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We also use a height-weight ratio called body-mass index (BMI) to determine if someone is overweight or obese. You can control your weight by eating a healthier diet and by incorporating physical activity into your normal routine. Vamos and colleagues examined seven years of data on nearly 125,000 people in England with type 2 diabetes, which is associated with aging and obesity and accounts for most cases of the disease. Vamos said that flu vaccine may not only lower incidences of stroke and heart attack in high risk patients, but it may also reduce the risk of death during the flu season.
Furthermore, flu infection has been found to increase the risk of heart attack or stroke in patients with cardiovascular disease.
The scientists found that, compared to patients who had not been vaccinated, those who received the jab had a 30 per cent reduction in hospital admissions for stroke, 22 per cent reduction in heart failure admissions and 15 per cent reduction in admissions for pneumonia or influenza.
The research team says that there have been quite a few studies in the past that looks at the effectiveness of the flu vaccine in diabetes patients. A 3-year-old girl was diagnosed with type 2 diabetes in what is believed to be one of the youngest cases of the disease ever documented, as presented in a case study at the European Association for the Study of Diabetes in Stockholm, Sweden. Breaking Medical News is a service of the Physicians Committee for Responsible Medicine, 5100 Wisconsin Ave., Ste.
A pair of studies published last week in Diabetologia, the journal of the European Association for the Study of Diabetes, concluded that taking blood pressure medications at night reduced the risk of type 2 diabetes by 57%. And while hypertension itself is considered a risk factor for type 2 diabetes, research has shown that some blood-pressure medications including diuretics and beta-blockers, especially when taken without other types of blood pressure drugs, may actually promote type 2 diabetes, especially in people who face an increased risk of the disorder.
Meanwhile, weight loss and regular physical activity remain the most effective ways to prevent and improve both hypertension and diabetes. It is predicted that by 2025, 1.56 billion people worldwide will have hypertension and that by 2030 an estimated 366 million people will have diabetes. Sign Up for the FREE EndocrineWeb eNewsletter and receive treatment and research updates, news, and helpful tips on managing your condition. Science, Technology and Medicine open access publisher.Publish, read and share novel research. Endoplasmic Reticulum Stress in the Endothelium: A Contribution to Athero-SusceptibilityAlessandra Stacchiotti1, Gaia Favero1 and Rita Rezzani1[1] Human Anatomy Division, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy1. Vasuri F, Fittipaldi S, Buzzi M, Degiovanni A, Stella A, D’Errico-Grigioni A, Pasquinelli G.
Ozcan U, Cao Q, Yilmaz E, Lee A, Iwakoshi N, Ozdelen E, Tuncman G, Gorgun C, Glimcher L, Hotamisligil G.
Tycinska A, Mroczko B, Musial W, Sawicki R, Kaminski K, Borowska H, Sobkowicz B, Smitkowski M.
Kassan M, Galan M, Partyka M, Saifudeen Z, Henrion D, Trebak M, Matrougui K Endoplasmic reticulum stress is involved in cardiac damage and vascular endothelial dysfunction in hypertensive mice. In this expert interview Professor Sir Alberti discusses why the epidemic rise in T2DM persists despite the availability of medicines. In GPRD data, current use of sulphonylureas only (with active or inactive metabolites) was associated with an increased risk of hypoglycaemic events, as compared with current use of metformin. Recent outcome trials of novel antidiabetic drugs shed new light on why diabetes patients develop heart disease. Out of 18 biomarkers, Lp-PLA2 and adiponectin were independently associated with a decreased risk for T2DM.
In females with gestational diabetes, the future risk of developing type 2 diabetes depends on certain pregnancy-related and maternal factors that could be used for postnatal counselling. EMPA-REG OUTCOME trial shows that empagliflozin reduces microvascular outcomes and progression of kidney disease in T2DM patients at high CV risk. ADA 2016 In T2DM patients at high CV risk, liraglutide on top of standard therapy was associated with lower rates of CV events and mortality, compared with placebo in the LEADER outcome trial. ADA 2016 New empagliflozin data show that reduced risk for cardiovascular death was consistent across age groups in adults with type 2 diabetes.
