ABSTRACT
OBJECTIVE: Shear stress patterns influence atherogenesis and plaque stability; low laminar shear stress (LLSS) promotes unstable plaques whereas oscillatory shear stress (OSS) induces more stable plaques. Endothelial connexin37 (Cx37) expression is also regulated by shear stress, which may contribute to localization of atherosclerotic disease. Moreover, Cx37 reduces initiation of atherosclerosis by inhibiting monocyte adhesion. The present work investigates the effect of Cx37 on the phenotype of plaques induced by LLSS or OSS. METHODS: Shear stress-modifying casts were placed around the common carotid artery of ApoE(-/-) or ApoE(-/-)Cx37(-/-) mice, and animals were placed on a high-cholesterol diet for 6 or 9 weeks. Atherosclerotic plaque size and composition were assessed by immunohistochemistry. RESULTS: Plaque size in response to OSS was increased in ApoE(-/-)Cx37(-/-) mice compared to ApoE(-/-) animals. Most plaques contained high lipid and macrophage content and a low amount of collagen. In ApoE(-/-) mice, macrophages were more prominent in LLSS than OSS plaques. This difference was reversed in ApoE(-/-)Cx37(-/-) animals, with a predominance of macrophages in OSS plaques. The increase in macrophage content in ApoE(-/-)Cx37(-/-) OSS plaques was mainly due to increased accumulation of M1 and Mox macrophage subtypes. Cx37 expression in macrophages did not affect their proliferation or their polarization in vitro. CONCLUSION: Cx37 deletion increased the size of atherosclerotic lesions in OSS regions and abrogated the development of a stable plaque phenotype under OSS in ApoE(-/-) mice. Hence, local hemodynamic factors may modify the risk for adverse atherosclerotic disease outcomes associated to a polymorphism in the human Cx37 gene.
Subject(s)
Apolipoproteins E/genetics , Connexins/genetics , Plaque, Atherosclerotic/genetics , Adenosine Triphosphate/chemistry , Animals , Apoptosis , Atherosclerosis , Cell Adhesion , Cell Differentiation , Cholesterol/chemistry , Connexins/physiology , Female , Gene Deletion , Hemodynamics , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/cytology , Oscillometry , Phenotype , Plaque, Atherosclerotic/metabolism , Polymorphism, Genetic , Shear Strength , Gap Junction alpha-4 ProteinABSTRACT
Energy-harvesting devices attract wide interest as power supplies of today's medical implants. Their long lifetime will spare patients from repeated surgical interventions. They also offer the opportunity to further miniaturize existing implants such as pacemakers, defibrillators or recorders of bio signals. A mass imbalance oscillation generator, which consists of a clockwork from a commercially available automatic wrist watch, was used as energy harvesting device to convert the kinetic energy from the cardiac wall motion to electrical energy. An MRI-based motion analysis of the left ventricle revealed basal regions to be energetically most favorable for the rotating unbalance of our harvester. A mathematical model was developed as a tool for optimizing the device's configuration. The model was validated by an in vitro experiment where an arm robot accelerated the harvesting device by reproducing the cardiac motion. Furthermore, in an in vivo experiment, the device was affixed onto a sheep heart for 1 h. The generated power in both experiments-in vitro (30 µW) and in vivo (16.7 µW)-is sufficient to power modern pacemakers.
