Endothelial damage and stem cell repair in atherosclerosis.
TL;DR: Key elements of endothelial turnover in atherosclerosis are examined, i.e. damage and repair, and recent reciprocal stem cell application is highlighted, which may provide a new hope to the treatment of severe atherosclerotic complications.
About: This article is published in Vascular Pharmacology.The article was published on 2010-05-01. It has received 47 citations till now. The article focuses on the topics: Vasculogenesis & Endothelial stem cell.
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TL;DR: In vitro and in vivo experiments have demonstrated that classical atherosclerosis risk factors can act as endothelial stressors that provoke the simultaneous expression of adhesion molecules and of HSP60 in mitochondria, in cytoplasm, and on the cell surface, where it acts as a "danger signal" for cellular and humoral immune reactions.
Abstract: Hallmarks of inflammation in various cardiovascular diseases, notably atherosclerosis, have been observed for a long time. However, evidence for an (auto)antigen-driven process at these sites of inflammation has come forward only recently. Heat shock proteins (HSPs) have been identified as playing either immunologically mediated disease promoting or protective roles. HSP60 has been shown to trigger innate and adaptive immune responses that initiate the earliest still reversible inflammatory stage of atherosclerosis. HSP60 is structurally highly conserved and abundantly expressed by prokaryotic and eukaryotic cells under stressful conditions. Beneficial protective immunity to microbial HSP60 acquired by infection or vaccination and bona fide autoimmunity to biochemically altered autologous HSP60 is present in all humans. In vitro and in vivo experiments have demonstrated that classical atherosclerosis risk factors can act as endothelial stressors that provoke the simultaneous expression of adhesion molecules and of HSP60 in mitochondria, in cytoplasm, and on the cell surface, where it acts as a “danger signal” for cellular and humoral immune reactions. Hence, protective, preexisting anti-HSP60 immunity may have to be “paid for” by harmful (auto)immune cross-reactive attack on arterial endothelial cells maltreated by atherosclerosis risk factors. These experimentally and clinically proven findings are the basis for the autoimmune concept of atherosclerosis.
167 citations
TL;DR: It is shown that circulating Th17 cells and IL-17 increased in patients with ACS compared to the patients with stable angina or health individuals; the plasma levels of IL-6 increased but TGF-β decreased in ACS patients, exhibiting a positive and negative correlation with that of IL -17, respectively.
97 citations
TL;DR: It is concluded that the diverse pleiotropic actions of pitavastatin may contribute to reducing cardiovascular morbidity and mortality beyond that achieved through LDL-C reduction.
Abstract: 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are established first line treatments for hypercholesterolaemia. In addition to the direct effects of statins in reducing concentrations of atherogenic low density lipoprotein cholesterol (LDL-C), several studies have indicated that the beneficial effects of statins may be due to some of their cholesterol-independent, multiple (pleiotropic) effects which may differ between different members of the class. Pitavastatin is a novel synthetic lipophilic statin that has a number of pharmacodynamic and pharmacokinetic properties distinct from those of other statins, which may underlie its potential pleiotropic benefits in reducing cardiovascular risk factors. This review examines the principal pleiotropic effects of pitavastatin on endothelial function, vascular inflammation, oxidative stress and thrombosis. The article is based on a systematic literature search carried out in December 2010, together with more recent relevant publications where appropriate. The available data from clinical trials and in vitro and animal studies suggest that pitavastatin is not only effective in reducing LDL-C and triglycerides, but also has a range of other effects. These include increasing high density lipoprotein cholesterol, decreasing markers of platelet activation, improving cardiac, renal and endothelial function, and reducing endothelial stress, lipoprotein oxidation and, ultimately, improving the signs and symptoms of atherosclerosis. It is concluded that the diverse pleiotropic actions of pitavastatin may contribute to reducing cardiovascular morbidity and mortality beyond that achieved through LDL-C reduction.
85 citations
TL;DR: MiR-22 plays an important role in SMC differentiation, and epigenetic regulation through MECP2 is required for miR- 22 mediated SMC differentiated cells.
Abstract: Objective—In this study, we attempted to uncover the functional impact of microRNA-22 (miR-22) and its target gene in smooth muscle cell (SMC) differentiation and delineate the molecular mechanism ...
65 citations
TL;DR: In this paper, the authors investigated the serum levels of endothelial progenitor cells (EPCs) in type 2 diabetic patients without documented ischemic disease and the association between EPCs and atherosclerotic plaque formation in the carotid artery.
