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Title: Transcriptional Profiling Uncovers a Network of Cholesterol-Responsive Atherosclerosis Target Genes}
Article:
Abstract:
Despite the well-documented effects of plasma lipid lowering regimes halting atherosclerosis lesion development and reducing morbidity and mortality of coronary artery disease and stroke, the transcriptional response in the atherosclerotic lesion mediating these beneficial effects has not yet been carefully investigated. We performed transcriptional profiling at 10-week intervals in atherosclerosis-prone mice with human-like hypercholesterolemia and a genetic switch to lower plasma lipoproteins( Ldlr−/−Apo100/100 Mttpflox/flox Mx1-Cre). Atherosclerotic lesions progressed slowly at first, then expanded rapidly, and plateaued after advanced lesions formed. Analysis of lesion expression profiles indicated that accumulation of lipid-poor macrophages reached a point that led to the rapid expansion phase with accelerated foam-cell formation and inflammation, an interpretation supported by lesion histology. Genetic lowering of plasma cholesterol( e. g., lipoproteins) at this point all together prevented the formation of advanced plaques and parallel transcriptional profiling of the atherosclerotic arterial wall identified 37 cholesterol-responsive genes mediating this effect. Validation by siRNA-inhibition in macrophages incubated with acetylated-LDL revealed a network of eight cholesterol-responsive atherosclerosis genes regulating cholesterol-ester accumulation. Taken together, we have identified a network of atherosclerosis genes that in response to plasma cholesterol-lowering prevents the formation of advanced plaques. This network should be of interest for the development of novel atherosclerosis therapies.
Introduction:
Atherosclerosis is a lifelong, progressive disease that becomes clinically significant in 50% of the population, leading to myocardial infarction( MI), stroke, and eventually death. Statin-based lipid-lowering regimens reduce morbidity and mortality from both MI and stroke[1]. Aggressive statin regimens can even cause regression of atherosclerosis[2] but sometimes generate severe side effects. To fully exploit the beneficial effects of lipid lowering, we need a better understanding of the transcriptional changes induced by lowering plasma lipoproteins[3]. Whole-genome measurement technologies developed in the aftermath of the human[4],[5] and mouse[6] genome projects offer the opportunity to uncover entire repertoires of changes in gene expression related to complex diseases like atherosclerosis and reveal their interplay in regulatory networks. We used the Ldlr−/−Apo100/100Mttpflox/floxMx1-Cre mouse model[7] that has a plasma lipoprotein profile similar to that of familial hypercholesterolemia( Ldlr−/−Apob100/100) and a genetic switch to block hepatic synthesis of lipoproteins and thereby lower plasma lipoproteins( Mttpflox/floxMx1-Cre) to investigate the effects of plasma cholesterol-lowering on atherosclerosis development and to identify cholesterol-responsive atherosclerosis genes.
Discussion:
In this study, we first used genome-wide expression profiling to identify a point before which atherosclerosis developed slowly and only low-level inflammation was present. After this point, lesions expanded rapidly and inflammation increased markedly. The inflammation persisted in late phases, leading to the formation of advanced plaques, but lesion size increased transiently during a 10-week period. The rapid lesion expansion was primarily caused by an equally rapid lipid accumulation in macrophages. In early lesions, macrophages with low degree of inflammation and low lipid content accumulated. At a certain point, this accumulation halted and was followed by a rapid increase in macrophage lipid content paralleled by an induction of inflammatory genes. Lowering plasma cholesterol at this point prevented the rapid expansion of the lesions and the formation of advanced plaques. The cholesterol-lowering effect was mediated by 37 cholesterol-responsive atherosclerosis genes. Validation of the macrophage-related part of these genes by additional transcriptional profiling of mRNA from siRNA-targeted THP1─macrophages incubated with AcLDL exposed a regulatory gene network of foam-cell formation. This network as a whole and some of its individual nodes( particularly PVRL2 and HSDL2) should be considered for therapies to prevent the formation of advanced plaques. Transcriptional profiles of atherosclerosis lesions are challenging to interpret[3]. Such lesions contains several cell types, and the average mRNA contribution of a given cell type is altered with disease development. Thus, changes in mRNA levels represent a mixture of actual changes in cellular mRNA concentrations and changes in cell type admixture. In addition, cells in different stages of proliferation and differentiation( e. g., macrophages differentiation into foam cells) adds to this problem also within a given cell type. However, the current lesion mRNA dataset over tight time intervals provides, to our best