The Synergy of ADAM17-Induced Myocardial Inflammation and Metabolic Lipids Dysregulation During Acute Stress: New Pathophysiologic Insights Into Takotsubo Cardiomyopathy

Abstract

Due to its reversible nature, Takotsubo cardiomyopathy (TTC) is considered an intriguing and fascinating cardiovascular disease characterized by a transient wall motion abnormality of the left ventricle, affecting more than one coronary artery territory, often in a circumferential apical distribution. Takotsubo cardiomyopathy was discovered by a Japanese cardiovascular expert and classified as acquired primary cardiomyopathy by the American Heart Association (AHA) in 1990 and 2006, respectively. Regardless of the extensive research efforts, its pathophysiology is still unclear; therefore, there are no well-established guidelines specifically for treating and managing TTC patients. Increasing evidence suggests that sympatho-adrenergic stimulation is strongly associated with the pathogenesis of this disease. Under acute stressful conditions, the hyperstimulation of beta-adrenergic receptors (β-ARs) resulting from excessive release of catecholamines induces intracellular kinases capable of phosphorylating and activating “A Disintegrin and Metalloprotease 17” (ADAM17), a type-I transmembrane protease that plays a central role in acute myocardial inflammation and metabolic lipids dysregulation which are the main hallmarks of TTC. However, our understanding of this is limited; hence this concise review provides a comprehensive insight into the key role of ADAM17 in acute myocardial inflammation and metabolic lipids dysregulation during acute stress. Also, how the synergy of ADAM17-induced acute inflammation and lipids dysregulation causes TTC is explained. Finally, potential therapeutic targets for TTC are also discussed.

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

“…Physiologically, ADAMs and their related metalloenzymes are widely expressed in various body tissues and regulate diverse cellular activities, including cell migration, adhesion, proteolysis, and cellular signaling ( Black et al, 1997 ; Jones et al, 2016 ). Hence, it is not astonishing that alterations in the expression or function of these proteases are implicated in several pathologies, including cancer, rheumatoid arthritis, kidney fibrosis, diabetes, Alzheimer’s disease, and cardiovascular diseases ( Sandgren et al, 1990 ; Black et al, 1997 ; Satoh et al, 2000 ; Umemura et al, 2014 ; Kefaloyianni et al, 2016 ; Zhang et al, 2016 ; Kim et al, 2020 ; Shalaby et al, 2020 ; Adu-Amankwaah et al, 2021a ). Increasing evidence suggests that various ADAMs and other related metalloenzymes play crucial roles in cardiovascular pathophysiology via the modulation of inflammation, angiogenesis, metabolism, cell proliferation, and cell migration ( Adu-Amankwaah et al, 2021a ; Kawai et al, 2021 ).…”

“…Hence, it is not astonishing that alterations in the expression or function of these proteases are implicated in several pathologies, including cancer, rheumatoid arthritis, kidney fibrosis, diabetes, Alzheimer’s disease, and cardiovascular diseases ( Sandgren et al, 1990 ; Black et al, 1997 ; Satoh et al, 2000 ; Umemura et al, 2014 ; Kefaloyianni et al, 2016 ; Zhang et al, 2016 ; Kim et al, 2020 ; Shalaby et al, 2020 ; Adu-Amankwaah et al, 2021a ). Increasing evidence suggests that various ADAMs and other related metalloenzymes play crucial roles in cardiovascular pathophysiology via the modulation of inflammation, angiogenesis, metabolism, cell proliferation, and cell migration ( Adu-Amankwaah et al, 2021a ; Kawai et al, 2021 ). Among the ADAMs identified so far (22 in humans, 34 in mice), ADAM8, 9, 10, 12, 17, 19 and closely related metalloenzymes including MMP2, MMP9, and meprin β are associated with cardiovascular conditions such as hypertension, atherosclerosis, aortic aneurysms, restenosis, acute coronary syndrome, cardiomyopathies and HF ( Papazafiropoulou and Tentolouris, 2009 ; Broder and Becker-Pauly, 2013 ; Zhang et al, 2016 ; Adu-Amankwaah et al, 2021a ; Kawai et al, 2021 ).…”

“…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 ).…”

“…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.…”

“…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 ).…”