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). Despite advances in understanding its pathophysiology and treatment, the prognosis of patients with HF remains poor. Approximately 2–17% of patients die during their first hospital stay, with over 50% of patients dying within 5 years (Ayoub et al., 2017).

Chronic stress-induced adverse cardiac remodeling and HF are generally associated with prolonged activation of proinflammatory responses (Adzika et al., 2021; Huo S. et al., 2021). In an inflammatory driven HF, the inflammatory responses are orchestrated by myosin and troponin (damage-associated molecular patterns (DAMPs)) released from necrotic cardiomyocytes. These cardiac antigens activate and induce the infiltration of neutrophils, macrophages, dendritic cells, as well as T and B cells into the myocardia (Lafuse et al., 2020; Adzika et al., 2021). Following cardiac injury, neutrophils and CD86⁺ macrophages are rapidly recruited to the injured area, where they initiate inflammatory responses with the goal of cleaning up dead cell debris. However, excessive accumulation and/or delayed switch from these proinflammatory cells infiltration to reparative inflammatory cells (such as CD206⁺ macrophages) has detrimental effects. By releasing reactive oxygen species, granular components, and proinflammatory mediators such as tumor necrosis factor-alpha (TNFα), soluble interleukin-6 receptor (sIL-6R), and CXC chemokine receptor 2 (CXCR2), neutrophils and macrophages contribute to adverse myocardial injury and remodeling (Adu-Amankwaah et al., 2021a; Ma, 2021). Additionally, the activation of T and B lymphocytes by dendritic cells has been shown to play crucial roles in myocardial inflammation (Santos-Zas et al., 2018; Santos-Zas et al., 2021). Ultimately, without timely resolution of these proinflammatory responses and initiates of reparative functions, genes encoding proinflammatory mediators and fibrotic factors are upregulated excessively (Epelman et al., 2014; Heidt et al., 2014; Adamo et al., 2020).

Proteolytic cleavage of transmembrane proteins is a vital post-translational modification that controls several transmembrane proteins’ biological function, including proinflammatory mediators and growth factors (Lichtenthaler et al., 2018; Düsterhöft et al., 2019). Amid the 560 proteases encoded in the human genome, A Disintegrin and Metalloprotease 17 (ADAM17) 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 (Düsterhöft et al., 2019). In immune and non-immune cells, ADAM17 cleaves a number of substrates, including ligands of the epidermal growth factor receptor (EGFR), adhesion molecules, proinflammatory cytokines, and chemokines and their receptors. Some of these substrates include amphiregulin (AREG), epigen, epiregulin, neuregulin, tomoegulin-2, transforming growth factor-alpha (TGF-α), heparin-binding epidermal growth factor (HB-EGF), TNFα, tumor necrosis factor β (TNFβ), the TNF receptors 1 and 2 (TNFR 1 and 2), and interlukin-6 receptor (IL-6R), CXCR2, collagen XVII, desmoglein-2 and nectin-4 (Black et al., 1997; Moss et al., 1997; Tellier et al., 2006; Reddy et al., 2009; Riethmueller et al., 2017; Kawai et al., 2021). According to Cabron et al. ADAM17 is a key regulator of soluble TNFα surface levels in proinflammatory macrophages and dendritic cells (Cabron et al., 2018). Additionally, sIL-6R and CXCR2 on human and mouse neutrophils surfaces are regulated by ADAM17 (Wright et al., 2014; Mishra et al., 2015).

In a physiological state, the expressions of ADAM17 in immune and non-immune cells are regulated by transcriptional and post-transcriptional factors, including nuclear factor kappa B (NF-κB) and Brahma-related gene 1 (BRG1). Furthermore, subcellular localization in the perinuclear region of cells has been shown to regulate ADAM17’s activity (Chemaly et al., 2017; Adu-Amankwaah et al., 2021a). 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. Increased levels of TNFα, sIL-6R and CXCR2 have been implicated in immune cells (CD86⁺ macrophages, neutrophils, and dendritic cells) trafficking, migration, and activation as well as inducing excessive fibrosis, myocardial stiffness, and left ventricular diastolic dysfunction (Cumberbatch and Kimber, 1992; Bozkurt et al., 1998; Satoh et al., 2000; Russo et al., 2009; Jones et al., 2010; Anderson et al., 2013; Arokiasamy et al., 2017).

