Chronic endoplasmic reticulum stress activates unfolded protein response in arterial endothelium in regions of susceptibility to atherosclerosis.

RATIONALE: Endothelial function and dysfunction are central to the focal origin and regional development of atherosclerosis; however, an in vivo endothelial phenotypic footprint of susceptibility to atherosclerosis preceding pathological change remains elusive. OBJECTIVE: To conduct a comparative multi-site genomics study of arterial endothelial phenotype in atherosusceptible and atheroprotected regions. METHODS AND RESULTS: Transcript profiles of freshly isolated endothelial cells from 7 discrete arterial regions in normal swine were analyzed to determine the steady state in vivo endothelial phenotypes in regions of varying susceptibilities to atherosclerosis. The most abundant common feature of the endothelium of all atherosusceptible regions was the upregulation of genes associated with endoplasmic reticulum (ER) stress. The unfolded protein response pathway, induced by ER stress, was therefore investigated in detail in endothelium of the atherosusceptible aortic arch and was found to be partially activated. ER transmembrane signal transducers IRE1alpha and ATF6alpha and their downstream effectors, but not PERK, were activated concomitant with a higher transcript expression of protein folding enzymes and chaperones, indicative of ER stress in vivo. CONCLUSIONS: The findings demonstrate the prevalence of chronic endothelial ER stress and activated unfolded protein response in vivo at atherosusceptible arterial sites. We propose that chronic localized biological stress is linked to spatial susceptibility of the endothelium to the initiation of atherosclerosis.

Prelesional arterial endothelial phenotypes in hypercholesterolemia: universal ABCA1 upregulation contrasts with region-specific gene expression in vivo.

Atherosclerosis originates as focal arterial lesions having a predictable distribution to regions of bifurcations, branches, and inner curvatures where blood flow characteristics are complex. Distinct endothelial phenotypes correlate with regional hemodynamics. We propose that systemic risk factors modify regional endothelial phenotype to influence focal susceptibility to atherosclerosis. Transcript profiles of freshly isolated endothelial cells from three atherosusceptible and three atheroprotected arterial regions in adult swine were analyzed to determine the initial prelesional effects of hypercholesterolemia on endothelial phenotypes in vivo. Cholesterol efflux transporter ATP-binding cassette transporter A1 (ABCA1) was upregulated at all sites in response to short-term high-fat diet. Proinflammatory and antioxidative endothelial gene expression profiles were induced in atherosusceptible and atheroprotected regions, respectively. However, markers for endoplasmic reticulum stress, a signature of susceptible endothelial phenotype, were not further enhanced by brief hypercholesterolemia. Both region-specific and ubiquitous (ABCA1) phenotype changes were identified as early prelesional responses of the endothelium to hypercholesterolemia.

Anxiety and stigma in dementia: a threat to aging in place.

The number of Americans with dementia is expected to increase as the population ages. Developing dementia is feared by many older adults and may result in anxiety in persons with dementia. This article focuses on anxiety, one of the least understood symptoms associated with dementia in community-dwelling older adults, the stigma of dementia, and the relationship between anxiety and stigma in dementia. When undetected and untreated, anxiety and associated stigma can adversely affect quality of life and the ability to age in place.

Coronary artery endothelial transcriptome in vivo: identification of endoplasmic reticulum stress and enhanced reactive oxygen species by gene connectivity network analysis.

BACKGROUND: Endothelial function is central to the localization of atherosclerosis. The in vivo endothelial phenotypic footprints of arterial bed identity and site-specific atherosusceptibility are addressed. METHODS AND RESULTS: Ninety-eight endothelial cell samples from 13 discrete coronary and noncoronary arterial regions of varying susceptibilities to atherosclerosis were isolated from 76 normal swine. Transcript profiles were analyzed to determine the steady-state in vivo endothelial phenotypes. An unsupervised systems biology approach using weighted gene coexpression networks showed highly correlated endothelial genes. Connectivity network analysis identified 19 gene modules, 12 of which showed significant association with circulatory bed classification. Differential expression of 1300 genes between coronary and noncoronary artery endothelium suggested distinct coronary endothelial phenotypes, with highest significance expressed in gene modules enriched for biological functions related to endoplasmic reticulum (ER) stress and unfolded protein binding, regulation of transcription and translation, and redox homeostasis. Furthermore, within coronary arteries, comparison of endothelial transcript profiles of susceptible proximal regions to protected distal regions suggested the presence of ER stress conditions in susceptible sites. Accumulation of reactive oxygen species throughout coronary endothelium was greater than in noncoronary endothelium consistent with coronary artery ER stress and lower endothelial expression of antioxidant genes in coronary arteries. CONCLUSIONS: Gene connectivity analyses discriminated between coronary and noncoronary endothelial transcript profiles and identified differential transcript levels associated with increased ER and oxidative stress in coronary arteries consistent with enhanced susceptibility to atherosclerosis.