Role of endoplasmic reticulum stress in endothelial dysfunction

Cimellaro, Antonio; Perticone, Maria; Fiorentino, Teresa Vanessa; Sciacqua, Angela; Hribal, Marta Letizia

doi:10.1016/j.numecd.2016.05.008

Cited by 44 publications

(36 citation statements)

References 55 publications

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“…Given our previous observations that Efavirenz induced ER stress in brain endothelial cells, we investigated the role of this process in alterations of claudin-5 expression and localization. This line of investigation is consistent with the reports on the role of ER stress in vascular dysfunction in coronary disease6768, diabetic retinopathy69 and, several other processes involving endothelium7071. While the role of claudin-5 in maintaining vessel integrity is well established, limited data is available on the impact ER stress on integrity of claudin-5 and other TJ proteins51727374.…”

Section: Discussionsupporting

confidence: 88%

Antiretroviral Treatment with Efavirenz Disrupts the Blood-Brain Barrier Integrity and Increases Stroke Severity

Bertrand

Dygert

Toborek

2016

Sci Rep

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The introduction of antiretroviral drugs (ARVd) changed the prognosis of HIV infection from a deadly disease to a chronic disease. However, even with undetectable viral loads, patients still develop a wide range of pathologies, including cerebrovascular complications and stroke. It is hypothesized that toxic side effects of ARVd may contribute to these effects. To address this notion, we evaluated the impact of several non-nucleoside reverse transcriptase inhibitors (NNRTI; Efavirenz, Etravirine, Rilpivirine and Nevirapine) on the integrity of the blood-brain barrier, and their impact on severity of stroke. Among studied drugs, Efavirenz, but not other NNRTIs, altered claudin-5 expression, increased endothelial permeability, and disrupted the blood-brain barrier integrity. Importantly, Efavirenz exposure increased the severity of stroke in a model of middle cerebral artery occlusion in mice. Taken together, these results indicate that selected ARVd can exacerbate HIV-associated cerebrovascular pathology. Therefore, careful consideration should be taken when choosing an anti-retroviral therapy regimen.

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Section: Discussionsupporting

confidence: 88%

Antiretroviral Treatment with Efavirenz Disrupts the Blood-Brain Barrier Integrity and Increases Stroke Severity

Bertrand

Dygert

Toborek

2016

Sci Rep

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“…Indeed, sustained weight increase and adipose tissue accumulation induces significant changes inside the various fat depots, resulting in dysregulated function with increased lipolysis, insulin resistance and altered adipokine production (e.g., increased production of pro-inflammatory adipokines, such as leptin, and cytokines such as TNF-α and IL-6; and decreased production of anti-inflammatory adipokines, such as adiponectin and omentin) [22]. These changes are considered responsible for the overall adipose tissue dysfunction, playing a vital role in the obesity-related cardiometabolic sequelae [22][23][24]. Visceral adiposity appears to be a critical factor in the underlying pathophysiological mechanisms [6], whilst it is also hypothesized that subcutaneous fat has a limited capacity to safely increase its mass [25].…”

Section: Discussionmentioning

confidence: 99%

Visceral adiposity index and 10-year cardiovascular disease incidence: The ATTICA study

Kouli

Panagiotakos

Kyrou

et al. 2017

Nutrition, Metabolism and Cardiovascular Diseases

149

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Background/Aims: Visceral adiposity index (VAI) has been proposed as a marker of visceral adipose tissue accumulation/dysfunction. Our aim was to evaluate potential associations between the VAI and the 10-year cardiovascular disease (CVD) incidence. Methods and Results: During 2001During -2002 Greek adults (1514 men; age: ≥ 18 years) without previous CVD were recruited into the ATTICA study, whilst the 10-year study follow-up was performed in 2011-2012, recording the fatal/nonfatal CVD incidence in 2020 (1010 men) participants. The baseline VAI scores for these participants were calculated based on anthropometric and lipid variables, while VAI tertiles were extracted for further analyses. During the study follow-up a total of 317 CVD events (15.7%) were observed. At baseline, the participants' age and the prevalence of hypertension, diabetes, hypercholesterolemia and metabolic syndrome increased significantly across the VAI tertiles. After adjusting for multiple confounders, VAI exhibited a significantly independent positive association with the 10-year CVD incidence (OR= 1.05, 95%CI: 1.01, 1.10), whereas the association of the body mass index (HR= 1.03, 95%CI: 0.99, 1.08), or the waist circumference (HR= 1.01, 95%CI: 0.99, 1.02) was less prominent. Sex-specific analysis further showed that VAI remained significantly predictive of CVD in men alone (HR= 1.06, 95%CI: 1.00, 1.11) but not in women (HR= 1.06, 95%CI: 0.96, 1.10). Conclusions:Our findings show for the first time in a large-sample, long-term, prospective study in Europe that the VAI is independently associated with elevated 10-year CVD risk, particularly in men. This suggests that the VAI may be utilized as an additional indicator of long-term CVD risk for Caucasian/Mediterranean men without previous CVD.

