Plasma Cholesterol-Induced Lesion Networks Activated before Regression of Early, Mature, and Advanced Atherosclerosis

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/flox)Mx1-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. Author Summary The main underlying cause of heart attacks and strokes is atherosclerosis. One strategy to prevent these often deadly clinical events is therefore either to slow atherosclerosis progression or better, induce regression of atherosclerotic plaques making them more stable. Plasma cholesterol lowering (PCL) is the most efficient way to induce atherosclerosis regression but sometimes fails to do so. In our study, we used a mouse model with elevated LDL cholesterol levels, similar to humans who develop early atherosclerosis, and a genetic switch to lower plasma cholesterol at any time during atherosclerosis progression. In this model, we examined atherosclerosis gene expression and regression in response to PCL at three different stages of atherosclerosis progression. PCL led to complete regression in mice with early lesions but was incomplete in mice with mature and advanced lesions, indicating that early prevention with PCL in individuals with increased risk for heart attack or stroke would be particularly useful. In addition, by inferring PCL-responsive gene networks in early, mature and advanced atherosclerotic lesions, we identified key drivers specific for regression of early (PPARG), mature (MLL5) and advanced (SRSF10/XRN2) atherosclerosis. These key drivers should be interesting therapeutic targets to enhance PCL-mediated regression of atherosclerosis

Commercial cultivation and bioremediation potential of sugar kelp, Saccharina latissima, in Danish waters

Several seaweed species have been successfully tested for their biofilter potential for integrated multi-trophic aquaculture (IMTA). In this study, Saccharina latissima bioremediation potential was assessed over 12 months with respect to the yield, phosphorous (P), nitrogen (N) content and N removal. The experiment took place at two commercial cultivation areas; in close proximity to a blue mussel and fish farm (IMTA) and at a reference site, both situated outside Horsens fjord in Denmark. The maximum biomass yield over the first growing season was achieved in August (1.08±0.09 and 1.51±0.13 kg FW m-1) and September (0.92±0.18 and 1.49±0.16 kg FW m-1).Yield was significantly higher at the IMTA compared to the reference site in August (P<0.05). A second growing season did not improve biofiltration efficiency. The highest N and P removal was achieved in August and September. Again the IMTA location showed better N and P removal compared with the reference site in August; 5.02-7.02 g N and 0.86-1.23 g P m-1 of cultivation line (P<0.05). S. latissima shows potential for assimilation and removal of nutrients, particularly nitrogen. Seasonal variations of biofilter efficiency, conditions and potential applications should be taken into account when evaluating the best suited harvest time. For Horsens fjord, our results showed that the harvest time should take place in August-September in order to achieve maximum biofiltration efficiency (including N and P in epiphytes). However, for human consumption, it is better to harvest in May where the seaweed is free of epiphytes