Several studies have shown that myocardial ADAM17, TNFα, and sIL-6R expressions in both mRNA and protein levels are higher in patients with cardiovascular diseases and complications, although ADAM17’s expression is downregulated in a normal state (Satoh et al., 1999; Damås et al., 2000; Satoh et al., 2000; Satoh et al., 2004; Anderson et al., 2013). Thus, establishing a positive correlation between ADAM17 and heart failure development. The increased expression of ADAM17, TNFα, and sIL-6R has a vital implication in aggravating cardiac dysfunction during heart failure development (Satoh et al., 1999; Satoh et al., 2000; Satoh et al., 2004; Adu-Amankwaah et al., 2021a). Additionally, pro-AREG, a bi-functional growth factor converted to its active form by ADAM17, is crucially involved in enhancing cardiac fibrosis and aggravating cardiac dysfunction (Liu et al., 2018). 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. This review highlights the inflammatory and fibrotic roles of ADAM17’s substrates; TNFα, sIL-6R, and sAREG. Finally, how ADAM17-induced chronic inflammation and progressive fibrosis aggravate cardiac dysfunction is also discussed.

Chronic stress is a renowned risk factor for several cardiovascular diseases (Kivimäki and Steptoe, 2018). One of the central neural pathways activated by stress is the autonomic nervous system. During chronic stress, the sympathetic nervous system can be continuously activated, which results in elevated levels of catecholamines (epinephrine and norepinephrine) (Won and Kim, 2016). Epinephrine and norepinephrine function as hormones and neurotransmitters that maintain homeostasis via adrenergic receptors (ARs), including alpha-adrenergic receptors (α-ARs) and beta-adrenergic receptors (β-ARs). Studies have demonstrated the involvement of ADAM17 with α1-AR (Chen et al., 2006) and β-AR signaling (Zhu and Steinberg, 2021). β-ARs account for the majority of the total ARs in the heart (O’Connell et al., 2014), particularly in apical myocytes (Paur et al., 2012; Machuki et al., 2019) and cardiac non-myocytes such as endothelial and immune cells (Myagmar et al., 2017; Adzika et al., 2021). Hence, a continuous increase in the levels of epinephrine and norepinephrine can result in overstimulation of β-ARs (Machuki et al., 2019). Epinephrine is a more potent ligand for β-ARs compared to norepinephrine (Scanzano and Cosentino, 2015). β-ARs are 7-transmembrane, G-protein coupled receptors which are divided into four subtypes, namely; β1-AR, β2-AR, β3-AR, and β4-AR (Ahlquist, 1948; Bylund et al., 1994; Granneman, 2001). In the heart, the β1-AR, β2-AR, and β3-AR are all broadly expressed, with the β1-AR having the highest expression and the β3-AR having the lowest (Ahlquist, 1948; Madamanchi, 2007). The β4-AR is a low-affinity state of the β1-AR that is yet to be genetically and pharmacologically characterized (Granneman, 2001). The β2-AR and β3-AR can couple with Gαs or Gαi while β1-AR primarily couples with Gαs when activated (Machuki et al., 2019; Schena and Caplan, 2019). In physiological state, the activation of β2-AR and β3-AR couple with Gαs (Adzika et al., 2019; Machuki et al., 2019) and Gαi (Tchivileva et al., 2009; Schena and Caplan, 2019), respectively. Among these βARs, β2-AR is rarely depleted during stress, and it is also the most implicated in mediating signaling cascades in ventricular apical myocytes, cardiac endothelial and immune cells resulting in the initiation and progression of cardiovascular diseases (Paur et al., 2012; Adzika et al., 2019; Adu-Amankwaah et al., 2021a).

