ADAM17, A Key Player of Cardiac Inflammation and Fibrosis in Heart Failure Development During Chronic Catecholamine Stress

Abstract

Heart failure development is characterized by persistent inflammation and progressive fibrosis owing to chronic catecholamine stress. In a chronic stress state, elevated catecholamines result in the overstimulation of beta-adrenergic receptors (βARs), specifically β2-AR coupling with Gαi protein. Gαi signaling increases the activation of receptor-stimulated p38 mitogen-activated-protein-kinases (p38 MAPKs) and extracellular signal-regulated kinases (ERKs). Phosphorylation by these kinases is a common way to positively regulate the catalytic activity of A Disintegrin and Metalloprotease 17 (ADAM17), a metalloprotease that has grown much attention in recent years and has emerged as a chief regulatory hub in inflammation, fibrosis, and immunity due to its vital proteolytic activity. ADAM17 cleaves and activates proinflammatory cytokines and fibrotic factors that enhance cardiac dysfunction via inflammation and fibrosis. However, there is limited information on the cardiovascular aspect of ADAM17, especially in heart failure. Hence, this concise review provides a comprehensive insight into the structure of ADAM17, how it is activated and regulated during chronic catecholamine stress in heart failure development. This review highlights the inflammatory and fibrotic roles of ADAM17’s substrates; Tumor Necrosis Factor α (TNFα), soluble interleukin-6 receptor (sIL-6R), and amphiregulin (AREG). Finally, how ADAM17-induced chronic inflammation and progressive fibrosis aggravate cardiac dysfunction is discussed.

Proteomic Characterization of Peritoneal Extracellular Vesicles in a Mouse Model of Peritoneal Fibrosis

“…Among these DEPs, ADAM17, a metalloprotease, has been indicated to participate in inflammation, fibrosis, and immunity using its proteolytic activity, eventually aggravating cardiac dysfunction. 27 Other study suggested that abnormal ADAM17 expression can cause airway fibrosis in chronic obstructive asthma. 28 ITGB3 is a multifunctional cell surface receptor and regulates downstream intracellular signals including cell adhesion, proliferation, migration, survival, and differentiation.…”

“…By analyzing the DEPs between Con EVs and PD EVs, we found that up-regulated proteins in PD EVs were enriched in response to wounding and leukocyte migration, supporting the development of fibrosis. Among these DEPs, ADAM17, a metalloprotease, has been indicated to participate in inflammation, fibrosis, and immunity using its proteolytic activity, eventually aggravating cardiac dysfunction . Other study suggested that abnormal ADAM17 expression can cause airway fibrosis in chronic obstructive asthma .…”

Dysregulated inflammasome activity in intestinal inflammation – Insights from patients with very early onset IBD

“…Mutations in A disintegrin and metalloprotease 17 (ADAM17) can cause VEO-IBD associated with skin inflammation and susceptibility to gastrointestinal and skin infections ( 209 ). ADAM17 has been shown to cleave the pro-inflammatory cytokine TNF-α, which is produced as membrane-bound precursor after activation ( 210 – 212 ). In line, PBMCs from patients with ADAM17 deficiency produce reduced amounts of TNF-α upon LPS stimulation ( 209 ).…”

“…In line, PBMCs from patients with ADAM17 deficiency produce reduced amounts of TNF-α upon LPS stimulation ( 209 ). TNF-α-mediated activation of NF-κB signaling has been shown to induce expression of NLRP3 inflammasome components (e.g., NLRP3, IL-1β, and IL-18) and modulate pyrin inflammasome activity ( 210 , 213 , 214 ). In line, targeting TNF-α in a mouse model of autoinflammation caused by NLRP3 mutations was shown to ameliorate symptoms ( 213 ).…”

Downregulation of amphiregulin improves cardiac hypertrophy via attenuating oxidative stress and apoptosis

“…Amphiregulin (AREG) is a ligand of epidermal growth factor receptor (EGFR), which is widely expressed in cardiomyocytes and fibroblasts [ 8 ]. Under physiological conditions, the activation of EGFR in the heart induces major intracellular signal cascades and control fibroblast proliferation, migration and collagen synthesis.…”