Microbial short chain fatty acid metabolites lower blood pressure via endothelial G protein-coupled receptor 41
Microbial short chain fatty acid metabolites lower blood pressure via endothelial G protein-coupled receptor 41
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DOI：
10.1152/physiolgenomics.00089.2016
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发表时间：
2016-11-01
影响因子：
4.6
通讯作者：
Pluznick, Jennifer L.
中科院分区：
文献类型：
--
作者：
Natarajan, Niranjana;Hori, Daijiro;Pluznick, Jennifer L.
短链脂肪酸（SCFA）代谢产物是肠道微生物代谢的副产物，已知其通过宿主G蛋白偶联受体（GPCR）影响宿主生理学。我们以前表明，急性SCFA推注降低麻醉小鼠的血压（BP），主要通过Gpr 41介导的效果。在这项研究中，我们的目的是确定Gpr 41的细胞定位，并确定其在BP调节中的作用。我们使用RT-PCR将Gpr 41定位于血管内皮：Gpr 41在完整的血管（有内皮）中检测到，但在裸露的血管（无内皮）中不存在。此外，使用压力肌造影术，我们证实SCFAs以内皮依赖性方式扩张阻力血管。由于我们先前发现Gpr 41介导对急性SCFA给药的过度反应，因此我们假设Gpr 41敲除（KO）小鼠会患高血压。在这里，我们报告说，Gpr 41基因敲除小鼠与野生型（WT）小鼠相比，有孤立的收缩期高血压，舒张压之间没有差异WT和KO。年龄较大的Gpr 41 KO小鼠也表现出脉搏波速度升高，与收缩期高血压的表型一致;然而，离体主动脉硬度没有增加（通过机械拉伸试验测量）。KO和WT小鼠的血浆肾素浓度也相似。Gpr 41 KO中的收缩期高血压不是盐敏感性的，因为它在高盐或低盐饮食中没有显著改变。总之，这些研究表明，内皮Gpr 41降低基线BP，可能是通过降低主动血管张力而不改变血管的被动特征，并且Gpr 41 KO小鼠具有血管源性高血压。
Short chain fatty acid (SCFA) metabolites are byproducts of gut microbial metabolism that are known to affect host physiology via host G proteincoupled receptor (GPCRs). We previously showed that an acute SCFA bolus decreases blood pressure (BP) in anesthetized mice, an effect mediated primarily via Gpr41. In this study, our aims were to identify the cellular localization of Gpr41 and to determine its role in BP regulation. We localized Gpr41 to the vascular endothelium using RT-PCR: Gpr41 is detected in intact vessels (with endothelium) but is absent from denuded vessels (without endothelium). Furthermore, using pressure myography we confirmed that SCFAs dilate resistance vessels in an endothelium-dependent manner. Since we previously found that Gpr41 mediates a hypotensive response to acute SCFA administration, we hypothesized that Gpr41 knockout (KO) mice would be hypertensive. Here, we report that Gpr41 KO mice have isolated systolic hypertension compared with wild-type (WT) mice; diastolic BP was not different between WT and KO. Older Gpr41 KO mice also exhibited elevated pulse wave velocity, consistent with a phenotype of systolic hypertension; however, there was no increase in ex vivo aorta stiffness (measured by mechanical tensile testing). Plasma renin concentrations were also similar in KO and WT mice. The systolic hypertension in Gpr41 KO is not salt sensitive, as it is not significantly altered on either a high-or low-salt diet. In sum, these studies suggest that endothelial Gpr41 lowers baseline BP, likely by decreasing active vascular tone without altering passive characteristics of the blood vessels, and that Gpr41 KO mice have hypertension of a vascular origin.