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.

Keywords: ADAM17; cardiac fibrosis; cardiac inflammation; fibrotic factors; heart failure; metalloenzymes; pro-inflammatory cytokines.

GRAPHICAL ABSTRACT

FIGURE 1

Schematic overview of the structure, function, maturation process, and regulation of ADAM17. The metalloprotease ADAM17 can be divided into seven domains with distinct functions, here separated by different colors. During maturation of ADAM17, the pro-domain is cleaved of by furin proteases. The activation of this metalloprotease is via its intracellular region by kinases; PKC, ERKs, and p38 MAPKs. These kinases are also known to phosphorylate and activate iRhoms for trafficking, stabilization, and cell surface expression of ADAM17. However, the inhibition of ADAM17 is mostly carried out by TIMP3, PDIs, and integrins.

FIGURE 2

Schematic illustration of ADAM17’s activation during chronic catecholamine stress. Elevated catecholamines owning to chronic stress results in overstimulation of β2-ARs coupling with Gαi. Gαi signaling induces the activation of intracellular kinases, ERKs and p38 MAPKs. These kinases are known to either directly phosphorylate and activate ADAM17 or activate iRhoms responsible for trafficking, stabilization, and cell surface expression of ADAM17, thereby initiating its cleaving process.

FIGURE 3

Schematic illustration of the inflammatory roles of ADAM17’s substrates, sTNFα and sIL-6R in a cardiac cell during chronic catecholamine stress. Following the proteolytic processing of ADAM17, sTNFα and IL-6 can bind to TNFR1/2 and sIL-6R, respectively activating downstream signaling cascades. Activated TNFR1 can directly induce inflammation and programmed cell death. The activation of TNFR2 can cause it to interact with the IκB kinase (IKK) complex resulting in the phosphorylation of IκB, thereby activating NF-κB. Also, the IL-6/sIL-6R complex formed from IL-6 binding to sIL-6R can directly activate the ubiquitously expressed glycoprotein-130 (gp130), thereby activating NF-κB. Activated NF-κB can either migrates into the nucleus or mitochondria. In the nucleus, it encodes genes of proinflammatory cytokines (pro-IL-18 and pro-IL-1β) and NLRP3, increasing their protein expression. NLRP3 inflammasome can activate caspase 1, which in turn cleaves pro- IL-1β and pro- IL-18 to release their soluble forms, to induce necrosis and inflammation in cardiac cells. Additionally, in the mitochondria, activated NF-κB can stimulate intrinsic apoptotic pathways via releasing cytochrome c, which triggers caspase cascades resulting in programmed cell death and inflammation.

FIGURE 4

Schematic illustration of the fibrotic role of sAREG, a substrate of ADAM17. After the proteolytic process of ADAM17, sAREG can activate EGFR, which is widely expressed on cardiac cells. The binding of sAREG to EGFR causes the receptor to undergo a conformational change known as “Dimerization,” resulting in homo- or heterodimers formation. This precedes an intracellular domain activation in its tyrosine residues by phosphorylation, promoting these same residues’ autophosphorylation in their homolog. Autophosphorylation of EGFR can activate it to induce the JAK/STAT pathway, leading to an increase in gene and protein expression of fibroblasts and pro-fibrotic factors such as TGF-β. Elevated fibroblasts can result in fibroblast activation, both mechanically by altered activation patterns and chemically by inflammatory mediators. Activated fibroblasts are transformed into myofibroblasts by TGF-β. Myofibroblasts are not present in normal cardiac tissue unless during cardiac injury and can induce pathological ECM remodeling, which characterizes cardiac fibrosis via the expression of α-SMA, collagen synthesis, and secretion of MMPs.