Aggravated myocardial infarction-induced cardiac remodeling and heart failure in histamine-deficient mice
Jinmiao Chen1,2, Tao Hong1,2, Suling Ding1
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
Insights
Histamine plays a protective role after myocardial infarction (MI) by reducing cardiac fibrosis and improving heart function. This effect is mediated through the STAT6 signaling pathway, highlighting histamine
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Histamine's role in myocardial infarction (MI)-induced cardiac remodeling is not fully understood.
- Histidine decarboxylase (HDC) is the primary enzyme for histamine synthesis.
- Myeloid cells expressing HDC increase in injured hearts post-MI.
Purpose of the Study:
- To investigate the function of HDC-expressing cells and histamine in post-MI heart failure.
- To elucidate the signaling pathways involved in histamine's effects on cardiac remodeling.
Main Methods:
- Utilized HDC-EGFP transgenic and HDC-knockout (HDC-/-) mouse models.
- Assessed cardiac remodeling, left ventricular function, and mortality post-MI.
- Performed in vitro assays on murine heart fibroblasts and utilized STAT6-knockout (STAT6-/-) mice.
Main Results:
- HDC-/- mice showed exacerbated cardiac remodeling, impaired function, and increased mortality post-MI.
- Histamine inhibited heart fibroblast proliferation in vitro.
- Histamine enhanced STAT6 phosphorylation in fibroblasts; blocking JAK3/STAT6 signaling abolished histamine's inhibitory effects.
- STAT6-/- mice exhibited phenotypes similar to HDC-/- mice, and exogenous histamine was ineffective in STAT6-/- mice.
Conclusions:
- Histamine exerts protective effects against adverse cardiac remodeling post-MI.
- These protective effects are partly mediated via the STAT6-dependent signaling pathway.
- Targeting the histamine-STAT6 axis may offer therapeutic potential for post-MI heart failure.
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.
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