Deficiency in TLR4 signal transduction ameliorates cardiac injury and cardiomyocyte contractile dysfunction during ischemia

Abstract

Toll-like receptor 4 (TLR4), a proximal signalling receptor in innate immune responses to lipopolysaccharide of gram-negative pathogens, is expressed in the heart. Accumulating evidence have consolidated the notion that TLR4 plays an essential role in the pathogenesis of cardiac dysfunction. However, the molecular mechanisms of TLR4 responsible for ischemia-induced cardiac dysfunction remain unclear. To address the signalling mechanisms of TLR4-deficiency cardioprotection against ischemic injury, in vivo regional ischemia was induced by occlusion of the left anterior descending coronary artery in wild-type (WT) C3H/HeN and TLR4-mutated C3H/HeJ mice. The results demonstrated that blunted ischemic activation of p38 mitogen-activated protein kinase and JNK signalling occurred in C3H/HeJ hearts versus C3H/HeN hearts, while ERK and AMP-activated protein kinase (AMPK) signalling pathways were augmented during ischemia in C3H/HeJ hearts versus C3H/HeN hearts. Intriguingly, ischemia-stimulated endoplasmic reticulum stress was higher in C3H/HeN hearts than that in C3H/HeJ as demonstrated by up-regulation of Grp78/BiP, Gadd153/CHOP and IRE-1α. Myocardial infarct, caspase-3 activity and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining demonstrated that C3H/HeN hearts suffered more damage than those of C3H/HeJ hearts during ischemia. Moreover, isolated cardiomyocytes from C3H/HeJ hearts showed resistance to hypoxia-induced contractile dysfunction compared to those from C3H/HeN hearts, which are associated with greater hypoxic activation of AMPK and ERK signalling, better intracellular Ca2+ handling in C3H/HeJ versus C3H/HeN cardiomyocytes. These findings suggest that the cardioprotective effects against ischemic injury of hearts with deficiency in TLR4 signalling may be mediated through modulating AMPK and ERK signalling pathway during ischemia.

TLR4 regulates cardiac lipid accumulation and diabetic heart disease in the nonobese diabetic mouse model of type 1 diabetes

“…TLR4 is expressed in the heart (4) and is linked to atherosclerosis (3) and ischemia-induced cardiac dysfunction (35). It has been reported to play a key role in metabolic dysfunction and heart disease (17).…”

Matrine pretreatment improves cardiac function in rats with diabetic cardiomyopathy via suppressing ROS/TLR-4 signaling pathway

“…Recent studies presented novel evidence that TLR-4 may contribute to myocardial apoptosis related to various cardiomyopathies in inflammation and oxidative stress, indicating that TLR-4 deficiency provides potent anti-apoptotic protection in myocytes [18][19][20] . Additionally, the excessive intracellular ROS generation induced by oxidative stress may activate the TLR-4 signaling pathway [21][22][23] .…”

Increased Th17 rather than Th1 alloimmune response is associated with cardiac allograft vasculopathy after hypothermic preservation in the rat

“…TLR4 is considered the prime mediator of the innate immune response and the subsequent adaptive immune responses after cardiac allograft transplantation. 20 It has also a critical role in IRI in kidney and heart 21,22 and other organ transplantations. 23 IRI was also characterized by diffuse leukocyte infiltration.…”