Recent Faculty Publication: Macrophages play critical roles in atherogenesis

Chia-Hua Wua, Alan Daugherty*, and Hong Lu*

This commentary summarizes three recent publications that  have  elucidated effects of mediator subunit 1 (MED1) [3&&], Ca2þ/calmodu- lin-dependent protein kinase II (CaMKII) [4&&], and melanocortin 1 receptor (MC1-R) [5] in macro- phages in the development of atherosclerosis.

MED1, a subunit of mediator, functions as a transcriptional coactivator [6]. MED1 binds peroxi- some  proliferator-activated  receptor  (PPAR)g[7]. Deficiency of MED1 impairs PPARg-regulated gene expression  [8].  PPARg  activation  drives  macro- phages toward the M2 phenotype that conveys anti- atherogenic properties [9]. Bai et al. [3&&] determined effects  of  MED1  on  atherosclerosis  and  related mechanisms. The authors used two  strategies to demonstrate roles of macrophage-derived MED1 in atherosclerosis. One strategy used apolipoprotein E   deficient   mice   with   monocyte/macrophage- specific  MED1  genetic  deficiency.  Another  was bone marrow transplantation by repopulating bone marrow cells from monocyte/macrophage-specific MED1 deficient mice into lethally irradiated low- density lipoprotein receptor deficient mice. MED1 regulated PPARg-induced M2 genes by enhancing the binding of PPARg on promoters of M2 marker genes and monomethylation at lysine 4 of histone H3  and  acetylation  at  lysine  27  of  histone  H3 modification.  MED1  deficiency  in  macrophages promoted              M1                phenotype         switch,  augmented inflammatory response in the aorta, and increased atherosclerosis.  These  findings  provide  evidence that MED1 shows antiatherosclerotic effects by reg- ulating PPARg-mediated macrophage polarization. CaMKII is a serine-threonine kinase that regu- lates Ca2þ-mediated functions [10,11]. Dr Tabas’s group  [4&&]  found  that  CaMKIIg expression  was increased in advanced atherosclerotic lesions. They then determined effects of macrophage CaMKIIg in efferocytosis of advanced atherosclerosis using myeloid-specific CaMKIIg deficient mice in a low- density lipoprotein receptor-/- background. Mer tyrosine kinase (MerTK) is a critical efferocytic recep- tor in macrophages and contributes to efferocytosis in atherosclerosis [12]. Genetic deletion of CaMKIIg in myeloid cells improved MerTK-mediated effero- cytosis and led to decreased necrotic cores and apoptosis in atherosclerotic lesions. Macrophage CaMKIIg inhibited a transcription factor, AMP- dependent transcription factor (ATF) 6, whereas ATF6 induced liver X receptor a, a MerTK inducer. These findings link macrophage CaMKIIg with ATF6, liver X receptor a, and MerTK to necrosis during atherosclerotic lesion development.

MC1-R is a G protein–coupled  receptor that binds  melanocortin  peptides.  It  is  abundant  in monocytes  and  macrophages  [13].  Rinne  et  al. [14&] reported previously that MC1-R activation pre- vented foam cell formation through increasing ATP- binding cassette transporter sub-family A member 1 (ABCA1) and ATP-binding cassette transporter sub- family G member 1 (ABCG1)-mediated reverse cho- lesterol transport. On the basis of this previous work, the authors [5] determined whether deficiency in MC1-R   signaling   would   affect   atherosclerosis. Whole body deficiency of MC1-R in apolipoprotein E deficient mice increased atherosclerosis, hyper- cholesterolemia,  and  hepatic  lipid  accumulation. Deficiency of MC1-R also increased accumulation of  lymphocyte  antigen  6  complex,  locus  Chigh monocytes and macrophages in aortas of mice fed a normal rodent laboratory diet. These data high- light the importance of MC1-R in cholesterol metab- olism, macrophage infiltration, and atherosclerosis. Although  this  commentary  only  introduces three  recent  reports,  many  other  studies  have also explored extended mechanisms using human tissues,  animal  models,  and  culture  systems  to understand how macrophages or molecules in mac- rophages contribute to atherosclerosis. It is worth noting that most studies either focus on one sex or have no description of the sex studied in animal models. We expect that more investigators will pay attention to sex differences in future studies of under- standing mechanisms of atherosclerosis [15].

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*Saha Cardiovascular Research Center Faculty