao

《The Chinese Journal of Physiology》 61卷4期 (2018/08) Pp. 210-220

https://doi.org/10.4077/CJP.2018.BAG554

摘要

The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is expressed in the vasculature; our previous work showed that FXR regulated vascular reactivity through NO mechanism. The underlying mechanism for the regulation of vascular tension by FXR remains unclear. The present work was designed to investigate whether FXR regulates calcium homeostasis in aortic vascular smooth muscle cells (VSMCs). Protein abundances of angiotensin II type 1 and 2 receptors (AT_1R, AT_2R), bradykinin type 1 and 2 receptors (B_1R, B_2R), and the inositol 1,4,5-trisphosphate receptor (IP_3R) were analyzed by Western blotting. Kallikrein activity and bradykinin content were assayed by using spectrophotometry and a bradykinin assay kit, respectively. Aortic contraction, intracellular Ca^(2+) concentrations ([Ca^(2+)]_i), sarco/endoplasmic reticulum Ca^(2+) ATPase (SERCA) activities, and IP_3-evoked Ca^(2+) release were investigated, following FXR activation in the presence or absence of AT_2R and B_2R blockade. We found that the FXR agonists GW4064 and INT-747 increased the protein abundance of AT_2R and B_2R in rat aortic VSMCs. AT_2R blockade with PD123319 reversed the effects of FXR agonists on kallikrein activity, B2_R, and bradykinin levels. Moreover, we found that GW4064 and INT-747 decreased [Ca^(2+)]_i, increased SERCA activity, downregulated IP_3R_1 expression, and attenuated IP_3-induced Ca^(2+) release. These effects were partially reversed by AT_2R and B_2R blockade with PD123319 and HOE140, respectively. Our data suggest that FXR regulates vascular tension by modulating extracellular C^a(2+) influx and intracellular Ca^(2+) release from the sarcoplasmic reticulum via activation of an AT_2R-B_2R pathway in rat aortic VSMCs.

關鍵字

angiotensin II type 2 receptor ； bradykinin type 2 receptor ； calcium homeostasis ； farnesoid X receptor ； inositol 1,4,5-trisphosphate receptor ； sarco/endoplasmic reticulum Ca^(2+) ATPase

參考文獻

Amberg, G.C. and Navedo, M.F. Calcium dynamics in vascular smooth muscle. Microcirculation 20: 281-289, 2013.

Bishop-Bailey, D., Walsh, D.T. and Warner, T.D. Expression and activation of the farnesoid X receptor in the vasculature. Proc. Natl. Acad. Sci. USA 101: 3668-3673, 2004.

Fiorucci, S., Rizzo, G., Donini, A., Distrutti, E. and Santucci, L. Targeting farnesoid X receptor for liver and metabolic disorders. Trends Mol. Med. 13: 298-309, 2007.

Ghebremariam, Y.T., Yamada, K., Lee, J.C., Johnson, C.L, Atzler, D. and Anderssohn, M. FXR agonist INT-747 upregulates DDAH expression and enhances insulin sensitivity in high-salt fed Dahl rats. PLoS One 8: e60653, 2013.

Hanniman, E.A., Lambert, G., McCarthy, T.C. and Sinal, C.J. Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice. J. Lipid Res. 46: 2595-2604, 2005.