Toll-like Receptor 4 Differentially Modulates Cardiac Function in Response to Chronic Exposure to High-Fat Diet and Pressure Overload

Liping Tian; Mohammad Jarrah; Hussein Herz; Yi Chu; Ying Xu; Yiqun Tang; Jinxiang Yuan; Mohamad Mokadem

doi:10.3390/nu15245139

Toll-like Receptor 4 Differentially Modulates Cardiac Function in Response to Chronic Exposure to High-Fat Diet and Pressure Overload

Nutrients. 2023 Dec 18;15(24):5139. doi: 10.3390/nu15245139.

Authors

Liping Tian^{1

2}, Mohammad Jarrah², Hussein Herz², Yi Chu², Ying Xu¹, Yiqun Tang¹, Jinxiang Yuan³, Mohamad Mokadem^{2

4

5

6}

Affiliations

¹ Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
² Division of Gastroenterology and Hepatology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA.
³ The Collaborative Innovation Center, Jining Medical University, Jining 272067, China.
⁴ Fraternal Order of Eagles Diabetes Research Center, The University of Iowa, Iowa City, IA 52242, USA.
⁵ Obesity Research and Education Initiative, The University of Iowa, Iowa City, IA 52242, USA.
⁶ Iowa City Veterans Affairs Health Care System, Iowa City, IA 52242, USA.

Abstract

Background/aim: The impact of myocardial stressors such as high-fat diet (HFD) and pressure overload has been extensively studied. Toll-like receptor 4 (TLR4) deficiency has been suggested to have a protective role in response to these stressors, although some conflicting data exist. Furthermore, there is limited information about the role of TLR4 on cardiac remodeling in response to long-term exposure to stressors. This study aims to investigate the effects of TLR4 deficiency on cardiac histology and physiology in response to chronic stressors.

Methods: TLR4-deficient (TLR4^-/-) and wild-type (WT) mice were subjected to either HFD or a normal diet (ND) for 28 weeks. Another group underwent abdominal aortic constriction (AAC) or a sham procedure and was monitored for 12 weeks. Inflammatory markers, histology, and echocardiography were used to assess the effects of these interventions.

Results: TLR4^-/- mice exhibited reduced cardiac hypertrophy and fibrosis after long-term HFD exposure compared to ND without affecting cardiac function. On the other hand, TLR4 deficiency worsened cardiac function in response to AAC, leading to decreased ejection fraction (EF%) and increased end-systolic volume (ESV).

Conclusions: TLR4 deficiency provided protection against HFD-induced myocardial inflammation but impaired hemodynamic cardiac function under pressure overload conditions. These findings highlight the crucial role of TLR4 and its downstream signaling pathway in maintaining cardiac output during physiologic cardiac hypertrophy in response to pressure overload.

Keywords: TLR4; Toll-like receptor; cardiac hypertrophy; high-fat diet; pressure overload.

MeSH terms

Animals
Cardiomegaly* / genetics
Cardiomegaly* / metabolism
Diet, High-Fat* / adverse effects
Heart
Mice
Mice, Inbred C57BL
Mice, Knockout
Toll-Like Receptor 4* / genetics
Toll-Like Receptor 4* / metabolism

Substances

Toll-Like Receptor 4

Grants and funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article. This work was supported by the Outstanding Research Start-up Fund of Jining Medical University (grant number 600791001P); the Postgraduate Research & Practice Innovation Program of Jiangsu Province (grant number KYCX20_0690); and ‘The Program of Exploring World’ Student Scholarship of China Pharmaceutical University.