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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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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