Aggravated myocardial infarction-induced cardiac remodeling and heart failure in histamine-deficient mice

Jinmiao Chen,Long Deng,Mieradilijiang Abudupataer,Tao Hong,Hui Gong,Junbo Ge,Yunzeng Zou,Weiwei Zhang,Minghong Tong,Xiangdong Yang,Suling Ding,Timothy C Wang,Jianguo Jia

doi:10.1038/srep44007

Abstract

Histamine has pleiotropic pathophysiological effects, but its role in myocardial infarction (MI)-induced cardiac remodeling remains unclear. Histidine decarboxylase (HDC) is the main enzyme involved in histamine production. Here, we clarified the roles of HDC-expressing cells and histamine in heart failure post-MI using HDC-EGFP transgenic mice and HDC-knockout (HDC−/−) mice. HDC+CD11b+ myeloid cell numbers markedly increased in the injured hearts, and histamine levels were up-regulated in the circulation post-MI. HDC−/− mice exhibited more adverse cardiac remodeling, poorer left ventricular function and higher mortality by increasing cardiac fibrogenesis post-MI. In vitro assays further confirmed that histamine inhibited heart fibroblast proliferation. Furthermore, histamine enhanced the signal transducer and activator of transcription (STAT)-6 phosphorylation level in murine heart fibroblasts, and the inhibitive effects of histamine on fibroblast proliferation could be blocked by JAK3/STAT6 signaling selective antagonist. STAT6-knockout (STAT6−/−) mice had a phenotype similar to that of HDC−/− mice post-MI; however, in contrast to HDC−/− mice, the beneficial effects of exogenous histamine injections were abrogated in STAT6−/− mice. These data suggest that histamine exerts protective effects by modulating cardiac fibrosis and remodeling post-MI, in part through the STAT6-dependent signaling pathway.

Highlights

In the bone marrow highly express HDC and are thought to represent immature myeloid cells[7]
As our previous study showed that STAT6 mRNA expression levels were significantly down-regulated in the CD11b+Gr1+ myeloid cells of HDC−/− mice compared with those of WT mice[7], whether the STAT6 signaling pathway is a downstream target of histamine in the setting of cardiac fibrogenesis and remodeling requires further investigation
The results of this study revealed that histamine was strongly induced in a permanent occlusion model of myocardial infarction (MI) and provided endogenous protection against MI-induced cardiac remodeling, at least in part, via the STAT6 signaling pathway

Summary

Introduction

In the bone marrow highly express HDC and are thought to represent immature myeloid cells[7]. The roles of HDC-expressing CD11b+ myeloid cells and histamine in MI-induced heart failure have not yet been elucidated. The signaling pathways downstream of these G-protein-coupled receptors with respect to cardiac remodeling have not been well studied[11]. As our previous study showed that STAT6 mRNA expression levels were significantly down-regulated in the CD11b+Gr1+ myeloid cells of HDC−/− mice compared with those of WT mice[7], whether the STAT6 signaling pathway is a downstream target of histamine in the setting of cardiac fibrogenesis and remodeling requires further investigation. We showed that genetic deficiency of histamine promoted cardiac fibrogenesis and dampened heart function post-MI. We showed that the STAT6 signaling pathway appeared to be involved in the critical functions of histamine post-MI

Methods

Results

Conclusion