Abstract
Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (≥80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr−/−Apob 100/100 Mttp flox/floxMx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage. However, near-complete regression was observed only in mice with early lesions; mice with mature and advanced lesions were left with regression-resistant, relatively unstable plaque remnants. Atherosclerosis genes responding to PCL before regression, unlike those responding to the regression itself, were enriched in inherited risk for coronary artery disease and myocardial infarction, indicating causality. Inference of transcription factor (TF) regulatory networks of these PCL-responsive gene sets revealed largely different networks in early, mature, and advanced lesions. In early lesions, PPARG was identified as a specific master regulator of the PCL-responsive atherosclerosis TF-regulatory network, whereas in mature and advanced lesions, the specific master regulators were MLL5 and SRSF10/XRN2, respectively. In a THP-1 foam cell model of atherosclerosis regression, siRNA targeting of these master regulators activated the time-point-specific TF-regulatory networks and altered the accumulation of cholesterol esters. We conclude that PCL leads to complete atherosclerosis regression only in mice with early lesions. Identified master regulators and related PCL-responsive TF-regulatory networks will be interesting targets to enhance PCL-mediated regression of mature and advanced atherosclerotic lesions.
Highlights
Atherosclerosis, primarily in coronary artery disease (CAD) or carotid stenosis, is the main cause of myocardial infarction (MI) and stroke, which together are responsible for more than 50% of deaths worldwide [1]
We examined atherosclerosis gene expression and regression in response to Plasma cholesterol lowering (PCL) at three different stages of atherosclerosis progression
After recombination of microsomal triglyceride transfer protein (Mttp), plasma total cholesterol levels were reduced by 80–95%, HDL-cholesterol 50–60% and, triglyceride levels by 40–60%; plasma glucose levels were generally unaffected (Table 1 and Table S1)
Summary
Atherosclerosis, primarily in coronary artery disease (CAD) or carotid stenosis, is the main cause of myocardial infarction (MI) and stroke, which together are responsible for more than 50% of deaths worldwide [1]. The extent of atherosclerosis in the arterial bed is an unreliable marker of risk for future events, advanced atherosclerotic plaques are present in most cases of MI and in most cases of stroke. It is important to prevent early harmless atherosclerotic lesions from progressing to ruptureprone plaques, and if possible, to induce regression of advanced atherosclerosis into more stable forms [2]. Drugs that lower LDL cholesterol, such as statins, slow atherosclerosis progression and reduce morbidity and mortality
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