CypA promotes oxidative stress, inflammation, and matrix degradation, notes Nature Medicine paper.

Removing a single protein prevents early damage in blood vessels from triggering a later-stage, frequently lethal complication of atherosclerosis, according to researchers at the University of Rochester School of Medicine and Dentistry. By eliminating the gene for cyclophilin A (CypA) from a strain of mice, they were able to provide complete protection against abdominal aortic aneurysm (AAA), according to a study in Nature Medicine.

AAA is a progressive outward dilation of the aorta under the stress of blood pressure due to a breakdown in the vessel’s structural integrity. It also shares vital biochemical pathways with atherosclerosis.

“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,” explains Bradford C. Berk, M.D., Ph.D., professor of medicine within the Aab Cardiovascular Research Institute at the university, and senior author of the study.

Among the hormones best known to stimulate oxidative stress in blood vessels is angiotensin II. It has also been seen to have a role in matrix degradation and inflammation. The current study sought to answer whether angiotensin II can achieve these disease-causing effects if CypA is not there to pass on its message.

To clarify the role of CypA, the team engineered mice to no longer produce apolipoprotein E, which increased their cholesterol levels and made them prone to atherosclerosis. From this original line, the team further engineered one group with no CypA, another with extra CypA, and compared both to normal mice as all were treated for a month with angiotensin II.

Mice lacking CypA saw greater than 75% decreases in ROS production, MMP activation, and inflammatory cell influx compared to normal mice. MMPs, or matrix metalloproteinases, degrade the matrix structure of the vessel wall. Additionally, they noticed increases in these elements for mice with extra CypA. Angiotensin II treatment also dramatically increased expression of cytokines, unless CypA was missing.

The team also found high CypA levels in the rupture-prone vessels of humans with AAA, and that major drugs like statins reduce CypA levels, which may partly explain their benefit.

The investigators thus propose that ROS generated via angiotensin II trigger CypA secretion from smooth muscle cells in vessel walls. Once outside the cell, CypA docks into CypA receptor proteins on the same cells to increase ROS production in a vicious cycle.

The scientists are now searching for the specific CypA receptors that if interfered with, would shut down ROS production, CypA secretion, MMP activation, and inflammatory cell recruitment in AAA. They are also working to complete a study that will confirm CypA deficiency significantly slows the progression of atherosclerosis.

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