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 −/− Apo 100/100 Mttp flox/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.
Highlights
Atherosclerosis is a lifelong, progressive disease that becomes clinically significant in 50% of the population, leading to myocardial infarction (MI), stroke, and eventually death
We used the Ldlr2/ 2Apo100/100Mttpflox/floxMx1-Cre mouse model [7] that has a plasma lipoprotein profile similar to that of familial hypercholesterolemia (Ldlr2/2Apob100/100) and a genetic switch to block hepatic synthesis of lipoproteins and thereby lower plasma lipoproteins (Mttpflox/ floxMx1-Cre) to investigate the effects of plasma cholesterollowering on atherosclerosis development and to identify cholesterol-responsive atherosclerosis genes
Occasional spots of Sudan IV staining were detected at 10 weeks (n = 10, not shown), but lesions were detected in all mice at 20 weeks
Summary
Atherosclerosis is a lifelong, progressive disease that becomes clinically significant in 50% of the population, leading to myocardial infarction (MI), stroke, and eventually death. Statinbased lipid-lowering regimens reduce morbidity and mortality from both MI and stroke [1]. Wholegenome 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 Ldlr2/ 2Apo100/100Mttpflox/floxMx1-Cre mouse model [7] that has a plasma lipoprotein profile similar to that of familial hypercholesterolemia (Ldlr2/2Apob100/100) and a genetic switch to block hepatic synthesis of lipoproteins and thereby lower plasma lipoproteins (Mttpflox/ floxMx1-Cre) to investigate the effects of plasma cholesterollowering on atherosclerosis development and to identify cholesterol-responsive atherosclerosis genes
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