TRPA1 inhibition ameliorates pressure overload-induced cardiac hypertrophy and fibrosis in mice

Zhen Wang; Yao Xu; Menglong Wang; Jing Ye; Jianfang Liu; Huimin Jiang; Di Ye; Jun Wan

doi:10.1016/j.ebiom.2018.08.022

TRPA1 inhibition ameliorates pressure overload-induced cardiac hypertrophy and fibrosis in mice

EBioMedicine. 2018 Oct:36:54-62. doi: 10.1016/j.ebiom.2018.08.022. Epub 2018 Oct 5.

Authors

Zhen Wang¹, Yao Xu¹, Menglong Wang¹, Jing Ye¹, Jianfang Liu¹, Huimin Jiang¹, Di Ye¹, Jun Wan²

Affiliations

¹ Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, Wuhan 430060, China.
² Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, Wuhan 430060, China. Electronic address: wanjun1963@126.com.

Abstract

Background: Recent evidence has indicated that the transient receptor potential ankyrin 1 (TRPA1) is expressed in the cardiovascular system and implicated in the development and progression of several cardiovascular diseases. However, the effects of TRPA1 on cardiac hypertrophy development remain unclear. The aim of this study was to determine the role of TRPA1 in cardiac hypertrophy and fibrosis development.

Methods: C57BL/6J mice were subjected to transverse aortic constriction (TAC) and were orally treated with the TRPA1 selective inhibitors HC-030031 (HC) and TCS-5861528 (TCS). Morphological assessments, echocardiographic parameters, histological analyses and flow cytometry were used to evaluate cardiac hypertrophy and fibrosis.

Results: Human and mouse hypertrophic hearts presented with noticeably increased TRPA1 protein levels. Inhibition of TRPA1 by HC and TCS attenuated cardiac hypertrophy and preserved cardiac function after chronic pressure overload, as evidenced by increased heart weight/body weight ratio, cardiomyocyte cross-sectional area and mRNA expression of hypertrophic markers, including ANP, BNP and β-MHC. Dramatic interstitial fibrosis was observed in the mice subjected to TAC surgery, and this was markedly attenuated in the HC and TCS treated mice. Mechanistically, the results revealed that TRPA1 inhibition ameliorated pressure overload-induced cardiac hypertrophy by negatively regulating Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and calcineurin signaling pathways. We also demonstrated that blocking TRPA1 decreased the proportion of M2 macrophages and reduced profibrotic cytokine levels, thereby improving cardiac fibrosis.

Conclusions: TRPA1 inhibition protected against cardiac hypertrophy and suppressed cardiac dysfunction via Ca²⁺-dependent signal pathways and inhibition of the M2 macrophages transition. These results suggest that TRPA1 may represent a potential therapeutic drug target for cardiac hypertrophy and fibrosis.

Keywords: CaMKII; Calcineurin; Fibrosis; Hypertrophy; Macrophages; TRPA1.