Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling.

The endoplasmic reticulum (ER) unfolded protein response (UPR) restores equilibrium to the ER, but prolonged expression of the UPR effector CHOP (GADD153) is cytotoxic. We found that CHOP expression induced by ER stress was suppressed by prior engagement of toll-like receptor (TLR) 3 or 4 through a TRIF-dependent pathway. TLR engagement did not suppress phosphorylation of PERK or eIF-2alpha, which are upstream of CHOP, but phospho-eIF-2alpha failed to promote translation of the CHOP activator ATF4. In mice subjected to systemic ER stress, pretreatment with low dose lipopolysaccharide (LPS), a TLR4 ligand, suppressed CHOP expression and apoptosis in splenic macrophages, renal tubule cells and hepatocytes, and prevented renal dysfunction and hepatosteatosis. This protective effect of LPS did not occur in Trif(-/-) mice or in wild-type mice in which CHOP expression was genetically restored. Thus, TRIF-mediated signals from TLRs selectively attenuate translational activation of ATF4 and its downstream target gene CHOP. We speculate that this mechanism evolved to promote survival of TLR-expressing cells that experience prolonged levels of physiological ER stress in the course of the host response to invading pathogens.

Overcoming electromagnetic interference by LVADs on ICD function by shielding the ICD programmer wand and extension cable.

Patients with end-stage cardiomyopathy and congestive heart failure are increasingly undergoing implantation with left ventricular assist devices (LVADs). In addition, implantable cardioverter-defibrillator (ICD) therapy has been proven to be an important part of the treatment for cardiomyopathy/congestive heart failure. Previous reports have noted a potential and dramatic electromagnetic interference from LVADs on ICDs that cause impaired telemetry communication between the ICD and ICD programmer. Such interference has necessitated explantation and generator replacement in order to resume communication between the ICD and programmer. We report two patients with advanced congestive heart failure and ICD programming impairment caused by a HeartMate II LVAD (Thoratec Corporation, Pleasanton, CA, USA) that was overcome by placing aluminum shielding around the ICD programmer wand and steel shielding around the extension cable during ICD interrogation.

The impact of insulin resistance on macrophage death pathways in advanced atherosclerosis.

Macrophage death in advanced atherosclerosis causes plaque necrosis, which promotes plaque rupture and acute atherothrombotic vascular events. Of interest, plaque necrosis and atherothrombotic disease are markedly increased in diabetes and metabolic syndrome. We discovered a novel 'multi-hit' macrophage apoptosis pathway that appears to be highly relevant to advanced atherosclerosis. The elements of the pathway include: (a) activation of the unfolded protein response (UPR) by cholesterol overloading of the endoplasmic reticulum or by other UPR activators known to exist in atheromata; and (b) pro-apoptotic signalling involving the type A scavenger receptor (SRA). The downstream apoptosis effectors include CHOP (GADD153) for the UPR and JNK for SRA signalling. Remarkably, components of this pathway are enhanced in macrophages with defective insulin signalling, including UPR activation and SRA expression. As a result, insulin-resistant macrophages show increased susceptibility to apoptosis when exposed to UPR activators and SRA ligands. Moreover, the advanced lesions of atherosclerosis-prone mice reconstituted with insulin-resistant macrophages show increased macrophage apoptosis and plaque necrosis. Based on these findings, we propose that one mechanism of increased plaque necrosis and atherothrombotic vascular disease in insulin resistant syndromes is up-regulation of a two-hit signal transduction pathway involved in advanced lesional macrophage death.