Abstract
In previous work we reported that ApoeKO mice transplanted with bone marrow cells deficient in the Transient Receptor Potential Canonical 3 (TRPC3) channel have reduced necrosis and number of apoptotic macrophages in advanced atherosclerotic plaques. Also, in vitro studies with polarized macrophages derived from mice with macrophage-specific loss of TRPC3 showed that M1, but not M2 macrophages, deficient in Trpc3 are less susceptible to ER stress-induced apoptosis than Trpc3 expressing cells. The questions remained (a) whether the plaque phenotype in transplanted mice resulted from a genuine effect of Trpc3 on macrophages, and (b) whether the reduced necrosis and macrophage apoptosis in plaques of these mice was a manifestation of the selective effect of TRPC3 on apoptosis of M1 macrophages previously observed in vitro. Here, we addressed these questions using Ldlr knockout (Ldlr−/−) mice with macrophage-specific loss of Trpc3 (MacTrpc3−/−/Ldlr−/− → Ldlr−/−). Compared to controls, we observed decreased plaque necrosis and number of apoptotic macrophages in MacTrpc3−/−/Ldlr−/− → Ldlr−/− mice. Immunohistochemical analysis revealed a reduction in apoptotic M1, but not apoptotic M2 macrophages. These findings confirm an effect of TRPC3 on plaque necrosis and support the notion that this is likely a reflection of the reduced susceptibility of Trpc3-deficient M1 macrophages to apoptosis.
Highlights
Atherosclerosis is the main cause of coronary heart disease, a leading determinant of morbidity and mortality in the United States[1]
In this study we directly examined the impact of macrophage-specific deletion of Trpc[3] on the characteristics of advanced atherosclerotic lesions in Ldlr−/− mice fed a conventional high fat diet
We previously showed that bone marrow-transplanted Ldlr−/− mice subjected to this regimen develop advanced atherosclerotic lesions[24]
Summary
Atherosclerosis is the main cause of coronary heart disease, a leading determinant of morbidity and mortality in the United States[1]. Compared to control animals, advanced lesions in the aortic root of mice with bone marrow deletion of Trpc[3] showed reduction in necrosis and in the content of apoptotic macrophages, with no changes in lesion size or cellularity[17] This was interpreted as potentially reflecting an effect of TRPC3 on polarized macrophages, which are abundant in plaques, and different from the observed in vitro effect on naïve macrophages. Whether the reduced necrosis and macrophage apoptosis observed in advanced plaques of the transplanted animals was to some extent a consequence of the selective effect of TRPC3 on apoptosis of M1 macrophages previously observed in vitro[17,18] To address these important questions, in the present work we used the low density lipoprotein receptor knockout (Ldlr−/−) mouse model of atherosclerosis transplanted with bone marrow from mice with macrophage-specific loss of TRPC3 (MacTrpc3−/−/Ldlr−/−) or control Ldlr−/− animals and examined the characteristics of advanced atherosclerotic lesions (14 weeks on high fat diet). These observations support the previous in vitro findings on polarized macrophages, and indicate that in advanced atherosclerotic plaques the beneficial impact of macrophage-specific deletion of Trpc[3] likely reflects the reduced susceptibility of Trpc3-deficient M1 macrophages to apoptosis in the plaque setting
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