ADA 2016 Two phase 3 studies of oral SGLT-2 inhibitor ertugliflozin met primary endpoints, showing significantly greater A1c reductions than placebo, alone or in combination with sitagliptin. ADA 2016 In 360 patients with T2DM and albuminuria, linagliptin significantly reduced blood glucose levels, is well tolerated and does not need dose adjustment in patients at risk for kidney impairment. Approximately 1%-2% of people in the United States, or about 5.5 million, have plaque psoriasis. Sometimes plaque psoriasis can evolve into more severe disease, such as pustular or erythrodermic psoriasis. Guttate psoriasis is a type of psoriasis that looks like small, salmon-pink drops on the skin. Read What Your Physician is Reading on Medscape Psoriasis »Psoriasis is a chronic, noncontagious, multisystem, inflammatory disorder.
Because Asians tend to store more fat around their waists and have more body fat for the same BMI,4 Asians have lower BMI cutoffs than for people of European ancestry. Ethnic comparisons of the cross-sectional relationships between measures of body size with diabetes and hypertension.
Elevated body fat percentage and cardiovascular risks at low body mass index levels among Singaporean Chinese, Malays and Indians. Chan School of Public Health, Department of Nutrition and the National University of Singapore, Saw Swee Hock School of Public Health to provide up-to-date, best practice information to the public, health and public health practitioners, business and community leaders, media, and policymakers.
The researchers also looked at records during the flu season and during summer, when the flue is less common. It’s also possible that people who get vaccinated are healthier in other ways than people who skip their annual flu vaccine, the authors also point out. Many countries encourage vaccination against influenza, especially in older people and people with multiple health issues such as diabetes, although there is uncertainty about vaccine effectiveness in these groups.
Hermida, PhD, director of the Bioengineering & Chronobiology Laboratory at University of Vigo, Spain. ER stress balance – Schematic representation of ER homeostasis: on the left, adaptive responses to acute stress that lead to recovery and on the right, reactions to chronic vascular stress that lead to apoptosis. Beneficial role of high density lipoproteins upstream ER stress and autophagy in endothelial cells. Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Assessment of endoplasmic reticulum stress and the unfolded protein response in endothelial cells.
Diabetes and angiotensin II-induced cardiac endoplasmic reticulum stress and cell death: metallothionein protection. Blood pressure in relation to neurogenic, inflammatory and endothelial dysfunction biomarkers in patients with treated essential arterial hypertension.
Integration of ER stress, oxidative stress and the inflammatory response in health and disease. Ultrastructural studies on macromolecular permeability in relation to endothelial cell turnover. The plastic nature of the vascular wall: a continuum of remodeling events contributing to control of arteriolar diameter and structure.
Endothelial heterogeneity associated with regional athero-susceptibility and adaptation to disturbed blood flow in vivo.
Biomechanical stress induced signaling and gene expression in the development of arteriosclerosis. Spatial heterogeneity of endothelial phenotypes correlates with side-specific vulnerability to calcification in normal porcine aortic valves. A person with psoriasis generally has elevated plaques of raised red skin covered with thick silvery scales. In psoriasis, a certain subset of T lymphocytes (a type of white blood cell) abnormally trigger inflammation in the skin as well as other parts of the body. This pattern, known as non-dipping, which can also occur in those with hypertension, is linked with glucose intolerance and other metabolic conditions. Evidence suggests, however, that these drugs work synergistically with other types of hypertension drugs including ACE inhibitors and ARBs, he said, which have been shown to reduce the incidence of diabetes.
Therefore in this scenario it is necessary to update the knowledge on the endothelium, which is the main player in the initial step of atherogenesis, and its involvement in a pivotal biological mechanism, called endoplasmic reticulum (ER) stress, associated to cardiovascular damage and invalidating pathologies such as stroke, cardiac ischemia, chronic renal failure, macular degeneration and obesity [8-11].
These T cells produce chemicals that cause skin cells to multiply abnormally quickly, as well as producing changes in small skin blood vessels, which result ultimately an elevated scaling plaque of psoriasis.Psoriasis has a genetic basis and can be inherited.
Individuals with psoriatic arthritis have inflammation in their joints that could result in permanent joint damage if not treated aggressively. You can measure waist circumference by putting a tape measure around your body halfway between your hip bone and your lowest rib, usually at the level of your belly button. You should seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. With a treatment that combined medication and a nutrition intervention, after six months the toddler gradually stopped her medication, dropped her HbA1c to 5.3, and lost 25 percent of her weight.