Abstract: Background The aim of the present study was to investigate the serum levels of endothelial progenitor cells (EPCs) in type 2 diabetic patients without documented ischemic disease and the association between EPCs and atherosclerotic plaque formation in the carotid artery. Methods and results A clinic-based, prospective study of type 2 diabetic patients was conducted. A total of 73 subjects were enrolled in this study after cardiac magnetic resonance imaging and ankle-brachial index measurements to exclude patients with ischemic disease. Plaque formation in the carotid artery was measured on ultrasonography. Circulating EPCs (CD34(+)/CD133(+)/CD309(+) cells) were counted on flow cytometry. Compared to subjects without carotid artery plaques, patients with plaques were significantly older (P=0.006) and had decreased EPC count (P=0.027). Serum glycated albumin (GA) level and the GA/glycated hemoglobin ratio tended to decrease in patients with plaques (P=0.091 and 0.067, respectively). Other cardiovascular disease risk factors were not significantly different between the 2 groups. On binary logistic regression analysis old age, low EPC count, and high serum GA level were independently correlated with carotid artery plaque formation. Conclusions EPC count and serum GA level appear to be a protective and an aggravating factor for endothelial damage, respectively, and therefore, a reduced EPC count or an increased GA level results in atherosclerotic plaque formation in type 2 diabetic patients.
53 citations
References
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TL;DR: Induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions is demonstrated and iPS cells, designated iPS, exhibit the morphology and growth properties of ES cells and express ES cell marker genes.
23,959 citations
TL;DR: The ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.
Abstract: Atherosclerosis, the principal cause of heart attack, stroke and gangrene of the extremities, is responsible for 50% of all mortality in the USA, Europe and Japan. The lesions result from an excessive, inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall. A large number of growth factors, cytokines and vasoregulatory molecules participate in this process. Our ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.
10,861 citations
TL;DR: A response-to-injury hypothesis of atherogenesis proposes that "injury" to the endothelium is the initiating event in atherosclerosis, and intimal smooth-muscle proliferation as the key event in the development of the advanced lesions of Atherosclerosis.
Abstract: CARDIOVASCULAR disease remains the chief cause of death in the United States and Western Europe, and atherosclerosis, the principal cause of myocardial and cerebral infarction, accounts for the majority of these deaths.1 This review, like its predecessor,2 will not attempt to cover all literature on atherosclerosis. In a previous review of the pathogenesis of atherosclerosis,2 Glomset and I discussed various hypotheses of atherogenesis2 3 4 5 6 7 and emphasized the importance of intimal smooth-muscle proliferation as the key event in the development of the advanced lesions of atherosclerosis. The response-to-injury hypothesis of atherogenesis2 3 4 5 6 proposes that "injury" to the endothelium is the initiating event in . . .
4,835 citations
TL;DR: It is shown that caspase-12 is localized to the ER and activated by ER stress, including disruption of ER calcium homeostasis and accumulation of excess proteins in ER, but not by membrane- or mitochondrial-targeted apoptotic signals, which may contribute to amyloid-β neurotoxicity.
Abstract: Apoptosis, or cellular suicide, is important for normal development and tissue homeostasis, but too much or too little apoptosis can also cause disease. The family of cysteine proteases, the so- called caspases, are critical mediators of programmed cell death, and thus far 14 family members have been identified. Some of these, such as caspase-8, mediate signal transduction downstream of death receptors located on the plasma membrane. Others, such as caspase-9, mediate apoptotic signals after mitochondrial damage. Stress in the endoplasmic reticulum (ER) can also result in apoptosis. Here we show that caspase-12 is localized to the ER and activated by ER stress, including disruption of ER calcium homeostasis and accumulation of excess proteins in ER, but not by membrane- or mitochondrial-targeted apoptotic signals. Mice that are deficient in caspase-12 are resistant to ER stress-induced apoptosis, but their cells undergo apoptosis in response to other death stimuli. Furthermore, we show that caspase-12-deficient cortical neurons are defective in apoptosis induced by amyloid-beta protein but not by staurosporine or trophic factor deprivation. Thus, caspase-12 mediates an ER-specific apoptosis pathway and may contribute to amyloid-beta neurotoxicity.
3,290 citations
TL;DR: Given its reversibility and granted the availability of a diagnostic tool to identify patients at risk and to control the efficacy of therapy in clinical practice, endothelial dysfunction may be an attractive primary target in the effort to optimize individualized therapeutic strategies to reduce cardiovascular morbidity and mortality.
Abstract: Endothelial dysfunction is a systemic disorder and a key variable in the pathogenesis of atherosclerosis and its complications. Current evidence suggests that endothelial status is not determined solely by the individual risk factor burden but rather, may be regarded as an integrated index of all atherogenic and atheroprotective factors present in an individual, including known as well as yet-unknown variables and genetic predisposition. Endothelial dysfunction reflects a vascular phenotype prone to atherogenesis and may therefore serve as a marker of the inherent atherosclerotic risk in an individual. In line with this hypothesis, dysfunction of either the coronary or peripheral vascular endothelium was shown to constitute an independent predictor of cardiovascular events, providing valuable prognostic information additional to that derived from conventional risk factor assessment. Interventions like risk factor modification and treatment with various drugs, including statins and angiotensin-converting enzyme inhibitors, may improve endothelial function and thereby, potentially prognosis. Hence, given its reversibility and granted the availability of a diagnostic tool to identify patients at risk and to control the efficacy of therapy in clinical practice, endothelial dysfunction may be an attractive primary target in the effort to optimize individualized therapeutic strategies to reduce cardiovascular morbidity and mortality.
2,145 citations