In the heart, the overstimulation of β-ARs on ventricular apical myocytes, cardiac endothelial and immune cells due to elevated levels of circulating catecholamine desensitize β1-ARs (Bristow et al., 1990; Paur et al., 2012; Machuki et al., 2019). According to Zhu and Steinberg, the inactivation of β1-ARs and its irresponsiveness to catecholamines in cardiomyocytes during stressful events is via a mechanism involving N-terminal truncation at R³¹↓L³² by ADAM17 (Zhu and Steinberg, 2021). As such, β2-ARs coupling to Gαi is induced (Bristow et al., 1990; Paur et al., 2012; Machuki et al., 2019; Adzika et al., 2021). In short-terms, Gαi signaling increases via Akt/PI3K/p38 MAPKs/ERKs to prevent cardiac insult (Magocsi et al., 2007; Lajevic et al., 2011; Hou et al., 2018). Recent findings have suggested that the prolonged hyperstimulation of β2-ARs on ventricular apical myocytes and cardiac immune cells induces the bindings of β-arrestin-2 and G protein-coupled receptor kinases (GRKs) to scaffold non-canonical signaling that activates ERKs and p38 MAPKs activities maladaptively, ultimately resulting in HF (Shenoy et al., 2006; Paur et al., 2012; Adzika et al., 2019; Adzika et al., 2021). Intriguingly, ADAM17 initiates its adverse remodeling cascade upon being phosphorylated by these kinases directly and indirectly. For instance, during the maturation of ADAM17, ERK-dependent threonine 735 (Thr735) phosphorylation is vital for it to reach the secretory pathway (Díaz-Rodríguez et al., 2002; Chemaly et al., 2017). Also, indirect ERKs or p38 MAPKs phosphorylation at 14-3-3 binding sites on the N-terminal of iRhoms turns to induce ADAM17’s trafficking, stabilization, and cell surface expressions (Bell and Gööz, 2010; Adrain and Freeman, 2012; McIlwain et al., 2012; Xu et al., 2012; Li et al., 2015; Grieve et al., 2017). On the cell surface, mature ADAM17 proteins exist as inactive homodimers coupled to their inhibitor, TIMP3. However, activation of the ERK or p38 MAPK pathway directly phosphorylates Thr735 on the intracellular domain of ADAM17 and transforms it from a dimer structure into an active monomer structure liberating it from TIMP3 (Xu et al., 2012; Chemaly et al., 2017). Following monomerization, ADAM17 then binds to the phosphatidylserine exposure at the outer leaflet of the cell membrane via its MPD and CANDIS, thereby initiating its cleaving process (Gooz, 2010; Figure 2).

ADAM17 plays a key role in cardiac inflammation, as it can cleave and activate several proinflammatory cytokines and their receptors. The most prominent examples include the cytokine TNFα, the TNFR 1 and 2, and the IL-6R (Black et al., 1997; Moss et al., 1997; Tellier et al., 2006; Reddy et al., 2009; Riethmueller et al., 2017).

