2. Academic Validation
  3. Trimethylamine N-oxide induces cardiac diastolic dysfunction by down-regulating Piezo1 in mice with heart failure with preserved ejection fraction

Trimethylamine N-oxide induces cardiac diastolic dysfunction by down-regulating Piezo1 in mice with heart failure with preserved ejection fraction

  • Life Sci. 2025 May 15:369:123554. doi: 10.1016/j.lfs.2025.123554.
Qian Chen 1,  Huaxing Zhang 2,  Yuhong Chen 3,  Yangxuan Peng 1,  Yuhan Yao 1,  Hongmei Xue 1,  Qi Guo 1,  Danyang Tian 1,  Lin Xiao 1,  Xu Teng 1,  Mingqi Zheng 4,  Bing Xiao 5,  Yuming Wu 6,  Sheng Jin 7
Affiliations

Affiliations

  • 1 Department of Physiology, Hebei Medical University, 050017, Hebei, China.
  • 2 Core Facilities and Centers, Hebei Medical University, 050017, Hebei, China.
  • 3 Department of Critical Care Medicine, The Fourth Hospital of Hebei Medical University, 050017, Hebei, China.
  • 4 Department of Cardiology, The First Hospital of Hebei Medical University, 050031, Hebei, China.
  • 5 Department of Cardiology, The Second Hospital of Hebei Medical University, 050000, Hebei, China. Electronic address: xiaobing@hebmu.edu.cn.
  • 6 Department of Physiology, Hebei Medical University, 050017, Hebei, China; Hebei Collaborative Innovation Center for Cardio-Cerebrovascular Disease, 050017, Hebei, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, 050017, Hebei, China; Hebei Key Laboratory of Cardiovascular Homeostasis and Aging, 050017, Hebei, China. Electronic address: wuym@hebmu.edu.cn.
  • 7 Department of Physiology, Hebei Medical University, 050017, Hebei, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, 050017, Hebei, China; Hebei Key Laboratory of Cardiovascular Homeostasis and Aging, 050017, Hebei, China. Electronic address: jinsheng@hebmu.edu.cn.
PMID: 40074144 DOI: 10.1016/j.lfs.2025.123554
Abstract

Aims: The present study aimed to investigate the direct link between trimethylamine N-oxide (TMAO) and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF).

Materials and methods: Diastolic dysfunction is the main manifestation of HFpEF, so the "two-hit" mouse HFpEF model are used. After treated with high-fat diet (HFD) and N[w]-nitro-l-arginine methyl ester (L-NAME) for 8 weeks, the cardiac function, myocardial fibrosis, oxidative stress levels, and molecular alterations were assessed.

Key findings: The HFpEF mice displayed a declined diastolic function, characterized by an increase in the E/E' ratio, accompanied by a significant increase in plasma brain natriuretic peptide levels and cardiac fibrosis and down-regulation of SERCA2 expression, while, DMB treatment improved diastolic function. Subsequently, TMAO was injected intraperitoneally into the mice for 1 month and found that TMAO induced diastolic dysfunction. In addition, we found that either the HFD and L-NAME or TMAO treatment down-regulated Piezo1 expression, and the cardiomyocyte-specific Piezo1 knockout mice (Piezo1ΔCM) also had diastolic dysfunction. Moreover, the NOX4 expression was up-regulated and the Reactive Oxygen Species levels were increased in the heart tissues of Piezo1ΔCM or TMAO-treated mice, which was reversed by a Piezo1 activator (Yoda1) in the TMAO-treated mice. Yoda1 also reversed diastolic dysfunction in the HFpEF mice.

Significance: In conclusion, our data revealed that TMAO-induced oxidative stress injury by down-regulating Piezo1 to be involve in cardiac diastolic dysfunction of HFpEF. It should be noted that this preclinical study did not evaluate HFpEF-related symptoms such as exercise intolerance or pulmonary congestion, which warrant further validation.

Keywords

Diastolic dysfunction; HFpEF; Oxidative stress injury; Piezo1; TMAO.

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