Prmt1 upregulated by Hdc deficiency aggravates acute myocardial infarction via NETosis

Neutrophils are mobilized and recruited to the injured heart after myocardial infarction, and neutrophil count has been clinically implicated to be associated with coronary disease severity. Histidine decarboxylase (HDC) has been implicated in regulating reactive oxidative species (ROS) and the differentiation of myeloid cells. However, the effect of HDC on neutrophils after myocardial infarction remains unclear. Here, we found that neutrophils were disorderly recruited into the ischemic injured area of the myocardium of Hdc deficiency (Hdc -/-) mice. Moreover, Hdc deficiency led to attenuated adhesion but enhanced migration and augmented ROS/neutrophil extracellular traps (NETs) production in neutrophils. Hdc -/- mouse-derived NETs promoted cardiomyocyte death and cardiac fibroblast proliferation/migration. Furthermore, protein arginine methyltransferase 1 (PRMT1) was increased in Hdc -/- mouse-derived neutrophils but decreased with exogenous histamine treatment. Its expression could be rescued by blocking histamine receptor 1 (H1R), inhibiting ATP synthesis or reducing SWItch/sucrose non fermentable (SWI/SNF) chromatin remodeling complex. Accordingly, histamine or MS023 treatment could decrease ROS and NETs ex vivo, and ameliorated cardiac function and fibrosis, along with the reduced NETs in plasma in vivo. Together, our findings unveil the role of HDC in NETosis by histamine-H1R-ATP-SWI/SNF-PRMT1-ROS signaling and provide new biomarkers and targets for identifying and tuning the detrimental immune state in cardiovascular disease.

 

Comments:

The passage you provided describes a research study that investigates the role of histidine decarboxylase (HDC) in regulating neutrophils and their involvement in myocardial infarction (heart attack). Here's a breakdown of the key findings and implications of the study:

1. Neutrophils and coronary disease severity: Neutrophils, a type of white blood cell, are mobilized and recruited to the injured heart after a myocardial infarction. The severity of coronary disease has been clinically associated with the count of neutrophils, suggesting their potential role in the progression of heart disease.

2. HDC deficiency and neutrophil recruitment: The study focused on mice with HDC deficiency (Hdc -/-). The researchers found that in these mice, neutrophils were recruited disorderly into the ischemic injured area of the heart. This suggests that HDC may play a role in regulating the recruitment process of neutrophils to the site of injury.

3. HDC deficiency and neutrophil function: The absence of HDC resulted in attenuated adhesion (attachment) of neutrophils, but enhanced migration and increased production of reactive oxidative species (ROS) and neutrophil extracellular traps (NETs). NETs are web-like structures composed of DNA and proteins released by neutrophils to capture and eliminate pathogens. The augmented production of NETs in HDC-deficient neutrophils suggests an altered immune response.

4. Effects of HDC-deficient NETs: The study found that NETs derived from HDC-deficient mice promoted cardiomyocyte death (cell death of heart muscle cells) and cardiac fibroblast proliferation and migration. This suggests that HDC deficiency-induced changes in neutrophils can have detrimental effects on the heart tissue.

5. Involvement of PRMT1 and histamine: The researchers observed an increase in protein arginine methyltransferase 1 (PRMT1) in HDC-deficient neutrophils. However, PRMT1 expression could be rescued by blocking histamine receptor 1 (H1R), inhibiting ATP synthesis, or reducing the SWI/SNF chromatin remodeling complex. This indicates that histamine, acting through H1R and ATP-SWI/SNF-PRMT1 signaling, may modulate the function of neutrophils.

6. Therapeutic interventions: Treatment with histamine or MS023 (a PRMT1 inhibitor) reduced ROS and NETs production in neutrophils. These treatments also ameliorated cardiac function and fibrosis in the mice, along with reducing the levels of NETs in the bloodstream. These findings suggest that targeting the histamine-H1R-ATP-SWI/SNF-PRMT1-ROS signaling pathway could serve as a potential therapeutic strategy for cardiovascular diseases.

7. Biomarkers and targets: The study identifies the altered immune state in cardiovascular disease and provides potential biomarkers (neutrophil count, NETs) and targets (HDC, histamine, PRMT1) for identifying and modulating this detrimental immune response.

In summary, this research study highlights the role of HDC in regulating neutrophil function and recruitment after myocardial infarction. HDC deficiency leads to altered neutrophil behavior, increased NETs production, and detrimental effects on heart tissue. Modulating the histamine-H1R-ATP-SWI/SNF-PRMT1-ROS signaling pathway may offer potential therapeutic avenues for cardiovascular diseases.