P737The pro-inflammatory environment of the atherosclerotic plaque influences the biology of vascular smooth muscle cells in by regulating calcium-calmodulin dependent Kinase II

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Abstract

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.

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