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“…Therefore, by using both gain- and loss-of-function approaches, our study clearly demonstrates that GPR4 is a functional pH sensor and is important for ECs to sense acidosis and elicit an ER stress response (Figure 7). While a mild ER stress is protective, a severe prolonged ER stress is detrimental to cells [13,14,15]. As discussed above, acidosis-induced ER stress has been shown to cause astrocyte death [9]; however, acidosis-induced ER stress and GRP78 expression is protective for ECs in response to the Sunitinib drug treatment [12].…”

Section: Discussionmentioning

confidence: 99%

“…Imbalance between the demand and aptitude of the protein-folding organelle institutes the UPR/ER-stress response [13,14,15]. Specifically, UPR is mediated through three pathways via the activation of three ER transmembrane sensors, including PERK (protein kinase R-like ER kinase), ATF6 (activating transcription factor 6), and IRE1 (inositol-requiring enzyme 1) [13,14,15]. PERK activation leads to the phosphorylation of eukaryotic initiation factor 2α (eIF2α), which halts protein translation in order to reduce the capacity of protein transportation to the ER.…”

Section: Introductionmentioning

confidence: 99%

“…Secondly, ATF6 translocates to the Golgi apparatus, where it is cleaved to the activated form p50, which is then translocated to the nucleus to regulate the gene expression of ER chaperones. The third sensor, IRE1, is responsible for the cleavage of X box-binding protein 1 (XBP-1) mRNA to its spliced isoform that encodes a transcription factor regulating multiple UPR genes, such as ER chaperones, and endoplasmic reticulum associated protein degradation (ERAD) [13,14,15]. Although acidosis has been shown to induce ER stress and UPR [2,9,10,11,12], it is largely unclear how cells sense the acidotic microenvironment to modulate the ER stress response.…”

Section: Introductionmentioning

confidence: 99%

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Acidosis Activates Endoplasmic Reticulum Stress Pathways through GPR4 in Human Vascular Endothelial Cells

Dong

Krewson

Yang

2017

IJMS

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Acidosis commonly exists in the tissue microenvironment of various pathophysiological conditions such as tumors, inflammation, ischemia, metabolic disease, and respiratory disease. For instance, the tumor microenvironment is characterized by acidosis and hypoxia due to tumor heterogeneity, aerobic glycolysis (the “Warburg effect”), and the defective vasculature that cannot efficiently deliver oxygen and nutrients or remove metabolic acid byproduct. How the acidic microenvironment affects the function of blood vessels, however, is not well defined. GPR4 (G protein-coupled receptor 4) is a member of the proton-sensing G protein-coupled receptors and it has high expression in endothelial cells (ECs). We have previously reported that acidosis induces a broad inflammatory response in ECs. Acidosis also increases the expression of several endoplasmic reticulum (ER) stress response genes such as CHOP (C/EBP homologous protein) and ATF3 (activating transcription factor 3). In the current study, we have examined acidosis/GPR4-induced ER stress pathways in human umbilical vein endothelial cells (HUVEC) and other types of ECs. All three arms of the ER stress/unfolded protein response (UPR) pathways were activated by acidosis in ECs as an increased expression of phosphorylated eIF2α (eukaryotic initiation factor 2α), phosphorylated IRE1α (inositol-requiring enzyme 1α), and cleaved ATF6 upon acidic pH treatment was observed. The expression of other downstream mediators of the UPR, such as ATF4, ATF3, and spliced XBP-1 (X box-binding protein 1), was also induced by acidosis. Through genetic and pharmacological approaches to modulate the expression level or activity of GPR4 in HUVEC, we found that GPR4 plays an important role in mediating the ER stress response induced by acidosis. As ER stress/UPR can cause inflammation and cell apoptosis, acidosis/GPR4-induced ER stress pathways in ECs may regulate vascular growth and inflammatory response in the acidic microenvironment.

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Role of endoplasmic reticulum stress in endothelial dysfunction

Cited by 44 publications

References 55 publications

Antiretroviral Treatment with Efavirenz Disrupts the Blood-Brain Barrier Integrity and Increases Stroke Severity

Antiretroviral Treatment with Efavirenz Disrupts the Blood-Brain Barrier Integrity and Increases Stroke Severity

Visceral adiposity index and 10-year cardiovascular disease incidence: The ATTICA study

Acidosis Activates Endoplasmic Reticulum Stress Pathways through GPR4 in Human Vascular Endothelial Cells

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