Drug Discovery Opinion

DDO Limited – Consultancy for Biotech and Pharma

May 13 2009

New Target for Treating Cardiovascular Disease

Posted by SR in News, tags: cardiovascular, target identification

Researchers from University of Rochester Medical Center have shown that eliminating the gene for cyclophilin A completely protects mice from developing abdominal aortic aneurysms, a late stage complication of atherosclerosis. An aortic aneurysm is a thin, weakened section of the aorta which can rupture, leading to massive internal blood loss and death. Aneurysms occur most frequently in the abdominal section of the aorta and cause around 15,000 deaths a year, most in older men. In abdominal aortic aneurysm, angiotensin II is known to stimulate oxidative stress in blood vessels leading to increased activity of matrix metalloproteinases which, in turn, degrade the matrix structure of the vessel wall. Increased activity of matrix metalloproteinases also plays a role in atherosclerosis, allowing smooth muscle cells from the blood vessel walls to contribute to the development of plaques. In both abdominal aortic aneurysm and atherosclerosis, angiotensin II also contributes to local inflammation by recruiting immune cells to the blood vessel wall.

Using genetically modified mice, cyclophilin A was found to promote all three events involved in angiotensin II mediated damage to blood vessels – oxidative stress, matrix degradation and inflammation. Cyclophilin A is highly expressed in vascular smooth muscle cells and studies showed that both intracellular and extracellular cyclophilin A are required for generation of reactive oxygen species and activation of matrix metalloproteinases. The team is hoping to develop anti-cyclophilin A drugs that will reduce the processes underlying cardiovascular diseases such as abdominal aortic aneurysm, atherosclerosis and hypertension. The study is published in full in the journal Nature Medicine.