Objectives-Although cadmium (Cd) is an important and common environmental pollutant and has been linked to cardiovascular diseases, little is known about its effects in initial stages of atherosclerosis. Methods and Results-In the 195 young healthy women of the Atherosclerosis Risk Factors in Female Youngsters(ARFY) study, cadmium (Cd) level was independently associated with early atherosclerotic vessel wall thickening (intima-media thickness exceeding the 90th percentile of the distribution; multivariable OR 1.6[1.1.-2.3], Pϭ0.016). In line, Cd-fed ApoE knockout mice yielded a significantly increased aortic plaque surface compared to controls (9.5 versus 26.0 mm 2 , PϽ0.004). In vitro results indicate that physiological doses of Cd increase vascular endothelial permeability up to 6-fold by (1) inhibition of endothelial cell proliferation, and (2) induction of a caspase-independent but Bcl-xL-inhibitable form of cell death more than 72 hours after Cd addition. Both phenomena are preceded by Cd-induced DNA strand breaks and a cellular DNA damage response. Zinc showed a potent protective effect against deleterious effects of Cd both in the in vitro and human studies. Conclusion-Our research suggests Cd has promoting effects on early human and murine atherosclerosis, which were partly offset by high Zn concentrations. Key Words: cadmium, zinc Ⅲ endothelial Ⅲ dysfunction Ⅲ injury Ⅲ permeability Ⅲ necrosis Ⅲ ApoE Ⅲ atherosclerosis Ⅲ vascular Ⅲ pathophysiology Ⅲ risk factor Ⅲ intima media thickness Ⅲ apoptosis Ⅲ cell death S ince the use of Cd in manifold industrial applications, sources for and the amount of Cd uptake by humans has increased dramatically. Cd is, for example, released into the air through the burning of fossil fuels (coal, oil) and the incineration of municipal waste (Environmental Protection Agency, 2000). The most relevant sources for Cd uptake by humans are, however, cigarette smoking (one cigarette contains Ϸ1 to 2 g; daily uptake of Cd Ϸ1 to 3 g per pack smoked) and food for nonsmokers (daily intake Ϸ30 g; daily uptake Ϸ1 to 3 g), as well as exhaust gases (Agency for Toxic Substances and Disease Registry, 1999). After inhalation or ingestion of Cd, it is transferred into the bloodstream (whole blood and serum Cd concentrations range between Ϸ0.2 and Ϸ20 nmol/L 1,2 ), where Cd is transported either as a free ion or protein-bound, eg, attached to albumin or metallothioneins. Cd is taken up by cells of Cd target organs (liver, kidneys, and testis) via solute carriers, calcium and manganese channels, and iron transporters. [3][4][5] In 2001, Abu-Hayyeh et al 6 demonstrated that the aortic vessel wall is another under-recognized target organ for Cd accumulation (aortic wall concentrations of Cd are up to 20 mol/ L). Epidemiologically, high Cd level was found to be associated with hypertension, stroke, and cardiac arrest, 7-9 but confirmatory data are sparse and the mechanistic basis for these interactions remains unclear. Houtman et al observed a higher than expected frequency of atherosclerosis in a...

Smoking is a significant risk factor for development of atherosclerosis. However, the pathophysiology of smoking-mediated vessel wall damage is not understood. With tools ranging from analytical chemistry to cell biology, we show that cigarette smoke contains metals that catalyze the direct oxidation of cellular proteins by smoke oxidants. Oxidation of cellular proteins causes a loss of microtubule function, culminating in microtubule depolymerization and proteasome-dependent degradation of alpha-tubulin. As a consequence of the microtubule collapse, cytoskeletal structures as well as intermediate filaments break down, leading finally to a contraction of vascular endothelial cells. We observed a smoke extract-induced, calpain-dependent degradation of the intracellular form of platelet-endothelial cell adhesion molecule 1/CD31, as well as a release of P-selectin/CD62P, IL-6, and IL-8 from endothelial cells into the supernatant. Increased levels of soluble CD62P and IL-6 are well known to be associated with smoking in humans. Increased permeability of the vascular endothelium is a crucial event in atherogenesis. This work highlights the compounds and mechanisms by which cigarette smoke induces leakiness of the vascular endothelium.

No abstract

Atherosclerosis is a multifactorial, chronic-inflammatory disease for which the underlying cause remains unknown. It is also well documented that T-cells are among the first cells to migrate into the arterial intimal vessel layer, but their function there is still unexplained. Clinical and experimental data have provided evidence that atherosclerosis starts as an autoimmune reaction based on humoral and cellular immunity against a phylogenetically highly conserved stress protein, heat shock protein 60 (HSP60). In the present study, we phenotypically characterized T-cells from endarterectomized specimens of the carotid artery, and tested their reactivity to human HSP60. In addition, the T-cell receptor repertoire of the T-cell lines was defined by immunoscope analysis. We found a mixed population of CD4(+) and CD8(+) intralesional T-cells, with a slight predominance of CD8(+) cells. IFN-gamma production prevailed over IL-4 production. The T-cell reaction against human HSP60 was significantly increased in intralesional cells compared to peripheral T-cells. The lesion-derived T-cells showed an oligoclonally-restricted repertoire, in contrast to the polyclonal pattern of PBMC. These results clearly show that HSP60 is a major antigenic candidate, and that an oligoclonal T-cell expansion takes place in advanced human atherosclerotic lesions.