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.