Jiaying Li1,2,3,4, Qingchun Zeng1,2,3,4, Zhenyu Xiong5, Gaopeng Xian1,2,3,4, Zuheng Liu1,2,3,4, Qiong Zhan1,2,3,4, Wenyan Lai1,2,3,4, Lihua Ao6, Xianzhong Meng6, Hao Ren2,7, Dingli Xu1,2,3,4. 1. State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 Northern Guangzhou Ave, Guangzhou, Guangdong 510515, China. 2. Key Laboratory for Organ Failure Research, Ministry of Education of the People's Republic of China, 1838 Northern Guangzhou Ave, Guangzhou, Guangdong 510515, China. 3. Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, 1838 Northern Guangzhou Ave, Guangzhou, Guangdong 510515,China. 4. Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Haizhu District, Guangzhou, Guangdong 510320, China. 5. Department of Cardiology, First affiliated hospital of Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China. 6. Department of Surgery, University of Colorado Denver, 12700 E. 19th Avenue Campus Box C-320, Aurora, CO 80045, USA. 7. Department of Rheumatology, Nanfang Hospital, Southern Medical University, 1838 Northern Guangzhou Ave, Guangzhou, Guangdong 510515, China.
Abstract
AIMS: Recent studies have shown that the choline-derived metabolite trimethylamine N-oxide (TMAO) is a biomarker that promotes cardiovascular disease through the induction of inflammation and stress. Inflammatory responses and stress are involved in the progression of calcified aortic valve disease (CAVD). Here, we examined whether TMAO induces the osteogenic differentiation of aortic valve interstitial cells (AVICs) through endoplasmic reticulum (ER) and mitochondrial stress pathways in vitro and in vivo. METHODS AND RESULTS: Plasma TMAO levels were higher in patients with CAVD (n = 69) than in humans without CAVD (n = 263), as examined by liquid chromatography-tandem mass spectrometry. Western blot and staining probes showed that TMAO-induced an osteogenic response in human AVICs. Moreover, TMAO promoted ER stress, mitochondrial stress, and nuclear factor-κB (NF-κB) activation in vitro. Notably, the TMAO-mediated effects were reversed by the use of ER stress, mitochondrial stress, and NF-κB activation inhibitors and small interfering RNA. Mice treated with supplemental choline in a high-fat diet had markedly increased TMAO levels and aortic valve thicknesses, which were reduced by 3,3-dimethyl-1-butanol (an inhibitor of trimethylamine formation) treatment. CONCLUSIONS: Choline-derived TMAO promotes osteogenic differentiation through ER and mitochondrial stress pathways in vitro and aortic valve lesions in vivo. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Recent studies have shown that the choline-derived metabolite trimethylamine N-oxide (TMAO) is a biomarker that promotes cardiovascular disease through the induction of inflammation and stress. Inflammatory responses and stress are involved in the progression of calcified aortic valve disease (CAVD). Here, we examined whether TMAO induces the osteogenic differentiation of aortic valve interstitial cells (AVICs) through endoplasmic reticulum (ER) and mitochondrial stress pathways in vitro and in vivo. METHODS AND RESULTS: Plasma TMAO levels were higher in patients with CAVD (n = 69) than in humans without CAVD (n = 263), as examined by liquid chromatography-tandem mass spectrometry. Western blot and staining probes showed that TMAO-induced an osteogenic response in human AVICs. Moreover, TMAO promoted ER stress, mitochondrial stress, and nuclear factor-κB (NF-κB) activation in vitro. Notably, the TMAO-mediated effects were reversed by the use of ER stress, mitochondrial stress, and NF-κB activation inhibitors and small interfering RNA. Mice treated with supplemental choline in a high-fat diet had markedly increased TMAO levels and aortic valve thicknesses, which were reduced by 3,3-dimethyl-1-butanol (an inhibitor of trimethylamine formation) treatment. CONCLUSIONS: Choline-derived TMAO promotes osteogenic differentiation through ER and mitochondrial stress pathways in vitro and aortic valve lesions in vivo. Published on behalf of the European Society of Cardiology. All rights reserved.