Gene Network Controls Atherosclerotic Plaque Formation

Cardiovascular disease researchers have used advanced genomic techniques to identify a network of genes related to atherosclerotic plaque formation.

Investigators at Karolinska Institutet (Stockholm, Sweden) worked with a line of atherosclerosis-prone mice with human-like hypercholesterolemia and a built-in genetic switch to reduce plasma lipoprotein synthesis. They determined the extent of plaque formation through microscopic and histological studies of the animals' arteries at ten-week intervals, and at each time point, they performed transcriptional profiling.

Ultimately they 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 rapid lesion expansion was primarily caused by an equally rapid lipid accumulation in macrophages. Lowering plasma cholesterol at this point (30 weeks) prevented the rapid expansion of the lesions and the formation of advanced plaques.

Data published in the March 14, 2008, edition of the journal PLoS Genetics revealed that gene profiling identified 37 cholesterol-responsive genes that in response to plasma cholesterol lowering prevented the formation of advanced plaques.

"The time when individual genes or gene pathways were thought to explain the development of complex common diseases, such as atherosclerosis, is past,” explained senior author Dr. Johan Björkegren, professor of computational medicine at Karolinska Institutet. "We now have enough tools and knowledge of system biology to take on the total complexity of these diseases. Previously, much atherosclerosis research was focused on identifying ways to stabilize the most dangerous plaques in order to prevent them rupturing and causing myocardial infarction or stroke. Our discovery means that we can now target the actual development of dangerous plaques.”


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