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Blocking Single Target May Prevent Lethal Aneurysms

Researchers have shown that removal of a single key protein can prevent early damage in blood vessels from triggering a later-stage, frequently lethal complication of atherosclerosis. By eliminating the gene for a signaling protein called cyclophilin A (CypA) from a strain of mice, the team was able to provide complete protection against abdominal aortic aneurysm (AAA). AAA leads to 15,000 deaths a year, mostly in aging men, when aneurysms rupture to spill blood into the abdomen, a fatal event in 90 percent of cases. 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 researchers 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. “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 Dr. Bradford C. Berk, of 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." This study was published in the May 10 online edition of Nature Medicine. [Press release] [Nature Medicine abstract]