Growing evidence suggests that non-dippers face a variety of increased cardiovascular risks.
The two disorders have common etiologies and disease mechanisms including obesity, inflammation, oxidative stress and insulin resistance. In particular we elucidate here the importance of the ER stress in the artery wall, because it very recently has emerged as a novel event able to promote athero-susceptibility and hypertension both in animal models and in clinical patients [11,12]. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
Remarkably this event is early detectable in the endothelial cells [13], sometimes concurrent with other well-known atherogenic processes, like inflammation, oxidative damage and endothelial cell death. Just because a person has genes that would make him more likely to have psoriasis doesn't mean he will have the disease. The endothelium and the endoplasmic reticulum homeostasis According to the most accredited theory that indicates inflammation as the first pathogenic mechanism of atherosclerosis, the endothelium is really the crucial target of circulating molecules or cells and constitutes the main entrance for LDL during the initial step of asymptomatic artery wall changes that end into plaques or atheromata and their dramatic clinical evolution [20-23]. Certain factors trigger psoriasis to flare up in those who have the genes.Environmental factors such as smoking, sunburns, streptococcal sore throat, and alcoholism may affect psoriasis by increasing the frequency of flares. Recent studies have outlined that in atherosusceptible sites in the artery tree, endothelial cells acquire a proinflammatory phenotype which is permissive in the plaque development by expressing pro-inflammatory sensors such as Toll-like receptors (TLRs), that in turn attract leukocytes adhesion in the intima layer.
For example, a skin infection, skin inflammation, or even excessive scratching can trigger psoriasis.
Indeed also in human vascular tree, by immunostaining and mRNA survey TLR2 and TLR4 have been well characterized in selected sites, including the aorta, subclavia, carotid, mesenteric, iliac and temporal arteries [24]. A number of medications have been shown to aggravate psoriasis.Psoriasis flare-ups can last for weeks or months. Nevertheless an important concept to remind here is that the relationship between the vascular endothelium and the blood is not only “passive” in receiving inflammatory or metabolic stimuli, but instead “active”, with pleiotropic activities like the secretion of regulatory factors for cholesterol and lipid homeostasis, platelets recruitment, and the adaptation to local changes of blood flow and pressure [25,26]. Psoriasis can go away for a time and then return.Plaque psoriasis is the most common type of psoriasis and is characterized by red skin covered with silvery scales and inflammation. Moreover the artery wall, in particular in healthy resistance arteries, is not a static but a dynamic and plastic structure, able to remodel its diameter and structure, adapting to rapid changes in the systemic pressure [27].Indeed also artery geometry directly influences the athero-susceptibility and the distribution of mechanical forces associated to blood flux, that impair the endothelium [25,28,29]. In particular during unstable hemodynamic flux and changes in blood direction, mainly in arterial branches and bifurcations, it is particularly evident the heterogeneity of endothelial phenotypes that change their common flat shape and assume a polygonal morphology together with a different turnover. These events are linked to the susceptibility of a specific vessel to develop atherosclerosis and to the onset of valve calcification in the heart [30-32].
Moreover it is well-known that the ER has different specialization and structure, called rough or smooth, if associated or not to ribosomes in the same cell, but in specialized cardiac and smooth muscle cells in the vascular wall it is called the sarcoplasmic reticulum [50,51]. Anyway, this dynamic organelle represents the elective site where nascent polypeptide chains are gradually converted in a stable tertiary structure, that is associated to a specific protein [52].
Among the main ER functions have been comprised the folding of neo-synthesized secretory and trans-membrane proteins, the regulation of calcium balance and the synthesis of lipids, like steroids and cholesterol [53].
