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.

Keywords: ADAM17; acute myocardial inflammation; acute stress; metabolic lipids dysregulation; pathophysiology; takotsubo cardiomyopathy; therapeutic targets.

Figure 1

A schematic diagram illustrating the key roles played by ADAM17 and its substrates in inducing acute myocardial inflammation and metabolic lipids dysregulation during acute stressful conditions. In an acute stress state, the hyperactivation of beta-adrenergic receptors resulting from the excessive release of catecholamines influences the activation of ADAM17 via intracellular phosphorylation by ERKs and p38 MAPKs. Hyperactive ADAM17 cleaves and activates TNFα and IL-6R to trigger cell signaling cascades, leading to NF-kB activation. Active NF-kB successfully causes acute myocardial inflammation via the gene elevation of pro-inflammatory cytokines (IL-18, IL-1β) and inflammasomes (NLRP3) in the nucleus, as well as the release of cytochrome c from the mitochondria. Additionally, the activation of NF-kB causes a reduction in the activity of PPARβ/δ and PPARα, thereby leading to a decreased mRNA and protein levels of key regulatory enzymes of fatty acid oxidation, which characterizes metabolic lipids dysregulation. Hence, the proposed therapeutic targets for the attenuation of acute myocardial inflammation and metabolic lipids dysregulation may include; the inhibition of ADAM17 and NF-kB's activation and enhancing the activities of PPARβ/δ and PPARα.

Figure 2

A schematic representation of how acute myocardial inflammation, in combination with metabolic lipid dysregulation, contributes to takotsubo cardiomyopathy. Elevated cytokines (TNFα, IL-6, IL-1β) and reduced fatty acid oxidation resulting from ADAM17-induced acute myocardial inflammation and metabolic lipids dysregulation successfully lead to left ventricular abnormalities characterized by reduced intracellular calcium and adenosine triphosphate (ATP) production; increased cell death (apoptosis/necrosis) and intramyocardial lipids accumulation (lipotoxicity), which are the main hallmarks of takotsubo cardiomyopathy.