NLRP3 deficiency accelerates pressure overload-induced cardiac remodeling via increased TLR4 expression
- 351 Downloads
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.
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.
KeywordsNLRP3 Aortic banding Cardiac remodeling TLR4
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.
- 13.Pavillard LE, Cañadas-Lozano D, Alcocer-Gómez E, Marín-Aguilar F, Pereira S, Robertson AAB, Muntané J, Ryffel B, Cooper MA, Quiles JL, Bullón P, Ruiz-Cabello J, Cordero MD (2017) NLRP3-inflammasome inhibition prevents high fat and high sugar diets-induced heart damage through autophagy induction. Oncotarget 8(59):99740–99756CrossRefGoogle Scholar
- 15.Shimamoto A, Chong AJ, Yada M, Shomura S, Takayama H, Fleisig AJ, Agnew ML, Hampton CR, Rothnie CL, Spring DJ, Pohlman TH, Shimpo H, Verrier ED (2006) Inhibition of Toll-like receptor 4 with eritoran attenuates myocardial ischemia-reperfusion injury. Circulation 114(1 Suppl):I270–I274PubMedGoogle Scholar
- 20.Mastrocola R et al (2016) Pharmacological inhibition of NLRP3 inflammasome attenuates myocardial ischemia/reperfusion injury by activation of RISK and mitochondrial pathways. Oxidative Med Cell Longev 2016:5271251Google Scholar