"Our lab has been studying CypA since the early 1990s," Berk said. "We had to determine that vessel walls were secreting something in response to ROS, then prove it was CypA, then prove CypA was required for oxidative stress and inflammation to take their toll in live animals. Our results should put an end to debates within the field and pharmaceutical companies about whether we have found a vital new role for this well known molecule. Incredibly, CypA is required both inside and outside of cells to promote angiotensin II-mediated pathogenic effects in vessel walls."

Berk and colleagues 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. When a signaling molecule docks into its receptor, like a key turning a lock, it changes the receptor's shape such that signals get passed on. Most drugs work by interfering with receptors, and Berk's team is 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. Also in the next phase, Berk expects to complete a study shortly that will confirm CypA deficiency significantly slows the progression of atherosclerosis.

Along with first author Kimio Satoh, M.D., Ph.D., and Berk, the paper was co-authored by Tetsuya Matoba, M.D., Ph.D.; Michael O'Dell, B.S.; Patrizia Nigro, Ph.D.; Zhaoqiang Cui, Ph.D.; Xi Shi, Ph.D.; Amy Mohan, B.S.; Chen Yan, Ph.D.; Jun-ichi Abe, M.D., Ph.D. and Karl Illig, M.D., all within the Aab CVRI and the University of Rochester School of Medicine and Dentistry. 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.

"Currently available and experimental therapies, including ACE inhibitors and antagonists of the angiotensin receptors, MCP-1 and MMPs have significant limits in terms of efficacy in AAA, and thus, CypA inhibitors have the potential to meet significant unmet need," Berk said. "Additionally, inhibition of CypA looks to have tremendous benefit in several diseases that involve blood vessels in the brain and heart. Furthermore, while drugs that inhibit CypA may overlap somewhat with other drugs targeting the same angiotensin II pathway, they also look to have additive effects that create potential for combination therapies."

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