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Aims: Arteriosclerosis is a degenerative process of the arterial wall implicating activation of macrophages and proliferation of vascular smooth muscle cells. Calcium-Calmodulin dependent Kinase II (CaMKII) regulates vascular smooth muscle cells (VSMCs) proliferation, as well as macrophage activities, such as diapedesis, infiltration and release of extracellular matrix enzymes. We investigated the role of CaMKII in the setup of arteriosclerosis.Methods and results: Clinically defined stable and unstable plaques obtained from patients undergoing carotid endoarteriectomy were processed for evaluation of CaMKs protein expression, activity and localization. The levels of expression and activation of CaMKII were significantly higher, and localized mostly in macrophages. The larger content of CaMKII was found in macrophages that were more abundant in unstable rather than stable plaques. Stable and unstable plaques also differed for the CaMKs isoforms, with a dominance of CaMKIId in unstable plaques. To test the biological effect of activated macrophages, VSMCs were exposed to the medium conditioned (CM) by macrophages extracted from carotid plaques. CM induced attenuation of CaMKs expression and activity in VSMCs, leading to the reduction of VSMCs proliferation. A possible role of proinflammatory cytokines interleukin-6 (IL6) and interleukin-8 (IL8) in CaMKII modulation was demonstrated. In a related model, CaMKII inhibition in macrophages prevents the inhibition VSMCs proliferation.Conclusion: Our results indicate a pivotal role of CaMKs in arteriosclerosis by regulating macrophages on VSMCs activity. CaMKII could represent a possible target for therapeutic strategies based on macrophages specific inhibition for the stabilization of atherosclerotic lesions. [ABSTRACT FROM PUBLISHER]

A series of 3-acyl derivatives of the dihydronaphtho[2,3-b]thiophen-4,9-dione system were studied with respect to cytotoxicity and topoisomerase II inhibitory activity. These analogues were designed as electron-deficient anthraquinone analogues with potential intercalation ability. Derivatives 3-(diethylamino)-N-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]thiophen-3-yl)propanamide (11m) and 3-(2-(dimethylamino)ethylamino)-N-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]thiophen-3-yl)propanamide (11p) showed a high efficacy in cell lines that were highly resistant to treatment with doxorubicin, such as MDA-MB435 (melanoma), IGROV (ovarian), and SF-295 (glioblastoma) human cell lines. Both compounds inhibit topoisomerase II mediated relaxation of DNA, while only 11pincites arrest at the S phase in Caco-2 cells, inducing a delay of cell cycle progression and an increase of cell differentiation. The ability of these derivatives to modulate small heat shock proteins and cardiotoxicy effects was also explored. In addition, the DNA-binding properties of these compounds were investigated and discussed. [ABSTRACT FROM AUTHOR]