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.
Highlights
Heart failure (HF) is a serious clinical and public health issue that affects over 23 million people globally, resulting in significant mortality, morbidity, and healthcare expenditures (Ayoub et al, 2017; Orso et al, 2017; Frantz et al, 2018)
A Disintegrin and Metalloprotease 17 (ADAM17) can be activated by intracellular kinases, which include phosphate kinase c (PKC), receptor-stimulated p38 mitogen-activated-protein-kinases (p38 MAPKs), and extracellular signal-regulated kinases (ERKs) (Bell and Gööz, 2010; Xu et al, 2012; Adu-Amankwaah et al, 2021a)
Evidence suggests that the number of identified substrates of this metalloprotease keeps increasing, implying that ADAM17 may play a central role in regulating several physiological and pathophysiological processes
Summary
Heart failure (HF) is a serious clinical and public health issue that affects over 23 million people globally, resulting in significant mortality, morbidity, and healthcare expenditures (Ayoub et al, 2017; Orso et al, 2017; Frantz et al, 2018). Overexpression and chronic activation of ADAM17 can trigger excessive release of TNFα, sIL-6R, and CXCR2 on the surface of proinflammatory cells, which play crucial roles in the pathogeneses of several inflammatory diseases, including heart failure. Besides inducing HF via facilitating hyperactive proinflammatory responses, ADAM17 has been implicated along with HB-EGF and betacellulin (BTC), and angiotensin-converting enzyme 2(ACE2) in causing congenital heart diseases and hypertensive-induced HF, respectively (Jackson et al, 2003; de Queiroz et al, 2015; Xu et al, 2017; Mukerjee et al, 2019) This comprehensive review provides an insight into the structure of ADAM17, how it is activated and regulated during chronic catecholamine stress in heart failure development. How ADAM17-induced chronic inflammation and progressive fibrosis aggravate cardiac dysfunction is discussed
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