NETosis as a Pathogenic Factor for Heart Failure

Abstract

Heart failure threatens the lives of patients and reduces their quality of life. Heart failure, especially heart failure with preserved ejection fraction, is closely related to systemic and local cardiac persistent chronic low-grade aseptic inflammation, microvascular damage characterized by endothelial dysfunction, oxidative stress, myocardial remodeling, and fibrosis. However, the initiation and development of persistent chronic low-grade aseptic inflammation is unexplored. Oxidative stress-mediated neutrophil extracellular traps (NETs) are the main immune defense mechanism against external bacterial infections. Furthermore, NETs play important roles in noninfectious diseases. After the onset of myocardial infarction, atrial fibrillation, or myocarditis, neutrophils infiltrate the damaged tissue and aggravate inflammation. In tissue injury, damage-related molecular patterns (DAMPs) may induce pattern recognition receptors (PRRs) to cause NETs, but whether NETs are directly involved in the pathogenesis and development of heart failure and the mechanism is still unclear. In this review, we analyzed the markers of heart failure and heart failure-related diseases and comorbidities, such as mitochondrial DNA, high mobility box group box 1, fibronectin extra domain A, and galectin-3, to explore their role in inducing NETs and to investigate the mechanism of PRRs, such as Toll-like receptors, receptor for advanced glycation end products, cGAS-STING, and C-X-C motif chemokine receptor 2, in activating NETosis. Furthermore, we discussed oxidative stress, especially the possibility that imbalance of thiol redox and MPO-derived HOCl promotes the production of 2-chlorofatty acid and induces NETosis, and analyzed the possibility of NETs triggering coronary microvascular thrombosis. In some heart diseases, the deletion or blocking of neutrophil-specific myeloperoxidase and peptidylarginine deiminase 4 has shown effectiveness. According to the results of current pharmacological studies, MPO and PAD4 inhibitors are effective at least for myocardial infarction, atherosclerosis, and certain autoimmune diseases, whose deterioration can lead to heart failure. This is essential for understanding NETosis as a therapeutic factor of heart failure and the related new pathophysiology and therapeutics of heart failure.

Figure 1

NETs' contribution to HF. NETs accelerate HF through promoting the deterioration of various heart diseases and systemic diseases. NETs: neutrophil extracellular traps.

Figure 2

Initiation of NETs by PRRs. Various DMAPs and cytokines activate NET formation through PRRs. FN-EDA: fibronectin extra domain A; HMGB1: high mobility box group box 1; LRP1: LDL receptor-related protein 1; mtDNA: mitochondrial DNA; PRRs: pattern recognition receptors; RAGE: receptor for advanced glycation end products; ST2: a receptor for IL-33; TLR: Toll-like receptor.

Figure 3

Possible pathways for the formation of NETs activated by oxidative stress. 2-ClFA: 2-chlorofatty acid; 2-ClFALD: 2-chlorofatty aldehyde; DAG: diacylglycerol; MPO: myeloperoxidase; NE: neutrophil elastase; PAD4: peptidylarginine deiminase 4; PAK1: P21 (Rac)-activated kinase 1; PLCγ2: a calcium-dependent phospholipase; PKC: protein kinase C; Rac: Rac GTPases, a small G-protein; SFKs: Src family protein tyrosine kinases, which include eight members: c-Src, c-Yes, Fyn, c-Fgr, Lyn, Hck, Lck, and Blk; SOD: superoxide dismutase; SYK: spleen tyrosine kinase; TLRs: Toll-like receptors; Vav: a guanine nucleotide exchange factor.

Figure 4

Possible mechanism of DMAPs activating NET-dependent thrombosis. (1) Migration of neutrophils driven by the chemokine receptor CXCR2 and ligand IL-8. (2) Various DMAPs induce thrombosis by activating NETs. (3) With the participation of activated platelets, endothelial cells, monocytes, red blood cells, and blood coagulation factors, neutrophils promote thrombosis. Coag. Factor: coagglutination factor; FN-EDA: fibronectin extra domain A; HMGB1: high mobility box group box 1; mtDNA: mitochondrial DNA; RBCs: red blood cells; vWF: von Willebrand factor.