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. (Arterioscler Thromb Vasc Biol. 2011;31:960-968.)Key Words: atherosclerosis Ⅲ endothelium Ⅲ immune system Ⅲ risk factors Ⅲ stress Ⅲ heat shock protein T ypical cellular hallmarks of chronic inflammation and infections, notably infiltration by mononuclear cells, are also present in the cardiovascular system, as has been known for more than 150 years. However, until quite recently, it was not clear whether these inflammatory immunologic processes are primary or secondary in nature. 1 One of the reasons for this uncertainty may have been the fact that most investigations in humans were conducted on surgical or autopsy specimens representing very advanced stages of cardiovascular disease (CVD) and thus did not provide information on the initial mechanisms triggering these processes. In complex situations, such as in atherosclerosis, it was also difficult to appreciate that different, clinically well-proven risk factors may provoke a similar, or even identical, pathophysiological outcome. The main thrust to resolve this dilemma was to delineate the array of nonspecific and specific humoral and cellular inflammatory reactions taking place within the afflicted vascular territories. The availability of animal models that, at least partly, mimic human CVD was of utmost importance for this progress. In recent decades, the aim has been to identify exogenous or autologous antigens that may induce the local cardiovascular immune reactions. Among the candidates for such antigens are infectious agents, such as Chlamydia pneumoniae, as well as autoantigens, such as b...

Non-protein-coding RNAs (ncRNAs) fulfill a wide range of cellular functions from protein synthesis to regulation of gene expression. Identification of novel regulatory ncRNAs by experimental approaches commonly includes the generation of specialized cDNA libraries encoding small ncRNA species. However, such identification is severely hampered by the presence of constitutively expressed and highly abundant ‘house-keeping’ ncRNAs, such as ribosomal RNAs, small nuclear RNAs or transfer RNAs. We have developed a novel experimental strategy, designated as subtractive hybridization of ncRNA transcripts (SHORT) to specifically select and amplify novel regulatory ncRNAs, which are only expressed at certain stages or under specific growth conditions of cells. The method is based on the selective subtractive hybridization technique, formerly applied to the detection of differentially expressed mRNAs. As a model system, we applied SHORT to Epstein–Barr virus (EBV) infected human B cells. Thereby, we identified 21 novel as well as previously reported ncRNA species to be up-regulated during virus infection. Our method will serve as a powerful tool to identify novel functional ncRNAs acting as genetic switches in the regulation of fundamental cellular processes such as development, tissue differentiation or disease.

Our results confirm and extend previous findings reporting on the induction of autophagy by CSE in the lung. We show that protein damage caused by CSE activates autophagy, ultimately resulting in necrotic death of HUVECs. Via this mechanism, cigarette smoking may contribute to the deterioration of vascular endothelial function and the initiation of atherosclerosis.

Objective-To validate the hypothesis that the toxic heavy metal lead (Pb) may be linked to cardiovascular diseases via the initiation of atherosclerosis, in vivo and in vitro studies were conducted. Methods and Results-During the human study part of this project, serum Pb levels of healthy young women were correlated to carotid intima-media thickness. Multivariate logistic regression analyses showed that increased serum Pb levels were significantly associated with an increased intima-media thickness (Pϭ0.01; odds ratio per SD unit, 1.6 [95% CI, 1.1 to 2.4]). In vitro, Pb induced an increase in interleukin 8 production and secretion by vascular endothelial cells. Nuclear factor erythroid 2-related factor-2 is the crucial transcription factor involved in Pb-induced upregulation of interleukin 8. Endothelial cell-secreted interleukin 8 triggered intimal invasion of smooth muscle cells and enhanced intimal thickening in an arterial organ culture model. This phenomenon was further enhanced by Pb-increased elastin synthesis of smooth muscle cells. Conclusion-Our data support the hypothesis that Pb is a novel, independent, and significant risk factor for intimal hyperplasia. Key Words: Pb Ⅲ heavy metal Ⅲ endothelial Ⅲ Nrf2 Ⅲ interleukin Ⅲ smooth muscle cell Ⅲ invasion Ⅲ migration Ⅲ vascular Ⅲ pathophysiology Ⅲ risk factor Ⅲ intima media thickness Ⅲ atherosclerosis C ardiovascular and cerebrovascular diseases related to atherosclerosis are the leading cause of death in developed countries. 1 The identification of new risk factors is gaining more and more importance for disease prevention.The toxic heavy metal lead (Pb) is second on the Agency for Toxic Substances and Disease Registry's list of most hazardous substances. 2 Although the environmental burden in most countries has been declining because leaded gasoline is being phased out, 3 sources for Pb uptake are still ubiquitous. For example, Pb is emitted into the air through oil and coal combustion and nonferrous metal production. Pb pipes, Pbsoldered copper pipes, or Pb containing brass joints frequently can be found in older houses 4 and are still an important source for Pb uptake. In developing countries, the recycling of discarded Pb acid batteries under uncontrolled conditions poses a serious problem.The Pb that is absorbed reaches the bloodstream and binds to erythrocytes to an extent of approximately 99%; only 1% of total blood Pb can be found in plasma/serum. The half-life of Pb in blood and soft tissue is short (30 days). However, Pb is deposited in bone (in adults, 94% of the total body burden of Pb is contained in bones and teeth, with a half-life of 27 years 5 ). In addition, Barry 6 found that Pb accumulates in aortal tissue (with concentrations Յ60 mol/L) and that Pb levels in atherosclerotic vessels tend to be higher than in unaffected vessels.In general, blood Pb concentrations of greater than 10 g/dL (ie, Ͼ0.5 mol/L) are defined as Pb poisoning 7 ; however, because of the reported adverse health effects of Pb concentrations less than these values, ...