Study in Nature Medicine Establishes New Target in Diseased Arteries

AnuerysmRemoving a single protein prevents early damage in blood vessels from triggering a later-stage, frequently lethal complication of atherosclerosis, according to research published in the journal Nature Medicine.

By eliminating the gene for cyclophilin A (CypA), researchers were able to provide complete protection against abdominal aortic aneurysm (AAA). Adding to the study’s importance, that process shares signaling pathways with atherosclerosis, and new classes of drugs targeting CypA could potentially address both diseases.

When study mice were engineered to remove their CypA gene, none from that group developed AAA in the face of the hypertension and high cholesterol known to accelerate it. In contrast, 78 percent of mice with “normal” amounts of CypA developed AAA under the same conditions, 35 percent with a fatal rupture. The team also found high CypA levels in the rupture-prone vessels of humans with the condition, and that major drugs like statins reduce CypA levels, which may partly explain their benefit.

“It is extremely unusual for the removal of one protein to provide absolute protection, but it makes perfect sense because cyclophilin A promotes three of the most destructive forces in blood vessels – oxidative stress, inflammation and matrix degradation,” said Bradford C. Berk, M.D., Ph.D., professor of Medicine within the Aab Cardiovascular Research Institute at the University of Rochester Medical Center and senior author of the study. “ We are working to design anti-CypA drugs that will diminish the disease processes underlying AAA, atherosclerosis and hypertension.”

Scientists know that abdominal aortic aneurysm involves action by angiotensin II, a hormone that is known to stimulate oxidative stress in blood vessels and which also causes inflammation. In AAA, the hormone works by driving up levels of reactive oxygen species. That action plays a role in excessively activating matrix metalloproteinases (MMPs), which degrade the matrix structure of the vessel wall. Overactive MMPs also digest the structural barriers in vessel walls that contain smooth muscle cells, freeing those cells to contribute to atherosclerotic plaques.

The current study analyzed the effects of angiotensin II in the absence of CypA. Mice lacking CypA saw greater than 75 percent decreases in the production of reactive oxygen species, MMP activation, and inflammatory cell influx compared to normal mice, with the opposite being true for mice with extra CypA.

The scientists propose that reactive oxygen species generated via angiotensin II trigger CypA secretion from smooth muscle cells in vessel walls. Once outside the cell, CypA docks into receptor proteins on the same cells to increase production of reactive oxygen species in a vicious cycle. Berk’s team is searching for the specific receptors that, if interfered with, would shut down production of these molecules, as well as CypA secretion, MMP activation, and inflammatory cell recruitment in AAA. The team is also investigating how CypA deficiency might slow the progression of atherosclerosis.

The work was supported by the National Heart, Lung and Blood Institute, part of the National Institutes of Health, and by the Japan Heart Foundation.