If one of these activities fails, the ER efficiency is lost and aberrant unfolded proteins accumulate within the ER membranes, causing the “ER stress”. This condition has been defined as “ any perturbation that compromises the protein folding functionality” in the organelle and implies an adaptive response to restore correct ER homeostasis [54,55]. So it has become clear that each perturbation in the ER balance interferes with folding process of different proteins, that are devoid of their intrinsic function, so unable to properly work in the cells and often degraded by a process called ER associated degradation (ERAD) [56-58]. In mammalian cells, disrupted ER homeostasis can be restored within short or long time according to the type of stimulus, if acute and transient or chronic and prolonged. It is accepted that endothelial cells may tolerate acute stressors that last short time, such as circulatory ischemia or hypoxia, calcium and nutrient deprivation, adapting themselves to clear dysfunctional proteins. In doing this activity, they use a rapid process that involves a transient intracellular signaling from the ER to the nuclear transcription mechanism of genes, called “unfolded protein response” or UPR [59-62]. Indeed UPR is able to rectify and limit the cellular damage induced by metabolic, genetic, environmental factors, enhancing cell survival, but strictly related to the duration of the stress. On the contrary, if the stressful stimuli are severe or last for a long time, like the majority of chronic inflammatory and hemodynamic factors in atherogenesis, UPR is unable to resolve persistent ER stress so leading to endothelial cell death, generally by apoptosis (Figure 1). Indeed UPR works also in collaboration with the Golgi apparatus and plasma membrane, and only correctly-assembled molecules are driven to their final destination. Therefore the kinetic and the amplitude of UPR are emerging as key events for combine a stress response in specific cell types to their final fate and eventually death [64].
In eukaryotic cells GRP78, a trans-membrane protein, is called “the master regulator” of ER stress response and usually works by binding to nascent polypeptides to ensure their proper secondary structure. In unstressed conditions, GRP78 is usually associated to three different UPR-sensors and renders them inactive through the direct interaction with their N-terminus [72].
In contrast, when unfolded proteins accumulate in the ER, GRP78 dissociates from three UPR-sensing elements, and allows their oligomerization and activation, so ensuring the start of the UPR cascade.
Currently, it is established that GRP78 is induced by chemical and inflammatory atherogenic factors, further associated to ER stress signaling, such as excess cholesterol, oxidized phospholipids, peroxynitrite, homocysteine [73,74]. In a recent in vitro model, that simulates human arterial shear stress waveforms, GRP78 was over-expressed in the endothelial cells as a compensatory effect before lesion development [75]. The mechanisms by which GRP78 increased were dependent on upstream alpha 2-beta1integrin linked to p38 activity localized to focal adhesion in the endothelial cells upon long-term shear stress [76].Remarkably in the above study it was further demonstrated that inflammatory cytokines associated to atheroprone environment, had no effect on GRP78 expression in the endothelial cells.
Modified from [15,78].This last enzyme is able to phosphorylate the translation initiation factor 2 alpha (eIF2alpha) after ER stress then reduces the further protein load on the ER by blocking mRNA translation.
In contrast, there are some mRNAs that require eIF2 alpha autophosphorylation for their translation, including the transcriptional factor ATF4, that is directly involved in the nuclear activation of UPR-related genes.
Furthermore eIF2 alpha influences, by endonuclease activity, the splicing of another transcriptional factor, called X-box binding protein 1 (XBP1), that regulates the transcription of UPR-related genes, although in the heart its function is largely unknown [79]. ATF6 is another crucial transcriptional factor that, moving from the Golgi complex, becomes activated and able to interact with XBP1 target genes for the synthesis of molecular chaperones and also for enzymes involved in the ER-associated protein degradation pathway (ERAD). The ERAD mechanism mediates the translocation of unfolded proteins from the ER into the cytosol where they are degraded by the ubiquitin-proteasome system and so alleviates the ER over-crowding [58].
Interestingly, a novel gene, called derlin-3, as a component of the ERAD induced by ATF6, was recently discovered in the mouse heart, and derlin-3 over-expression was able to protect cardiomyocytes from ischemia-induced apoptosis in vitro [80].Besides ER chaperones involvement, dysfunctional proteins may be degraded directly in the ER in a chaperone-independent manner, by a specialized protease system called the ubiquitin-proteasome, that works independently or in synergy with the UPR. Evidence is emerging that the ER provides membrane for autophagosome formation and that autophagy is crucial for ER homeostasis due to its ability to remove unwanted or damaged organelles like abnormal mitochondria by mitophagy [83].