ADAM17 is known to activate amphiregulin (AREG) via its proteolytic cleavage activity (Liu et al., 2018). AREG is synthesized as a type-I transmembrane protein (pro-AREG) that can engage in juxtracrine signaling on adjacent cells (Berasain and Avila, 2014). Alternatively, after proteolytic processing, the release of soluble AREG (sAREG) can act as an autocrine or paracrine factor (Berasain and Avila, 2014). sAREG is a ligand of the EGFR (Berasain and Avila, 2014; Liu et al., 2018), widely expressed on cardiac myocytes and fibroblasts (Berasain and Avila, 2014; Liu et al., 2018). In a physiological state, activation of EGFR in the heart induces major intracellular signaling cascades governing fibroblasts proliferation, migration, and collagen synthesis. However, prolonged activation of EGFR in a chronic stress state characterized by continuous elevation of sAREG can enhance cardiac fibroblast activation, proliferation, differentiation to myofibroblast, migration, and collagen synthesis (Liu et al., 2018). The binding of sAREG to EGFR, causes the receptor to undergo a conformational change inducing homo- or heterodimers formation (Dawson et al., 2005; Rayego-Mateos et al., 2018). 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 (Dawson et al., 2005; Rayego-Mateos et al., 2018). This signaling pathway plays a vital role in transducing stress and growth signals in the heart during cardiac fibrosis (Wagner and Siddiqui, 2012). The activation of the JAK/STAT pathway can increase the gene expression of fibroblasts and pro-fibrotic factors such as transforming growth factor-beta (TGF-β) (Wang et al., 2002). Physiologically, cardiac fibroblasts are responsible for the homeostasis of the extracellular matrix (ECM), which provides a structural scaffold for cardiomyocytes, distributes mechanical forces through the cardiac tissue, and mediates electrical conduction (Travers et al., 2016). However, elevated fibroblasts can result in fibroblast activation, both mechanically by altered activation patterns and chemically by inflammatory mediators (Wang et al., 2002). Notably, elevated TNFα and IL-6 secretions from macrophages, T and B lymphocytes during chronic inflammation also contributes to the aggravation of cardiac fibrosis as these cytokines stimulate fibroblast proliferation, differentiation to myofibroblast, and their migration (Wang et al., 2002; Adekunle et al., 2021). Also, TGF-β plays a vital role in ECM remodeling, cell mobility, and modulation of immune function. Increased levels of it are crucial in cell differentiation and proliferation of activated fibroblasts to myofibroblasts (Baum and Duffy, 2011). Myofibroblasts are not present in normal cardiac tissue unless during cardiac injury (Manabe et al., 2002). Myofibroblasts can induce pathological ECM remodeling (Manabe et al., 2002) via the expression of smooth muscle alpha-actin (α-SMA) (Sousa et al., 2007), collagen synthesis, and secretion of MMPs (Manabe et al., 2002). MMPs are responsible for the breakdown of the extracellular matrix in many diseases (Liu et al., 2006). Chronic secretion of MMPs in the heart leads to the degradation of collagen and elastin into peptide fragments resulting in elevated collagen deposition in the ECM, leading to scar formation. Although the formation of fibrotic scar tissue is an adaptive way of maintaining the structural integrity and pressure-generating capacity of the heart, myofibroblast persistence due to chronic stress can eventually result in the development of adverse changes in ventricular structure and compliance, which characterizes cardiac fibrosis (Liu et al., 2006; Figure 4). Intriguingly, ADAM17 upregulation does enhance the secretions of the aforementioned cytokine from both innate and adaptive immune cells either via direct or indirect cascade to cause maladaptive interstitial fibrosis.

HF development is characterized by a progressive condition associated with left ventricular (LV) systolic or diastolic dysfunction resulting in insufficient oxygen and nutrient supply to peripheral organs. It can exist in two main forms, namely, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) (Van Linthout and Tschöpe, 2017; Adu-Amankwaah et al., 2021b). HFpEF is accompanied by diastolic dysfunction characterized by impaired ventricle relaxation and filling, increased ventricle stiffness, and elevated filling pressure to respond to pressure overload (Adekunle et al., 2021). On the flip side, HFrEF is associated with systolic dysfunction characterized by impaired left ventricular contractility, resulting in a reduced ejection fraction (Tanai and Frantz, 2015). Cardiac inflammation and fibrosis play a central role in HF development (Liu et al., 2018). Both can trigger HF development under several conditions, ranging from acute stress to chronic catecholamine stress.

The outcome of inflammation and fibrosis can contribute to the pathogenesis of the two main forms of HF. Although elevated serum concentrations of proinflammatory cytokines and fibrotic factors are common in both forms of HF, the pathomechanisms involved in each are different. For HFpEF, studies reveal that the outcome of chronic inflammation leads to progressive fibrosis, which eventually results in LV hypertrophy (Manabe et al., 2002; Salles et al., 2007; Wynn, 2008). Excessive increase in ECM components and cross-linking during LV hypertrophy can induce myocardial stiffness, thereby triggering HFpEF-specific, characterized by concentric cardiac remodeling and LV diastolic dysfunction (Paulus and Tschöpe, 2013). For example, collagen I which stiffens the myocardia, accounts for about 80% of the total collagen in the myocardia and increases most during LV hypertrophy (Barison et al., 2015). In addition, excessive cross-linking during LV hypertrophy stiffens the collagen matrix, making it more difficult to be broken down by proteinases (Travers et al., 2016). According to Hieda et al., increased myocardial stiffness is frequently observed in patients with HFpEF (Hieda et al., 2020). Regarding HFrEF, excessive cardiomyocyte death preceding necrosis or apoptosis due to persistent cardiac inflammation can result in cardiac atrophy. Continued loss of cardiac tissue can induce systolic dysfunction leading to HFrEF-specific, characterized by eccentric cardiac remodeling and dysfunction (Van Linthout and Tschöpe, 2017). Undeniably, several large studies have reported that patients with HFrEF characterized by systolic dysfunction have elevated serum levels of proinflammatory cytokines such as TNFα, IL-6, and IL-1β (Torre-Amione et al., 1996; Rauchhaus et al., 2000; Deswal et al., 2001).

