ABSTRACT
Emerging evidence indicates that alteration of gut microbiota plays an important role in chronic kidney disease (CKD)-related vascular calcification (VC). We aimed to investigate the specific gut microbiota and the underlying mechanism involved in CKD-VC. We identified an increased abundance of Prevotella copri (P. copri) in the feces of CKD rats (induced by using 5/6 nephrectomy followed by a high calcium and phosphate diet) with aortic calcification via amplicon sequencing of 16S rRNA genes. In patients with CKD, we further confirmed a positive correlation between abundance of P. copri and aortic calcification scores. Moreover, oral administration of live P. copri aggravated CKD-related VC and osteogenic differentiation of vascular smooth muscle cells in vivo, accompanied by intestinal destruction, enhanced expression of Toll-like receptor-4 (TLR4), and elevated lipopolysaccharide (LPS) levels. In vitro and ex vivo experiments consistently demonstrated that P. copri-derived LPS (Pc-LPS) accelerated high phosphate-induced VC and VSMC osteogenic differentiation. Mechanistically, Pc-LPS bound to TLR4, then activated the nuclear factor κB (NF-κB) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome signals during VC. Inhibition of NF-κB reduced NLRP3 inflammasome and attenuated Pc-LPS-induced VSMC calcification. Our study clarifies a novel role of P. copri in CKD-related VC, by the mechanisms involving increased inflammation-regulating metabolites including Pc-LPS, and activation of the NF-κB/NLRP3 signaling pathway. These findings highlight P. copri and its-derived LPS as potential therapeutic targets for VC in CKD.
Subject(s)
Gastrointestinal Microbiome , Lipopolysaccharides , NF-kappa B , Prevotella , Renal Insufficiency, Chronic , Signal Transduction , Toll-Like Receptor 4 , Vascular Calcification , Animals , Vascular Calcification/metabolism , Vascular Calcification/pathology , NF-kappa B/metabolism , Lipopolysaccharides/metabolism , Rats , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/microbiology , Renal Insufficiency, Chronic/chemically induced , Renal Insufficiency, Chronic/pathology , Humans , Male , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 4/genetics , Prevotella/metabolism , Rats, Sprague-Dawley , Myocytes, Smooth Muscle/metabolism , Osteogenesis/drug effects , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Feces/microbiology , Inflammasomes/metabolismSubject(s)
Catheter Ablation , Tachycardia, Ventricular/therapy , Electrocardiography , Heart Ventricles , HumansSubject(s)
Catheter Ablation/methods , Hematoma/surgery , Thrombosis/surgery , Aged , Female , HumansABSTRACT
OBJECTIVE: To investigate the serum level of carboxy-terminal telopeptide of type I collagen (ICTP) and explore its correlation with MMP-2 and MMP-9 in patients with coronary artery disease (CHD). METHODS: A total of 103 CHD patients treated in our hospital between October, 2013 and May, 2014 were enrolled, including 39 with stable angina pectoris (SAP), 39 with unstable angina (UA), and 25 with acute myocardial infarction (AMI), with 38 non-CHD volunteers as the control group. The serum levels of ICTP, MMP-2, and MMP-9 were detected in all the subjects using enzyme-linked immunosorbent assay (ELISA). RESULTS: No significant difference in serum levels of MMP-2, MMP-9, or ICTP was found between the control and SAP groups or between UA and AMI groups (P>0.05), but the latter two groups had significantly higher serum levels of MMP-2, MMP-9, and ICTP than the former two groups (P<0.05). Serum ICTP level was found to negatively correlated with the fibrotic area and positively with the lipid component in the plaques (P<0.05). Regression analysis revealed significant positive correlations of serum ICTP with MMP-2 and MMP-9 (P<0.05). CONCLUSION: An elevated serum ICTP level is indicative of the presence of unstable plaques in CHD patients. Serum ICTP is more strongly correlated with MMP-2 than with MMP-9, and can be used as a non-invasive marker for assessing vulnerable plaques in patients with acute coronary syndrome.