Moreover the ER contributes also lipids and specific proteins, such as beclin-1, to initiate autophagosome formation very close to itself. This physical proximity probably reflects a functional dependence between ER and autophagy process, that in the endothelial cells often occurs in response to reactive oxygen species (ROS) by circuits localized to the ER surface [84]. However in dividing cells with high turnover, autophagy may not be so relevant, but in long-lived cells like smooth muscle cells and cardiomyocytes, it is critical to maintain optimal cellular function. Remarkably autophagy is a suitable mechanism to eliminate abnormal proteins and organelles, during fast and relatively mild ER stress conditions, but if the ER stress is severe, this mechanism is overwhelmed. In this scenario it is intriguing the proposed role of macrophages, able to remove apoptotic cell debris in the advanced atherosclerotic plaque by a mechanism called efferocytosis. It is well-known the active role of these cells in the inflammatory cascade inside the vascular wall, where they enter as adherent monocytes then become macrophages and foam cells, according to the progression of atherosclerosis [91]. The efferocytosis process seems necessary to limit atherosclerosis, because only a selective fully-operative efferocytosis retards the progression of this inflammatory disease [92-94]. The apolipoprotein E (ApoE) family comprises crucial lipoproteins present in the blood to transport the cholesterol and also to modulate several metabolic diseases like atherosclerosis and Alzheimer’s [95].
A recent study demonstrated that peritoneal macrophages isolated from ApoE4 mice were defective in the efferocytosis mechanism and if stimulated by inflammatory molecules, such as oxidized lipoproteins (ox-LDLs), were sensitive to apoptosis throughout the abnormal intensification of ER stress pathway [96].
However the above condition was greatly ameliorated by chemical stimulation of ER signaling, that reduced inflammation linked to apoE4, and balanced ER stress response.Anyway if the UPR involvement in pathological complications has been largely outlined, it is important to remind that this signaling is commonly evoked during the heart morphogenesis and in healthy physiological conditions [97]. Really the strict association between the UPR signaling and pathology has been reported since about 20 years ago, in different pioneering papers [98,99] that discussed the relationship between dysfunctional ER and proteotoxicity, and its direct role in neurodegenerative conditions characterized by abnormal protein deposition, like Parkinson’s and Alzheimer’s diseases.Seminal studies have then elucidated the crucial role of the disruption of the regular ER activity in several metabolic disorders like obesity, diabetes insipidus up to neurodegenerative diseases like Creuzfeld-Jacob, Hungtington’s, Parkinson’s [9,100]. Moreover this mechanism has been actually involved in the pathogenesis of chronic disorders, including cancer, liver diseases, heart failure and in particular atherosclerosis [101,102]. ER stress induced-cell death in the vascular wallA growing body of evidence indicates that prolonged ER stress, due to the persistent accumulation in the ER of misfolded proteins beyond the ability of transient UPR, causes cell death in the vascular wall and may contribute to the pathogenesis of atherosclerosis and other cardiovascular disorders, such as cardiac hypertrophy, and acute coronary syndrome [78,105-107]. In the endothelial cells, different atherosclerotic-relevant UPR inducers have been identified in many in vitro and in vivo studies.
In particular, the strict association between ER stress marker GRP78 and CHOP has been reported in patients and in coronary artery samples, mainly in thin-wall or ruptured plaques associated with unstable angina respect to stable plaques. Evident localization of two ER-stress signals was further correlated to mRNA expression by in situ hybridization in thin-walled plaques and results indicated a positive relationship between these markers and plaque vulnerability in human coronary arteries [109]. In this murine model, ER stress markers such as GRP78 and CHOP are up-regulated in macrophages at all stages of lesion development in the aortic root [111]. Furthermore in transgenic CHOP-deficient mice less macrophages have been found in advanced atherogenic lesions, such as instable plaques, respect to wild-type mice. Intriguingly in double knockout mice (CHOP and ApoE-deficient) the rupture of atherosclerotic plaques was significantly reduced despite their high-cholesterol diet [113]. Indeed also in primary cultured macrophages free cholesterol accumulated in the ER and stimulated apoptosis in a CHOP-dependent pathway, so CHOP probably contributed in vivo and in vitro to instability of plaques due to macrophage cell death. It is emerging that, in crucial artery wall sites, the IRE1 branch of the canonical UPR mechanism and its downstream CHOP signaling are activated also by various factors like disturbed blood flow and hypertension [19,114,115] and modified LDL.


