11/4/2023 0 Comments Jing zhang illinois![]() These are prevailing issues in understanding the pathogenesis of numerous heart diseases that involve comorbidity of β-AR over-activation and crucial for identification of novel targets to inhibit inflammatory injury of the heart. Moreover, the type of cells and molecular mechanisms responsible for inflammatory cytokine production upon β-AR stimulation still remain unknown. The temporal and spatial profiles of inflammatory cytokine proteins in the heart induced by β-adrenergic stimulation have not been characterized. However, the precise mechanisms by which β-adrenergic insults elicit inflammatory responses in the heart are not understood. Blocking the over-activation of inflammatory responses is proposed as a promising strategy to attenuate cardiac pathological remodelling. 5, 6 These proinflammatory cytokines are known to contribute to myocardial damage and long-term pathological remodelling such as myocardial fibrosis. Indeed, chronic β-adrenergic stimulation using isoproterenol (ISO), a non-selective β-AR agonist, is sufficient to induce expression of several myocardial proinflammatory cytokines, including tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-18. 4 These cardiotoxic effects are known to arise from over-activation of β-adrenergic receptor (β-AR). 3 Acute stress elicits exacerbated secretion of catecholamines (epinephrine and norepinephrine), which in turn increases inflammatory and oxidative responses. 3 Catecholamine overload has been proposed as an important contributing factor for stress cardiomyopathy. 2 Takotsuo cardiomyopathy, also called stress cardiomyopathy, is probably the most striking example of how acute stress directly promotes heart injuries. 1 On the other hand, acute sympathetic insult induced by rapidly developing stress conditions is associated with increased risks of morbidity and mortality in cardiovascular diseases such as ischaemic disease and arrhythmias. ![]() Increases in sympathetic activity are necessary during the flight-or-fight response under acute stress conditions. Our findings identify IL-18 as a novel therapeutic target for amelioration of cardiac damages while retain physiological function of β-adrenergic activity. Blocking IL-18 activity alone soon after β-adrenergic insult effectively prevents adverse cardiac remodelling. Rapid activation of interleukin (IL)-18 specifically in the cardiomyocytes is essential for triggering inflammatory cascades and macrophage infiltration into the heart. Moreover, blocking IL-18 early after ISO treatment effectively attenuated cardiac inflammation and fibrosis. In addition, IL-18 neutralizing antibodies selectively abated ISO-induced chemokines, proinflammatory cytokines and adhesion molecules but not growth factors. Genetic deletion of IL-18 or the up-stream inflammasome component NLRP3 significantly attenuated ISO-induced chemokine expression and macrophage infiltration. Indeed, a positive correlation was observed between the serum levels of norepinephrine and IL-18 in patients with chest pain. Further investigation revealed that the rapid inflammasome-dependent activation of IL-18, but not IL-1β, was the critical up-stream regulator for elevated chemokine expression in the myocardium upon ISO induced β 1-AR-ROS signalling. Cytokine array profiling demonstrated that chemokines dominated the initial cytokines upregulation specifically within the heart upon β-AR insult, which promoted early macrophage infiltration. Male C57BL/6 mice were injected with a single dose of β-AR agonist, isoproterenol (ISO, 5 mg/kg body weight) or saline subcutaneously.
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