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The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction.

ABSTRACT: Impaired cardiac function is associated with myocardial triglyceride accumulation, but it is not clear how the lipids accumulate or whether this accumulation is detrimental. Here we show that hypoxia/ischemia-induced accumulation of lipids in HL-1 cardiomyocytes and mouse hearts is dependent on expression of the VLDL receptor (VLDLR). Hypoxia-induced VLDLR expression in HL-1 cells was dependent on HIF-1? through its interaction with a hypoxia-responsive element in the Vldlr promoter, and VLDLR promoted the endocytosis of lipoproteins. Furthermore, VLDLR expression was higher in ischemic compared with nonischemic left ventricles from human hearts and was correlated with the total lipid droplet area in the cardiomyocytes. Importantly, Vldlr-/- mice showed improved survival and decreased infarct area following an induced myocardial infarction. ER stress, which leads to apoptosis, is known to be involved in ischemic heart disease. We found that ischemia-induced ER stress and apoptosis in mouse hearts were reduced in Vldlr-/- mice and in mice treated with antibodies specific for VLDLR. These findings suggest that VLDLR-induced lipid accumulation in the ischemic heart worsens survival by increasing ER stress and apoptosis.

SUBMITTER: Perman JC

PROVIDER: S-EPMC3223818 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction.

Perman Jeanna C JC Boström Pontus P Lindbom Malin M Lidberg Ulf U StÅhlman Marcus M Hägg Daniel D Lindskog Henrik H Scharin Täng Margareta M Omerovic Elmir E Mattsson Hultén Lillemor L Jeppsson Anders A Petursson Petur P Herlitz Johan J Olivecrona Gunilla G Strickland Dudley K DK Ekroos Kim K Olofsson Sven-Olof SO Borén Jan J

The Journal of clinical investigation 20110613 7

Impaired cardiac function is associated with myocardial triglyceride accumulation, but it is not clear how the lipids accumulate or whether this accumulation is detrimental. Here we show that hypoxia/ischemia-induced accumulation of lipids in HL-1 cardiomyocytes and mouse hearts is dependent on expression of the VLDL receptor (VLDLR). Hypoxia-induced VLDLR expression in HL-1 cells was dependent on HIF-1α through its interaction with a hypoxia-responsive element in the Vldlr promoter, and VLDLR p ...[more]

PMID: 21670500

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Project description:Preclinical data suggest that an acute inflammatory response following myocardial infarction (MI) accelerates systemic atherosclerosis. Using combined positron emission and computed tomography, we investigated whether this phenomenon occurs in humans.Overall, 40 patients with MI and 40 with stable angina underwent thoracic 18F-fluorodeoxyglucose combined positron emission and computed tomography scan. Radiotracer uptake was measured in aortic atheroma and nonvascular tissue (paraspinal muscle). In 1003 patients enrolled in the Global Registry of Acute Coronary Events, we assessed whether infarct size predicted early (?30 days) and late (>30 days) recurrent coronary events. Compared with patients with stable angina, patients with MI had higher aortic 18F-fluorodeoxyglucose uptake (tissue-to-background ratio 2.15±0.30 versus 1.84±0.18, P<0.0001) and plasma C-reactive protein concentrations (6.50 [2.00 to 12.75] versus 2.00 [0.50 to 4.00] mg/dL, P=0.0005) despite having similar aortic (P=0.12) and less coronary (P=0.006) atherosclerotic burden and similar paraspinal muscular 18F-fluorodeoxyglucose uptake (P=0.52). Patients with ST-segment elevation MI had larger infarcts (peak plasma troponin 32 300 [10 200 to >50 000] versus 3800 [1000 to 9200] ng/L, P<0.0001) and greater aortic 18F-fluorodeoxyglucose uptake (2.24±0.32 versus 2.02±0.21, P=0.03) than those with non-ST-segment elevation MI. Peak plasma troponin concentrations correlated with aortic 18F-fluorodeoxyglucose uptake (r=0.43, P=0.01) and, on multivariate analysis, independently predicted early (tertile 3 versus tertile 1: relative risk 4.40 [95% CI 1.90 to 10.19], P=0.001), but not late, recurrent MI.The presence and extent of MI is associated with increased aortic atherosclerotic inflammation and early recurrent MI. This finding supports the hypothesis that acute MI exacerbates systemic atherosclerotic inflammation and remote plaque destabilization: MI begets MI.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01749254.

Project description:Background Important administrative-based measures of hospital quality, including those used by Centers for Medicare and Medicaid Services, may not adequately account for patient illness and social factors that vary between hospitals and can strongly affect outcomes. Do-not-resuscitate (DNR) order on admission (within the first 24 hours) is one such factor that may reflect higher preadmission illness burden as well as patients' desire for less-intense therapeutic interventions and has been shown to vary widely between hospitals. We sought to evaluate how accounting for early DNR affected hospital quality measures for acute myocardial infarction. Methods AND RESULTS We identified all patients admitted with acute myocardial infarction using the California State Inpatient Database, which captures early DNR use within 24 hours of admission. We generated hospital risk-standardized mortality and readmissions using random-effects logistic regression, before and after including early DNR status, to examine changes in overall model fit and hospital outlier designations. We included 109?521 patients from 289 hospitals and found that 8.5% (9356) patients had early DNR. Early DNR use varied widely, with median (interquartile range) hospital rates of 7.9% (4.1%-14.0%). Including early DNR in models used to assess hospital quality resulted in improvement in the mortality model (C statistics from 0.754 [0.748-0.759] to 0.784 [0.779-0.789]) but not the readmissions model. Of the hospitals designated high outliers for mortality and readmissions by the Centers for Medicare/Medicaid Services model, and therefore destined for a financial penalty, 6/25 (24%) were reclassified as nonoutliers for mortality and 2/14 (14.3%) for readmissions after including DNR status. Agreement in outlier status between the models before and after inclusion of early DNR status was moderate for mortality (?, 0.603 [0.482-0.724]; P<0.001) and high for readmissions (?, 0.888 [0.800-0.977]; P<0.001). Conclusions Including early DNR status in risk-adjustment models significantly improved model fit and resulted in substantial reclassification of hospital performance rankings for mortality and moderate reclassification for readmissions. DNR status at hospital admission should be considered when reporting risk-standardized hospital mortality.

Dataset Information

The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction.

Publications

The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction.

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