Abstract-Oxidized low-density lipoproteins (oxLDLs) trigger various biological responses potentially involved in atherogenesis. Disturbing endoplasmic reticulum (ER) function results in ER stress and unfolded protein response, which tends to restore ER homeostasis but switches to apoptosis when ER stress is prolonged. We aimed to investigate whether ER stress is induced by oxLDLs and can be prevented by the ER-associated chaperone ORP150 (150-kDa oxygen-regulated protein). oxLDLs and the lipid oxidation products 7-ketocholesterol and 4-hydroxynonenal induce ER stress in human endothelial cells (HMEC-1), characterized by the activation of ER stress sensors (phosphorylation of Ire1␣ and PERK, nuclear translocation of ATF6) and of their subsequent pathways (eukaryotic initiation factor 2␣ phosphorylation, expression of XBP1/spliced XBP1, CHOP, and KDEL chaperones GRP78, GRP94, ORP150). ER stress was inhibited by the antioxidant N-acetylcysteine. In advanced atherosclerotic lesions, phospho-Ire1␣, KDEL, and ORP150 staining were localized in lipid-rich areas with 4-hydroxynonenal adducts and CD68-positive macrophagic cells. By comparison, staining for 4-hydroxynonenal, phospho-Ire1␣, KDEL, and ORP were faint and more diffuse in intimal hyperplasia. ER stress takes part in the apoptotic effect of oxLDLs, through the Ire1␣/c-Jun N-terminal kinase pathway, as assessed by the protective effect of specific small interfering RNAs and c-Jun N-terminal kinase inhibitor. Key Words: ER stress Ⅲ apoptosis Ⅲ ORP150 Ⅲ oxidized LDL Ⅲ atherosclerosis L ow oxidized low-density lipoprotein (oxLDL) concentration exhibit proinflammatory and mitogenic effects, whereas higher concentrations elicit a progressive inhibition of survival mechanisms and the induction of proapoptotic signaling pathways. 1-5 oxLDLs may alter the fragile balance between survival and death of vascular cells, thereby leading to stable-to-vulnerable plaque transition and finally to atherothrombotic events. 6 -8 The stress of the endoplasmic reticulum (ER) occurs in atherosclerotic lesions of hypercholesterolemic (apolipoprotein [apo]E Ϫ/Ϫ ) mice, 9 and could be associated with acute coronary syndrome. 10 ER stress emerges as a new adaptive system determining the fate of cells to survive or die 11 and may thereby be implicated in the erosion or rupture of atherosclerotic plaques.Altered protein folding and ER stress occurs in various pathological conditions, including ischemia, hypoxia, heat shock, proteasome inhibition, glycosylation inhibition, oxidative stress, and calcium depletion of ER stores. 12,13 The accumulation of unfolded protein aggregates leads to the activation of transmembrane sensors/transducers inositolrequiring enzyme (Ire)1␣, PERK (RNA-dependent protein kinase-like endoplasmic reticulum kinase), and activating transcription factor (ATF)6 that regulate several signaling pathways, gene expression, and protein synthesis. 11 The presence of ER-resident chaperones is crucial for facilitating and maintaining the protein folding, thereby preventing ER...
MSCT-CA appears to be a useful initial triage tool in the ED. When the MSCT-CA result is negative, it allows safe early discharge because of its high negative predictive value. In a significant number of cases of low-risk ACS, MSCT-CA detects severe coronary lesions and allows further dedicated diagnostic and therapeutic intervention. Reduction of radiation exposure would help acceptance in clinical practice.
TOMPOOL is accurate: measurements of EDV, EF, and CO are reproducible and correlate with CMR and thermodilution. However, thresholds must be adjusted.
Ventriculoatrial shunt (VAS) is an accepted treatment for hydrocephalus, submitting intra-cranial pressure to right atrial pressure. Several pathological situations can increase right atrial pressure, frequently as a consequence of pulmonary hypertension, and lead to the recurrence of intra-cranial hypertension. We report an unusual aetiology of invalidating headaches in a 26-year-old woman with history of Dandy-Walker syndrome treated initially by multiple ventriculoperitoneal shunts (VPS) switch 2 years ago by a VAS. Congenital heart disease was excluded during the childhood. She was current smoker, obese (body mass index 32.5 kg/m 2 ) and took combined oral contraceptive pill. She also reported a stage II NYHA class dyspnoea aggravated for 2 weeks. On physical examination, the heart rate was 95 beats per minute and the blood pressure 120/70 mmHg. She had an elevated jugular venous pressure and an accentuated pulmonary component of the second heart sound. Cerebral computed tomography (CT) showed a DandyWalker cyst in the posterior fossa (Fig. 1a). ECG reported a sinus rhythm with tachycardia, S1Q3 pattern and negative T waves in the right precordium (Fig. 1b). Arterial blood gas showed hypoxemia (PaO 2 70 mmHg) and hypocapnia (PaCO 2 32 mmHg; pH 7.43). CT pulmonary angiogram confirmed lingular pulmonary emboli with chronic pulmonary embolism signs as pulmonary artery enlargement and pulmonary vascular thickening (Fig. 1c). There was no abnormality of VAS catheter confirmed by transesophageal echocardiography but there was an interauricular septum curve inversion with a right ventricle dilatation (Fig. 1d), and transthoracic echocardiography confirmed a pulmonary hypertension with 65 mmHg systolic pulmonary arterial pressure. There was no intra-cardiac thrombosis. Bilateral leg venogram ultrasound was normal. The final diagnosis was pulmonary emboli with chronic pulmonary heart complicated by exacerbation of intracranial hypertension because of right atrium pressure overload. Search of thrombophilia was negative. Finally, the VAS was replaced by a ventriculoperitoneal shunt, permitting the retrocession of the pain. Retrospective test of the device didnÕt shown dysfunction. Two years later, she is still alive. She takes an oral anticoagulation and reports a NYHA stage 2 dyspnoea. Transthoracic echocardiography follow-up shows pulmonary hypertension stability. DiscussionVentriculoatrial shunt became accepted treatment for hydrocephalus in the late 1950s [1]. Previous studies reported development of severe pulmonary hypertension after placement of a VAS [2][3][4]. In patients with a VAS, pulmonary embolism and pulmonary hypertension were recognized clinically in 0.4% and 0.3%, respectively, whereas, at necropsy the frequency of these complications was 59.7% and 6.3% respectively [2]. Several hypotheses could explain this phenomenon: latent shunt infection could induce a persistent activation of clotting factors, which leads to recurrent pulmonary embolism [5]; other hypothesis suggests a possible role for cerebrosp...
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