Adapted by [117].However not only in the initial pro-atherogenic phase but also in advanced phase, associated to the plaque rupture, it is crucial that the endothelium maintains its integrity, so hampering the diffusion in the blood of the circulating plaque. In particular during this advanced step, it has been reported that increased apoptotic endothelial cells may act as a pro-coagulant and favor the increase of platelet adhesion during the plaque erosion [118]. In human coronary arteries plaque vulnerability is associated to the expression of ER stress proteins like CHOP and macrophage apoptosis [119,120].
In this double transgenic model, ER stress has different impacts on the vascular damage, according to the lesion stage of the artery.
Indeed it is possible that in an early atherogenic phase, the UPR mechanism may be protective in macrophages and smooth muscle cells, but after persistent damage, the UPR-induced apoptosis is associated to plaque vulnerability and rupture.
Besides the endothelium, also smooth muscle cells in artery wall can be susceptible to ER stress-UPR and compromise plaque integrity by reducing the protective fibrous cap in advanced atherosclerosis [123]. Moreover atherogenic stressors like cholesterol and homocysteine are able to up-regulate CHOP and apoptosis in smooth muscle cells in vitro [124].
Indeed in human aortic cells the delivery of 7-ketocholesterol, an oxysterol linked in patients to high cardiovascular risk and atherosclerosis, activated UPR pathway up to apoptosis [125]. However unfortunately clear molecular evidences of pathways linking UPR to smooth muscle cells in atherosclerosis are still lacking.
This is not true for macrophages, and the role of UPR in macrophages apoptosis is an emerging field of investigation [91].
Remarkably in atherosclerosis dual impact of macrophages resistance to apoptosis has been related to different stages of the disease: it may be beneficial in early lesions, where they hinder inflammation, but is detrimental in advanced phases, where they contribute to a significant increase in the lesion size associated to elevated chemokines expression and monocytes recruitment [126].
Furthermore it is important to point out that if inflammatory foam cells in the sub-endothelium space are cleared by active macrophages to prevent further secondary necrosis, in parallel many inflammatory pathways are activate to potentiate atherogenic damage, including nuclear factor k-B (NFkB) and mitogen-activated protein kinase (MAPK), in particular p38-MAPK cascade [127].
As commonly accepted, the chronic activation of the three canonical UPR pathways in the ER, triggers different pro-apoptotic mechanisms in the vascular wall, that may be mitochondria-dependent or independent, but largely complementary and integrated [128]. Remarkably, CHOP is also involved in the activation of a mitochondria-independent mechanism of apoptosis that relies on inositol-1,4,5-triphosphate receptor (IP3R), able to trigger abnormal calcium (Ca2+) flux from the ER and the death receptor Fas [129].Although three branches may be activated by any prolonged stressful event, the timing of each pathway can differ and persistent ER stress leads to sequential progression of IRE1, then ATF6, finally PERK respectively. Moreover it is important to outline that each pro-apoptotic mechanism is strictly cell-type and stimulus-specific.IRE 1 isoforms are activated by auto-phosphorylation and trigger the splicing and translation of mRNA transcript for a specific transcription factor, called XBP1s, that induces chaperones and other molecules able to limit ER stress. However in mammalian cells, IRE1 stimulates also another mechanism known as regulated IRE1 dependent decay (RIDD) [130], that may directly lead to apoptosis even if this branch is still controversial in cardiovascular diseases. Nevertheless the major downstream effector of IRE1 signaling is the BCL-2 family of proteins, that includes both anti-apoptotic and pro-apoptotic members able to regulate the activity of ER and mitochondria [131]. In human and mice anti-apoptotic domains are called Bcl-2 and Bcl-XL, while the most well characterized pro-apoptotic are Bcl2-associated x protein (BAX) and Bcl2-homologous antagonist (BAK) proteins. When these last two members become activated in the mitochondria, release cytochrome c and other death factors that may amplify the caspases cascade up to overt cell death. Despite in vitro observations on IRE1 signaling, actually there is not yet in vivo evidence for apoptosis along this pathway [132].Remarkably CHOP signaling is common also to PERK and ATF6 pathways in the ER stress response, where it may act like in the IRE1, even if there is the possibility to by-pass the mitochondria and to stimulate calcium flux, working on the ER calcium channel called inositol-1, 4, 5-triphosphate or IP3R [133]. In advanced atherosclerosis, the level of ER stress-CHOP expression in macrophages is very high despite the presence of TRLs ligands and the activation of TRIF-signaling.
