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2024

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08

Harbin Medical University Yu Bo and other teams work together to discover new strategies to prevent the progression of heart failure!

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Heart failure (HF) is the leading cause of death worldwide and is characterized by significant comorbidities and poor prognosis. Neutrophil extracellular traps (NETs) exacerbate inflammation in various cardiovascular diseases; however, their function and mechanism of action in the pathogenesis of heart failure remain unclear.

August 21, 2024, Harbin Medical University Yu Bo, Zhang Maomao,Wu Jian、Jin Jiaqi mutual communication inEuropean Heart Journal（IF=37.6）Published online entitled"Von Willebrand factor exacerbates heart failure through formation of neutrophil extracellular traps"'s research paper,The study showedVon Willebrand factor exacerbates heart failure through the formation of neutrophil extracellular traps.

Elevated levels of NET were observed in HF patients and in the TAC mouse model.PAD4Knockout and NET inhibitors improve cardiac function. Mechanismically, NETs induce mitochondrial dysfunction in cardiomyocytes and inhibit mitochondrial biogenesis through NE-TLR4-mediated PGC-1α. In addition, VWF/ADAMTS13 throughSLC44A2Regulation of the formation of NET. In addition, sacubitril/valsartan may enhance the cardioprotective effect of VWF-SLC44A2-NET axis blockade.TheStudies have identified a novel VWF-SLC44A2-NET axis in regulating mitochondrial homeostasis and function, leading to cardiac apoptosis and the pathogenesis of HF. Targeting this axis may provide a potential therapeutic approach for the treatment of heart failure.

Heart failure (HF), a clinical syndrome caused by abnormalities in the structure and function of the heart, is the leading cause of death worldwide. Persistent inflammation is believed to influence the onset and progression of heart failure, leading to poor clinical outcomes.While anti-inflammatory therapy is considered a potential treatment strategy, most clinical trials are investigating this therapy.has produced disappointing results, thereby underscoring the need for more effective inflammation-targeted therapies.

Neutrophils are key effectors of inflammation and tissue damage and play a key role in mediating inflammation and heart failure progression. When activated, neutrophils can release neutrophil extracellular traps (NETs) consisting of decompacted chromatin and proteases. Due to their unique structure, NETs link inflammation to thrombosis and are significant contributors to cardiovascular disease, including HF. Studies have shown that NETs are associated with HF and indicate that the formation of NETs has an adverse effect on cardiac remodeling in HF.However, the exact mechanism of NET formation in HF is mostly unknown. Although the development of heart failure is associated with cardiomyocyte injury, there is limited knowledge about the interaction of NETs and cardiomyocytes in the pathogenesis of heart failure.

Von Willebrand factor (VWF) is a glycoprotein that plays a central role in hemostasis, thrombosis, and inflammation. Pharmacological or genetic inhibition of VWF reduces leukocyte recruitment in models of skin inflammation, intracerebral hemorrhage, and myocardial ischemia/reperfusion (MI/R) injury. VWF activity is mainly affectedADAMTS13regulation,ADAMTS13Cleavage of the Y1605-M1606 peptide bond at the VWF multimer A2 domain.The VWF/ADAMTS ratio has been investigated as a potential predictor of various diseases, including HF. However, VWF/ADAMTS13The role and potential mechanism of action in the pathophysiology of HF is unclear.VWF/ADAMTS13Also regulates NET generation. However, during HF development, VWF/ADAMTS13The crosstalk between and net generation is largely unknown.
SLC44A2 is a member of the choline transporter-like protein 2 (CTL2) family and a receptor for VWF. Recent reports suggest that SLC44A2 is involved in neutrophil recruitment and platelet activation.In addition, SLC44A2 induces neutrophil activation and NET formation. However, it is unclear whether SLC44A2 promote cardiac remodeling by modulating the production of NETs.
Here, the authors identify the causal role of the VWF-SLC44A2-NET axis in the pathogenesis of HF and the mechanisms underlying the regulation of mitochondrial function. The findings suggest that inhibition of NET formation is essential for improving the prognosis of HF and underscore the potential of using VWF-SLC44A2-NET axis antagonists as drug candidates for the treatment of HF.In addition, LCZ696 amplifies the cardioprotective effect of SLC44A2 blockade in an additive manner, providing a mechanistic understanding of the pleiotropic benefit of LCZ696 through modulation of NETosis.

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