Journal Article

KLF2 regulates neutrophil activation and thrombosis in cardiac hypertrophy and heart failure progression

Zhang, Rongli, Chang, Eugene, Jeong, Hyun-Woo, Jain, Mukesh K., Nayak, Lalitha, Luo, Jiemeng, Wang, Peiwei, Zhang, Teng, Vinayachandran, Vinesh, Liao, Sarah, Lapping, Stephanie, Liao, Xudong, Madera, Annmarie, Fei, Jinsong, Tang, Xinmiao, Sweet, David R., Watanabe, Ippei, Adams, Ralf H.

2022

Overview

It is widely recognized that inflammation plays a critical role in cardiac hypertrophy and heart failure. However, clinical trials targeting cytokines have shown equivocal effects, indicating the need for a deeper understanding of the precise role of inflammation and inflammatory cells in heart failure. Leukocytes from human subjects and a rodent model of heart failure were characterized by a marked reduction in expression of Klf2 mRNA. Using a mouse model of angiotensin II-induced nonischemic cardiac dysfunction, we showed that neutrophils played an essential role in the pathogenesis and progression of heart failure. Mechanistically, chronic angiotensin II infusion activated a neutrophil KLF2/NETosis pathway that triggered sporadic thrombosis in small myocardial vessels, leading to myocardial hypoxia, cell death, and hypertrophy. Conversely, targeting neutrophils, neutrophil extracellular traps (NETs), or thrombosis ameliorated these pathological changes and preserved cardiac dysfunction. KLF2 regulated neutrophil activation in response to angiotensin II at the molecular level, partly through crosstalk with HIF1 signaling. Taken together, our data implicate neutrophil-mediated immunothrombotic dysregulation as a critical pathogenic mechanism leading to cardiac hypertrophy and heart failure. This neutrophil KLF2-NETosis-thrombosis mechanism underlying chronic heart failure can be exploited for therapeutic gain by therapies targeting neutrophils, NETosis, or thrombosis.

• Publisher: American Society for Clinical Investigation
• Subject: Angiotensin / Angiotensin II / Animals / Biomedical research / Blood clot / Cardiology / Cardiomegaly - metabolism / Cell activation / Cell death / Clinical trials / Complications and side effects / Congestive heart failure / Cytokines / Development and progression / Disease Models, Animal / Gene expression / Genes / Genetic aspects / Health aspects / Heart enlargement / Heart failure / Heart Failure - metabolism / Humans / Hypertrophy / Hypoxia / Infections / Inflammation / Krueppel-like factor / Kruppel-Like Transcription Factors - metabolism / Leukocytes (neutrophilic) / Mice / Mortality / mRNA / Neutrophil Activation / Neutrophils / Neutrophils - metabolism / Pathogenesis / Physiological aspects / Proteins / Risk factors / Thrombosis / Thrombosis - metabolism / Transcription factors