IL-1β reduces cardiac lymphatic muscle contraction via COX-2 and PGE2 induction: Potential role in myocarditis

Abstract

The role of lymphatic vessels in myocarditis is largely unknown, while it has been shown to play a key role in other inflammatory diseases. We aimed to investigate the role of lymphatic vessels in myocarditis using in vivo model induced with Theiler's murine encephalomyelitis virus (TMEV) and in vitro model with rat cardiac lymphatic muscle cells (RCLMC). In the TMEV model, we found that upregulation of a set of inflammatory mediator genes, including interleukin (IL)-1β, tumor necrosis factor (TNF)-αand COX-2 were associated with disease activity. Thus, using in vitro collagen gel contraction assays, we decided to clarify the role(s) of these mediators by testing contractility of RCLMC in response to IL-1β and TNF-α individually and in combination, in the presence or absence of: IL-1 receptor antagonist (Anakinra); cyclooxygenase (COX) inhibitors inhibitors (TFAP, diclofenac and DuP-697). IL-1β impaired RCLMC contractility dose-dependently, while co-incubation with both IL-1β and TNF-α exhibited synergistic effects in decreasing RCLMC contractility with increased COX-2 expression. Anakinra maintained RCLMC contractility; Anakinra blocked the mobilization of COX-2 induced by IL-1β with or without TNF-α. COX-2 inhibition blocked the IL-1β-mediated decrease in RCLMC contractility. Mechanistically, we found that IL-1β increased prostaglandin (PG) E release dose-dependently, while Anakinra blocked IL-1β mediated PGE release. Using prostaglandin E receptor 4 (EP4) receptor antagonist, we demonstrated that EP4 receptor blockade maintained RCLMC contractility following IL-1β exposure. Our results indicate that IL-1β reduces RCLMC contractility via COX-2/PGE signaling with synergistic cooperation by TNF-α. These pathways may help provoke inflammatory mediator accumulation within the heart, driving progression from acute myocarditis into dilated cardiomyopathy.

Myocardial oedema: pathophysiological basis and implications for the failing heart

“…146,147 Moreover, inflammation-driven up-regulation of ECM-degrading enzymes promotes both ECM and basement membrane degradation, decreasing interstitial exclusion effect and facilitating the interstitial passage of fluid, proteins and immune cells. 148 ECM degradation has been shown in acute high-grade myocardial inflammation, especially in experimental myocarditis 149 and sepsis, 150 where a significant acute decrease in total myocardial collagen content and collagen degradation were observed and associated with MO, systolic and diastolic dysfunction. Further supporting this experimental observation, post-mortem evaluation of human septic myocardium found significant ECM disruption and interstitial oedema at the subepicardium, which colocalized with macrophage infiltration and cardiomyocyte apoptosis.…”

Function of the P2X7 receptor in hematopoiesis and leukemogenesis

“…IL-1b further activates the downstream targets of cyclooxygenase-2 (COX-2) and prostaglandin 2 (PGE2). These results indicate that the P2X7 receptor may participate in the pathologic process through the IL-1b/COX/PGE pathways [90,91]. The P2X7 receptor also activates the P38/MAPK pathways to sustain the p38 phosphorylation level by mediating the flux of K + and Ca 2+ [92] and upregulation of cysteine cathepsin S (CatS) in cells.…”

Lymphatic Function and Dysfunction in the Context of Sex Differences

“…It is possible that LECs may also have sex dimorphisms in Cx protein expression. Notably, differential expression of Cx proteins even within cardiomyocytes could have indirect effects on the lymphatic system, especially within cardiac lymphatics that require cardiac contractions to propel cardiac lymphatic flow. − Sex differences exist in key components of cellular connections between LECs, and because proper maintenance and function of lymphatics depends on junctional integrity and permeability of lymphatic vessels, further studies are warranted to fully understand biological differences of the sexes in lymphatic barrier and permeability.…”

“…Recent work has highlighted the importance of cardiac lymphatics in the healing and remodeling process post-MI. ,,, However, until recently cardiac lymphatics had been largely unexplored compared to lymphatics of other organ systems. Cardiac edema is extremely common and even mild edema can have profound detrimental long-term consequences on cardiovascular health and function. , General cardiovascular health plays an important role in cardiac lymphatics, because unlike other lymphatic systems, cardiac lymphatics generally lack contractile lymphatic smooth muscles cells thus lymph flow relies heavily on extrinsic cardiac contractile forces and central venous pressures. − There are many innate sex-specific physiological differences in the cardiovascular system that may indirectly affect cardiac lymphatic function: men have a larger left ventricular mass, women have increased contractility compared to age-matched men, cardiac apoptosis associated with aging is three-times higher in men than women, women have lower blood pressure but higher heart rates, and women have smaller coronary arteries. ,− New studies in mice show that males and females have innate differences in cardiac lymphatic development; women have more cardiac lymphatic vessels than males, which is even further exacerbated with Adm overexpression . This may be a new explanation for some of the innate cardioprotective phenotypes observed in women.…”