In a new study on mice, which is presented in the open-access journal PLoS Genetics, the research group has shown that the accumulation of the plaque that causes myocardial infarction and stroke can be prevented if levels of the bad LDL cholesterol are reduced before atherosclerotic plaque has progressed beyond a particular point. The group has also identified a network of 37 genes that lowers levels of blood cholesterol and brings about the beneficial effect.

Previously, much atherosclerosis research was focused on identifying ways to stabilise the most dangerous plaques in order to prevent them rupturing and causing myocardial infarction or stroke, says Associate Professor Johan Bj?¶rkegren, who has led the study. Our discovery means that we can now target the actual development of dangerous plaques.

Rather than covering individual vessel wall genes, their discovery encompasses a network of genes, and one that explains their mutual interaction. It is on account of years of network algorithm development under Jesper Tegn?©r, professor of computational biology, that the discovery of gene networks has been made possible.

The time when individual genes or gene pathways were thought to explain the development of complex common diseases, such as atherosclerosis, is past, says Dr Bj?¶rkegren. We now have enough tools and knowledge of system biology to take on the total complexity of these diseases.

Atherosclerosis is the main cause of myocardial infarction and stroke, which cause almost half of all deaths in Sweden and other countries in the West.

info.ki.se/

These findings led the research team to look for pharmacological treatments that also could inhibit cyclophilin D. The drug cyclosporine is a well-documented inhibitor of the protein, but its use is problematic because it also inhibits a protein, calcineurin, crucial to skeletal muscle cell repair after injury and to the development of skeletal muscle cells. The advantage of Debio-025 is that while it inhibits cyclophilin D and blocks cell death in a number of situations, the drug does not suppress the immune system or block calcineurin. The drug is manufactured by DebioPharm S.A. of Lausanne, Switzerland, which provided Debio-025 for use in the study.

The researchers also found their study may have implications beyond skeletal muscle disease as cyclophilin D deletion reduced cardiac dysfunction caused by calcium-overload induced necrosis. This led the team to suggest that mitochondrial-dependent necrosis may also function as a common disease mechanism underlying a number of long-term degenerative disorders, something they plan to study in future research projects.

Muscular dystrophies are inherited disorders that mostly affect striated muscle tissue and more commonly occur in boys. This disease results in progressive muscle weakness, wasting and in many instances death. There is no known cure for muscular dystrophy, although Cincinnati Children's is a recognized leader in disease-related research and a multi-disciplinary approach to patient treatment focused on maximizing ambulatory function and quality of life.

cincinnatichildrens/