Introduction and aims: Heart failure (HF) is a pathological disorder defined by myocardial anatomical and functional defects that impair left ventricular (LV) filling or blood ejection (or both). HF with preserved ejection fraction (HFpEF) is closely associated with systemic and local cardiac persistent chronic low-grade aseptic inflammation and microvascular damage which is characterized by endothelial dysfunction, oxidative stress, myocardial remodeling and fibrosis. In this project, we aimed to investigate the role of oxidation of the Il-6 receptor neutrophil trafficking during the inflammatory response and how this process may boost the release of the neutrophil extracellular traps (NETs), Gronolla proteases, cytochrome, and DNase-1. 

Methods and Results: Donor tissues and HFpEF human biopsies (8 sample per group) were studied to investigate the inflammasome markers via western blot technique. Interleukin-6 receptor (IL-6 R), Neutrophil Elastase (NE), and Histone 3 (H3) levels were significantly elevated while IL-6 poly protein was downregulated in human HFpEF biopsies compared to the human donors. This decrease in IL-6 poly protein expression suggests a dysregulation of IL-6 signaling in HFpEF. Specifically, increased levels of MPO and IL-18 have been found in patients with HFpEF and have been associated with worse clinical outcomes. Expression level and oxidation of inflammatory mediators in human biopsies and its role in activate inflammation in HFpEF patients measured by mass spectrometry indicates increased oxidation of many proteins involved in inflammasome pathway with HFpEF compared to donor groups is an interesting finding that may help to further elucidate the role of proteins oxidation in HFpEF pathophysiology. We also found that most of the cardiac proteins are highly oxidized and most oxidized proteins that are involved in cardiomyocyte dysfunction were IL6 receptor. We also found that oxidation of the receptor, which we believe promotes human neutrophils produce biologically active amounts of IL-6. Moreover, myofilament proteins titin, myosin binding protein C, troponin I, and actin were highly oxidized in HFpEF patients. In addition to the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a, phospholamban, and ryanodine receptor. This is a valuable observation in understanding the underlying mechanisms of HFpEF pathophysiology and needs to be further explored.  

Conclusion: Our data indicates that protein oxidation and specifically proteins in the inflammasome pathways play an essential role in HFpEF development and could be used as therapeutic targets.

Keywords: heart failure, inflammation, oxidative stress, Neutrophils, interleukin 6.