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Journal of Molecular Medicine

, Volume 96, Issue 11, pp 1189–1202 | Cite as

NLRP3 deficiency accelerates pressure overload-induced cardiac remodeling via increased TLR4 expression

  • Fangfang Li
  • Hao Zhang
  • Lu Yang
  • Hui Yong
  • Qingqing Qin
  • Mengtong Tan
  • Luhong Xu
  • Kai Liang
  • Jing ZongEmail author
  • Wenhao QianEmail author
Original Article
  • 351 Downloads

Abstract

NLRP3, a member of the nucleotide-binding oligomerization domain (NOD)-like receptor family, is involved in cardiac inflammation. However, the functional role of NLRP3 in cardiac remodeling is not clear. To investigate the roles of NLRP3 in pressure overload-induced cardiac remodeling, NLRP3 knockout and wild-type mice were subjected to aortic banding to induce cardiac remodeling. The data showed that NLRP3 expression was downregulated in the remodeling process. NLRP3 deficiency accelerated cardiac hypertrophy, fibrosis, and inflammation responses with deteriorating cardiac dysfunction in the pressure overload-induced cardiac remodeling mouse model. Neonatal rat cardiomyocytes were isolated and stimulated with phenylephrine (PE). We identified NLRP3 as a negative regulator of cardiomyocyte remodeling in PE-stimulated cardiomyocyte remodeling using adenovirus-NLRP3 and NLRP3 siRNA. Mechanistically, we found that the expression of Toll-like receptor (TLR) 4 was upregulated in NLRP3-deficient mouse hearts and PE-stimulated cardiomyocytes. NLRP3 knockout mice subjected to a TLR4 inhibitor revealed a relieved cardiac remodeling response with improved cardiac dysfunction. Our data suggested that NLRP3 could be a therapeutic target for cardiac remodeling and heart failure.

Key messages

  • NLRP3 expression was downregulated in the remodeling process.

  • NLRP3 deficiency accelerated pressure overload-induced cardiac remodeling.

  • NLRP3 acted as a negative regulator of cardiomyocyte remodeling via downregulating TLR4.

Keywords

NLRP3 Aortic banding Cardiac remodeling TLR4 

Notes

Authors’ contribution

LF, ZJ, and QW contributed to study conception and designed experiments; ZH, YL, YH, and QQ carried out experiments; TM, XL, and LK analyzed experimental results. LF, ZJ, and QW wrote and revised the manuscript.

Source of funding

This research was supported by the Natural Science Foundation of Jiangsu Province (Grant No. BK20160231 and BK20140226) and the National Natural Science Foundation of China (Grant No. 81400178).

Compliance with ethical standards

Written informed consent was obtained from the families of the prospective heart donors. This study complied with the protocol approved by the First Affiliated Hospital of Xuzhou Medical University Human Research Ethics Committee, and samples were collected after informed consent. All of the animal care and experimental procedures conformed to the Guidelines for the Care and Use of Laboratory Animals, published by the United States National Institutes of Health (NIH Publication, revised 2011) and the institutional guidelines of the Animal Care and Use Committee of Xuzhou Medical University (Xuzhou, China; Approval number JSXZ-2016-1005-001; Approval data 05/10/2016). NLRP3 knockout (KO) mice (Stock No. 000664) were purchased from the Jackson Laboratory through the Model Animal Research Center of Nanjing University.

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

109_2018_1691_MOESM1_ESM.docx (2.8 mb)
ESM 1 (DOCX 2842 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Fangfang Li
    • 1
    • 2
  • Hao Zhang
    • 1
    • 2
  • Lu Yang
    • 1
    • 2
  • Hui Yong
    • 1
    • 2
  • Qingqing Qin
    • 1
    • 2
  • Mengtong Tan
    • 1
    • 2
  • Luhong Xu
    • 1
    • 2
  • Kai Liang
    • 1
    • 2
  • Jing Zong
    • 1
    • 2
    Email author
  • Wenhao Qian
    • 1
    • 2
    Email author
  1. 1.Department of CardiologyThe Affiliated Hospital of Xuzhou Medical UniversityXuzhouChina
  2. 2.Institute of Cardiovascular Disease ResearchXuzhou Medical UniversityXuzhouChina

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