Objective-We studied by microarray analysis whether symptomatic and asymptomatic carotid plaques from the same patient differ in gene expression and whether the same changes are present in an independent sample set. Methods and Results-Carotid plaques from four patients with bilateral high-grade stenosis, one being symptomatic and the other asymptomatic, were analyzed on Affymetrix U95Av2 arrays. 33 genes showed Ͼ1.5-fold change between symptomatic and asymptomatic plaques in an intraindividual comparison with FDR ranging from 0.28 to 0.40. Three genes involved in iron-heme homeostasis, CD163, HO-1, and transferrin receptor, were further analyzed in 40 independent plaques. HO-1 (fold-change 1.93, 95%CI 1.04 to 3.94, Pϭ0.040) and CD163 (1.58, 1.11 to 2.40, Pϭ0.013) mRNAs were again induced, and also HO-1 protein was overexpressed in symptomatic plaques (4.38, 1.54 to 12.20, Pϭ0.024). The expression of HO-1 and CD163 correlated with tissue iron content but iron itself was not associated with the symptom status. Conclusions-Symptomatic plaques show overexpression of CD163 and HO-1 both in intraindividual and interindividual comparison. Their expression correlates with iron deposits but asymptomatic and symptomatic plaques from isolated patients do not differ in macroscopic hemorrhages or iron deposits. We suggest that symptomatic plaques show a more pronounced induction of CD163 and HO-1 in response to plaque hemorrhages. Key Words: atherosclerosis Ⅲ carotid arteries Ⅲ gene expression Ⅲ microarray Ⅲ stroke S evere atherosclerotic narrowing of the internal carotid artery was found in 20% to 30% of patients with ischemic stroke in its supply territory. 1 Features associated with a symptomatic plaque include the degree of vessel stenosis, prior symptoms, and plaque characteristics, such as ulceration, inflammatory cell infiltration, and a thin fibrous cap. [2][3][4] However, these characteristics are poor predictors of the risk of thromboembolism and, as a result, 80% of patients undergoing carotid endarterectomy are needlessly exposed to surgical risks. 1 Thus better markers for the symptom causing carotid disease are needed. See coverMicroarray technology provides a rapid means to screen gene expression in the tissues of interest. Several efforts have been made to study large-scale gene expression in human atherosclerosis, for example by comparing gene expression in normal and atherosclerotic arteries. 5,6 Changes involved in destabilization of the atherosclerotic plaque have been less in focus. [7][8][9] Whereas symptomatic high-grade carotid plaque remains highly susceptible to recurrent ipsilateral symptoms, the risk of stroke from contralateral asymptomatic plaque is low, comparable to that of asymptomatic carotid stenosis in general. 10 Thus intraindividual differences in the carotid stenoses exist in the same patient causing one plaque to become symptomatic and the other to remain silent. The causes of these differences are unknown. This led us to a microarray study on patients operated due to bilateral sig...
Background-Fatty acid-binding protein 4 (FABP4 or aP2 in mice) has been identified as a key regulator of core aspects of cardiometabolic disorders, including lipotoxic endoplasmic reticulum stress in macrophages. A functional promoter polymorphism (rs77878271) of human FABP4 gene has been described resulting in reduced FABP4 transcription. Methods and Results-We investigated the effects of this low-expression variant of FABP4 on cardiovascular morbidity and carotid atherosclerosis on a population level (n=7491) and in patient cohorts representing endarterectomized patients with advanced carotid atherosclerosis (n=92) and myocardial infarction (n=3432). We found that the low-expression variant was associated with decreased total cholesterol levels (P=0.006) with the largest reduction in variant allele homozygotes. Obese variant allele carriers also showed reduced carotid intima-media thickness (P=0.010) and lower prevalence of carotid plaques (P=0.060). Consistently, the variant allele homozygotes showed 8-fold lower odds for myocardial infarction (P=0.019; odds ratio, 0.12; 95% confidence interval, 0.003-0.801). Within the carotid plaques, the variant allele was associated with a 3.8-fold reduction in FABP4 transcription (P=0.049) and 2.7-fold reduction in apoptosis (activated caspase 3; P=0.043). Furthermore, the variant allele was enriched to patients with asymptomatic carotid stenosis (P=0.038). High FABP4 expression in the carotid plaques was associated with lipid accumulation, intraplaque hemorrhages, plaque ulcerations, and phosphoactivated endoplasmic reticulum stress markers. Conclusions-Our results reveal FABP4 rs77878271 as a novel variant affecting serum total cholesterol levels and cardiovascular risk. A therapeutic regimen reducing FABP4 expression within the atherosclerotic plaque may promote lesion stability through modulation of endoplasmic reticulum stress signaling, and attenuation of apoptosis, lipid burden, and inflammation. (Circ Cardiovasc Genet. 2014;7:588-598.)
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