ADAM17 is widely expressed by several mammalian cells. 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. Hence, its implicated in several human diseases as such heart failure is expected. Although, current drug treatments and the subsequent use of recognized medications have reduced mortality and hospitalization rate, particularly in HF patients with reduced ejection fraction (Berliner and Bauersachs, 2017), HF remain a major clinical and public health concern since it affects more than 23 million worldwide (Ayoub et al., 2017; Orso et al., 2017; Frantz et al., 2018); hence there is still a lot to discover about this condition which will serve as a key in establishing specific treatment and management guidelines to significantly reduced the rate of HF. This comprehensive review has provided extensive insight into the mechanisms underlying catecholamine-induced HF. Therefore, therapeutic prospects for the treatment and management of catecholamine-induced HF should also target the inhibition of ADAM17 and/or antagonize its activation and activities.

For decades, ADAM17 has been the subject of intense research. Since its identification as the tumor necrosis factor convertase, it has been an important therapeutic target, particularly in the setting of inflammatory diseases. Nonetheless, developing medications that target ADAM17 has proven more difficult than anticipated. This is owing to ADAM17’s multifunctionality, which includes the release of approximately 90 other substrates aside from tumor necrosis factor (TNF), as well as its structural similarities to other metalloproteinases (Calligaris et al., 2021). The most promising targets of ADAM17 (without any significant physiological consequences) appear to be inhibiting its phosphorylation by ERKs, p38 MAPKs, iRhom1, and iRhom2. These regulators are vital for trafficking, stabilization, and activation of ADAM17 (Bell and Gööz, 2010; Adrain and Freeman, 2012; McIlwain et al., 2012; Xu et al., 2012; Li et al., 2015; Grieve et al., 2017). Usage of pharmacologic agents capable of impeding ADAM17 phosphorylation by ERKs and p38 MAPKs may be an attractive potential target for downregulating ADAM17’s proteolytic activity. Also, it is well-known that iRhom2 is mainly expressed in proinflammatory immune cells, such as macrophages and neutrophils (Adrain and Freeman, 2012), whereas iRhom1 is predominantly expressed in non-immune cells (Issuree et al., 2013; Chemaly et al., 2017). Hence, it is tempting to hypothesize that inhibition of iRhom2 would aid in the downregulation of ADAM17 with no effects on non-immune cells. iRhom1 activities may then compensate for the iRhom2 blockade. Also, the inhibition of ADAM17 could be achieved by injecting its natural inhibitors (TIMP3, PDIs, and integrins). Notably, injection of TIMP3 has been shown to prevent heart failure post-myocardial infarction (Martz, 2014; Takawale et al., 2017; Chintalgattu et al., 2018). PDIs can also interact directly with ADAM17’s MPD, which catalyzes the isomerization of two disulfide bridges, lowering ADAM17’s activity (Willems et al., 2010). Furthermore, the binding of integrin α5β1 to ADAM17 via its disintegrin domain, according to Bax et al., inhibited its activity by altering its mediated cell adhesion and migration (Bax et al., 2004). Besides its natural inhibitors, miRNAs such as miR-124 (Sun et al., 2013), miR-145 (Doberstein et al., 2013), miR-152 (Su et al., 2014), and miR-326 (Cai et al., 2015) have been shown to suppress ADAM17 expression and limit substrate release by binding directly to the ADAM17 3′-UTR.

The modulation of ADAM17 is key in ameliorating cardiac function via attenuation of myocardial inflammation during chronic catecholamine stress. Thus, minimizing the levels of TNFα and other proinflammatory cytokines is necessary for the heart’s normal function; hence, inhibiting ADAM17 which facilitates the activities of these cytokines, might enhance cardiac health or delay the progression of its pathological remodeling into HF.