knowledge, the most comprehensive compendium of lesion expression profiles representing known and novel biological processes and pathways activated during atherogenesis( Figure 2A). Analysis of lesion mRNA clusters( Figure 2A) indicated that, at first, macrophages infiltrate the arterial wall, leading to the formation of fatty streaks. Then, at what appears to be a rather specific time point, these cells become activated, leading to a burst of inflammatory activity that, in combination with a rapid accumulation of CE in macrophages, generates advanced plaques; documented as a critical step in atherogenesis[12]. We believe this transformation can be related to the density of macrophages in the arterial wall. At a given density, the macrophages not only stimulate themselves( autocrine) but also stimulate each other( paracrine), leading to a burst of inflammatory activities and increasing lipid uptake. If such a mechanism is also present in humans, the timing of therapies to prevent or slow atherosclerosis development may be very important. Indeed, in these mice, the formation of advanced plaques was all together prevented by genetic lowering of plasma cholesterol immediately before the rapid lesion expansion( Figure 3A). In contrast to mRNA profiles isolated during lesion development, the extent and relative composition of different cell types in the lesions were similar before and after the subacute lowering of plasma cholesterol( Figure 3B–3D). Thus, in this case the changes in mRNA concentration monitored by the GeneChips reflect actual changes in cellular mRNA levels. Since the accumulation of lipids in macrophages was a central process in the rapid lesion expansion and formation of advance plaques( clusters 1 and 3 in Figure 2A–2C), we used siRNA in THP-1 macrophages incubated with AcLDL to validate the cholesterol-responsive genes( Table S12). Eight genes were found to belong to a regulatory gene network in which PVRL2 and HSDL2 had central roles. Little is known about PVRL2 and HSDL2( generating 6 and 3 hits in PubMed, respectively). A sequence variant in PVRL2 is associated with the severity of multiple sclerosis[13]. HSDL encodes the sterol carrier protein-2, a small intracellular basic protein domain that enhances the transfer of lipids between membranes in vitro[14]. Although pointing out isolated candidates as being more promising than others is tempting, the lesson from whole-genome approaches will most certainly be that complex diseases like atherosclerosis will not be defeated by targeting single genes( probably not even single regulatory genes) but instead to target several genes belonging to a similar network of pathology[9],[15]. This notion is supported by studying a small gene network as the present( Figure 4A) where none of the nodes( i. e., genes) can be said to solely promote or inhibit foam-cell formation. Our findings imply that the timing of interventions with plasma cholesterol-lowering agents may be very critical. Patients at risk of developing complications of atherosclerosis( e. g., stroke and MI) may benefit from being treated very early in life. The development of noninvasive technologies to detect early atherosclerosis or molecular markers of atherosclerosis stages will be important in this respect. For normo-cholesterolemic individuals but with other atherosclerosis risk factors, novel regimens targeting atherosclerosis genes that mediate the beneficial effects of plasma cholesterol-lowering may be useful. In summary, the network of cholesterol-responsive atherosclerosis target genes and regulators of foam-cell formation identified in our study merits further attention.
Atherosclerosis is present in the major arteries of all adults . In industrial societies , atherosclerosis progression in ∼50% of adults leads to clinical manifestations such as stroke and myocardial infarction , and eventually death . Lowering circulating LDL-cholesterol levels can slow atherosclerosis progression and even cause regression . Yet , little is known about the genes in the atherosclerotic arterial wall that mediate those effects . To identify such genes , we studied genetically modified mice in which high levels of human-like LDL-cholesterol cause rapid progression of atherosclerosis; the mice also had a genetic “switch” to lower LDL-cholesterol . Lowering LDL-cholesterol at a critical point before advanced plaques developed stopped lesion progression . Analysis of gene expression in response to the lowering of plasma LDL-cholesterol revealed 37 lesion genes as possible mediators of this effect . We validated some of these genes in macrophages using siRNA incubated with acetylated-LDL to mimic foam cells , which are central to atherosclerosis progression . “Reverse engineering” of whole-genome expression data from these experiments revealed a regulatory gene network of cholesterol-responsive atherosclerosis genes that control foam cell formation . This network and the individual genes within it merit further attention as targets for drugs to prevent the transformation of early harmless lesions into advanced , clinically significant plaques .