A crucial concept in the regulation of macrophage apoptosis in atherosclerosis is called “the two-hit concept”, that consists in the eventuality of a milder ER stress in vivo respect to in vitro.
So different cumulative sub-apoptotic stimuli may lead to a synergic more effective response in the artery vessel, and in particular because generally TLRs act as a second pro-apoptotic stimuli.
ER stress as a therapeutic target in atherosclerosis and metabolic diseasesIn metabolic diseases such as atherosclerosis, hypertension, diabetes and related cardiovascular complications, improved understanding of ER stress pathways and their relationship with inflammation and apoptosis represents the basis on which to try novel drugs, to test therapeutic interventions and to identify targets for different therapeutic options.
In cardiovascular diseases but also in the endothelial cells and cardiomyocytes in vitro, the regulation of the UPR arms can lead to an adaptation phase and survival or to a detrimental phase that ends into cell death.
These opposite effects, considered as “the double-edged sword”, are an important issue for vascular biology, even if the molecular mechanisms that differentially regulate survival or cell death are yet to be clarified [137,138].
In particular the activation of XBP1s in endothelial cells, negatively regulates IRE1-alpha phosphorylation and suppresses inflammation.
So, improving this branch of ER stress pathway may be useful to prevent or limit retinopathy in diabetes [141].Furthermore emerging data on angiotensin II-induced cardiac hypertrophy in mice, have demonstrated a direct involvement of ER stress and related markers, GRP78 and CHOP, in cardiac remodeling and fibrosis [18]. ER chaperones represent a group of low-molecular compounds able to increase ER folding capacity and alleviate the accumulation of dysfunctional proteins, so maintaining ER homeostasis [142]. Different chaperones like 4-phenyl butyrate (PBA) and taurine-conjugated deoxycholic acid (TUDCA) have been successfully tested in vivo in different murine models of atherosclerosis, diabetes and leptin resistance where ER stress was attenuated [143].Moreover PBA and TUDCA, have been successfully tested against endothelium-dependent relaxation and oxidative damage in the aorta and mesenteric artery in hypertensive mice [19]. Indeed ER signaling might represent a potential target to reverse hypertension-induced vascular and cardiac dysfunctions. In particular ER stress was linked also to oxidative damage, due to abnormal calcium flux from the ER driven by protein misfolding and its uptake into the mitochondria where calcium disrupted the electron transport chain [144].
Nevertheless further studies are required to elucidate how these two mechanisms can activate each other [145]. In a mouse model of type 2 diabetes chemical chaperones increased insulin sensitivity acting by antioxidant properties, this finding is particularly interesting because ER stress may also induce insulin-resistance [146,147].
Indeed it reduces oxidative damage in the aorta but also potentiates the adaptive beneficial role of ER signaling by increasing GRP78 expression in the intima layer. This effect might be related to the reduction of plasma level of LDL and lipids deposition in the aorta [148]. Furthermore up-regulation of T-cadherin has emerged as an effective tool that limits the progression of atherosclerotic lesions in endothelial cells in vitro. This molecule is a glycosylphosphatidylinositol-anchored element belonging to the cadherin family, that colocalizes with GRP78 on the plasma membrane [149]. Its over-expression or silencing by genetic manipulations selectively attenuates or amplifies the PERK branch of the UPR cascade obtained by ER stressors like homocysteine, thapsigargin and brefeldin A, so influencing apoptosis [150].
Indeed T-cadherin up-regulation is able to directly limit the phosphorylation of the eukaryotic translation initiation factor 2 alpha (phospho-eIF2alpha) and CHOP-driven cell death, even if how it communicates with ER-stress machinery in vitro is not yet known.Salubrinal is another chemical chaperone that modulates the dephosphorylation of eIF2alpha, so reducing abnormal protein load on the ER and prolonged UPR, and it has been demonstrated to limit ischemia-reperfusion damage in the mice brain [151].
