Cytokines Link Toll-Like Receptor 4 Signaling to Cardiac Dysfunction After Global Myocardial Ischemia

Abstract

Background-Although Toll-like receptor 4 (TLR4) has been implicated in the myocardial injury caused by regional ischemia/reperfusion, its role in the myocardial inflammatory response and in contractile dysfunction after global ischemia/reperfusion is unclear. Cytokines, particularly tumor necrosis factor-α (TNF-α), contribute to the mechanism of myocardial dysfunction after global ischemia/reperfusion. We hypothesized that a TLR4-mediated cytokine cascade modulates myocardial contractile function after global ischemia/reperfusion. This study examined whether TLR4 regulates TNF-α and interleukin (IL)-1β peptide production during global ischemia/ reperfusion and whether TLR4 signaling influences postischemic cardiac function through TNF-α and IL-1β.

VEGF is critical for stem cell-mediated cardioprotection and a crucial paracrine factor for defining the age threshold in adult and neonatal stem cell function

“…The medical management of the more severe cases of cardiac ischemia is often inadequate, thereby warranting revascularization via percutaneous stenting or arterial bypass. The subsequent reperfusion injury associated with the ischemic episode is also detrimental and results in significant aberrations to the inflammatory cascade (3,8,22). In this regard, bone marrow mesenchymal stem cells (MSCs) represent a novel treatment modality with increasing therapeutic potential (1,12,17,23,27).…”

Critical role of extracellular heat shock cognate protein 70 in the myocardial inflammatory response and cardiac dysfunction after global ischemia-reperfusion

“…In mice treated with the TLR4 antagonist eritoran, myocardial mRNA levels of TNF-␣, IL-1␤, and IL-6 were significantly reduced after regional ischemia-reperfusion (26). In a mouse model of isolated global myocardial ischemia-reperfusion, defective TLR4 was associated with reduced myocardial production of TNF-␣ and IL-1␤ peptides and attenuated postischemic cardiac dysfunction (5). These studies link TLR4 signaling to the postischemic myocardial inflammatory response and cardiac dysfunction, but it remains unclear how TLR4 is activated during myocardial ischemia-reperfusion.…”

Attenuated Recovery of Contractile Function in Aging Hearts Following Global Ischemia/Reperfusion: Role of Extracellular HSP27 and TLR4

“…to regional I/R (21,22) and global I/R (16,23). Our previous studies found that TLR4, particularly myocardial tissue TLR4, plays a major role in mediating myocardial expression of proinflammatory mediators in response to global I/R (16,24).…”

“…Our previous studies found that TLR4, particularly myocardial tissue TLR4, plays a major role in mediating myocardial expression of proinflammatory mediators in response to global I/R (16,24). Furthermore, cardiodepressant cytokines TNF-α and IL-1β link TLR4 to postischemic cardiac dysfunction (16).…”

“…Isolated hearts were perfused with Krebs-Henseleit solution, pH 7.4, using the isovolumetric Langendorff technique as described previously (16,31). For global myocardial I/R experiments, hearts were equilibrated by perfusion of the Krebs-Henseleit solution for 20 min, then subjected to 20 min of normothermic global ischemia and 60 min reperfusion.…”