Suppression of Gut Bacterial Translocation Ameliorates Vascular Calcification through Inhibiting Toll-Like Receptor 9-Mediated BMP-2 Expression.

Yang Zhao,Li-Yan Cui,Wen-Zhe Si,Xian Wang,Wen Tang,Jia-Jia Zheng,Ming-Jiang Xu,Bo Liu,Yan Cai

doi:10.1155/2019/3415682

Abstract

Aims Vascular calcification (VC) is a primary risk factor for cardiovascular mortality in chronic renal failure (CRF) patients; thus, effective therapeutic targets are urgently needed to be explored. Here, we identified the role of intestinal bacterial translocation in CRF-related VC. Methods and Results Antibiotic supplementation by oral gavage significantly suppressed intestinal bacterial translocation, CRF-related VC, and aortic osteogenic gene and Toll-like receptor (TLR) gene expression in CRF rats. Furthermore, TLR4 and TLR9 activation in vascular smooth muscle cells (VSMCs) aggravated inorganic phosphate- (Pi-) induced calcification. TLR9 inhibition, but not TLR4 inhibition, by both a pharmacological inhibitor and genetic methods could significantly reduce CRF rats' serum or CRF-induced VC. Interestingly, bone morphogenic protein-2 (BMP-2) levels were increased in the aorta and sera from CRF rats. Increased BMP-2 levels were also observed in VSMCs treated with TLR9 agonist, which was blocked by NF-κB inhibition. Both siRNA knockdown of BMP-2 and NF-κB inhibitor significantly blocked TLR9 agonist-induced VSMC calcification. Conclusions Gut bacterial translocation inhibited by oral antibiotic significantly reduces CRF-related VC through inhibition of TLR9/NF-κB/BMP-2 signaling.

Highlights

Vascular calcification (VC) is the major cardiovascular complication in chronic renal failure (CRF) patients
We demonstrate that antibiotic administration alleviates intestinal bacterial translocation and suppresses vascular calcification in adenine-induced CRF rats through inhibition of TLR9/NF-κB/bone morphogenic protein-2 (BMP-2) signaling
The colony number of bacteria per gram tissue was significantly increased in the mesenteric lymph node of CRF rats and reduced to normal level in antibiotic treatment rats; there was no significant difference in bacteria number in the spleen tissue among the three groups (Figures 1(a) and 1(b))

Summary

Introduction

Vascular calcification (VC) is the major cardiovascular complication in chronic renal failure (CRF) patients. The risk factors for VC in CRF patients include renal function decline, disordered mineral metabolism, and systemic inflammation [1]. Systemic inflammation is a common feature of CRF patients and closely related to morbidity and cardiovascular events [2]. The colon wall inflammation is along with destruction of the intestinal epithelial tight junction barrier, which leads to translocation of bacterial DNA and lipopolysaccharide (LPS) into bloodstream. Gut bacterial DNA and LPS can be detected in the serum of CRF animals and dialysis patients and correlate with severity of systemic inflammation, suggesting that intestinal bacterial translocation is an important cause of systemic inflammatory response in CRF [3, 4]

Methods

Results

Discussion

Conclusion