Despite some promising reports, it is important to consider that there are different commercial preparations of the drug providing different level of protection, so the real efficacy is currently debated. Finally among ER-resident chemical chaperones oxygen-regulated protein150 (ORP150), a 150 kDa oxygen-regulated protein, has been implicated not only in reducing apoptosis during oxidative damage but also in preventing ox-LDLs induced ER stress in transfected vascular endothelial cells.
In particular, by immune-precipitation assay it has been demonstrated that ORP150 is bound to three ER stress sensors IRE1alpha, PERK and ATF6 so maintaining them in an inactive status and contributing to delay UPR activation. Furthermore ORP150 and IRE1alpha were also linked in situ in atherosclerotic lesions from human carotid plaque, but no ORP150-IRE1 alpha association was detected in normal human mammary artery [152].A growing body of evidence indicates that LDLs, modified by oxidation, enzymatic attack, glycation and aggregation in ox-LDL, trigger local vascular inflammation and toxic events implicated in atherosclerosis, but in contrast high density lipoproteins (HDLs) have anti-atherogenic properties that have been linked to reduced ER stress and autophagy [153]. In endothelial cells in vitro HDLs pretreatment was able to prevent detrimental UPR pathways inhibiting IRE1 alpha activation and phosphorylation in the PERK arm and the nuclear translocation of ATF6 that triggered the pro-apoptotic CHOP signaling. All these mechanisms were stimulated by prolonged ER stress induced by ox-LDLs that in parallel activated also autophagy then overwhelmed by apoptosis if the vascular stress lasted too much. However, calcium deregulation was a common upstream signal for two parallel pathways in this in vitro model, where ER stress-UPR but also autophagy are involved. Indeed HDLs were able to prevent the increase in autophagic markers like LC3-II and beclin-1 in the endothelial cells that, silenced for beclin 1 and then stimulated by toxic ox-LDLs, displayed less ability to be recognized by macrophages. Remarkably, even if autophagy is not involved in apoptosis, probably contributes like a beneficial “eat-me” signal on the cell surface by exposing phosphatydylserine, necessary to the clearance by efferocytosis of apoptotic cells [154] (Figure 5).
All these important findings suggest a potential efficacy for HDLs-based therapeutic opportunities in atherosclerosis. Figure 5.Beneficial role of high density lipoproteins upstream ER stress and autophagy in endothelial cells.
Adapted from [154].Recently an interesting study reported the peculiar expression on endothelial cells and macrophages of a novel GRP78-interacting protein induced by ER stress, called Gipie [155]. Gipie belongs to the Girdin family protein and is localized in the ER and Golgi apparatus in the endothelial cell lines (human umbilical vein endothelial cell-HUVEC and human coronary artery endothelial cells-HCAEC), but not in epithelial or mesenchymal cells in vitro. The transfection of Gipie into HUVEC cells exposed to ER inducer thapsigargin, a specific blocker of ER calcium ATP-ase pumps, was able to decrease CHOP expression and apoptosis.
Moreover the same protection was demonstrated by Gipie’s over-expression in rat carotid artery endothelial cells after baloon injury, a well-known in vivo model of endothelial damage and restenosis. Finally also in adult P65 mice aorta, Gipie was superimposed with GRP78 in atheroprone sites like the inner curvature of the aortic arch, but not in the outer curvature or in the ascending aorta, less sensitive to hemodynamic stress. Anyway even if more studies on transgenic Gipie-deficient animals will improve the understanding of the proper function in circulatory system, Gipie may be considered a reliable therapeutic target in atherosclerosis yet.6. ConclusionsActually the pivotal role of ER stress response in atherosclerosis and cardiovascular diseases is widely accepted.
Nevertheless it remains much work to do in particular to discover the multiple relationship between different integrated pathways associated to ER signaling and to maintain the best ER stress modulation in the endothelium and vascular wall.
Indeed it is important to point out that in biology the UPR is considered a surviving mechanism, so its complete deregulation may not be useful but dangerous. However additional experimental studies are required to help identify novel therapies to restore proper ER homeostasis but in particular, those to stabilize the minority of dangerous plaques associated with acute cardiovascular damage.



Genetic background of diabetes mellitus type 2
Impact of medication errors in nursing research


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