The Antioxidant/Nitric Oxide-Quenching Agent Cobinamide Prevents Aortic Disease in a Mouse Model of Marfan Syndrome.

Major pathologic changes in the proximal aorta underlie the life-threatening aortic aneurysms and dissections in Marfan Syndrome; current treatments delay aneurysm development without addressing the primary pathology. Because excess oxidative stress and nitric oxide/protein kinase G signaling likely contribute to the aortopathy, we hypothesized that cobinamide, a strong antioxidant that can attenuate nitric oxide signaling, could be uniquely suited to prevent aortic disease. In a well-characterized mouse model of Marfan Syndrome, cobinamide dramatically reduced elastin breaks, prevented excess collagen deposition and smooth muscle cell apoptosis, and blocked DNA, lipid, and protein oxidation and excess nitric oxide/protein kinase G signaling in the ascending aorta. Consistent with preventing pathologic changes, cobinamide diminished aortic root dilation without affecting blood pressure. Cobinamide exhibited excellent safety and pharmacokinetic profiles indicating it could be a practical treatment. We conclude that cobinamide deserves further study as a disease-modifying treatment of Marfan Syndrome.

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© 2024 The Authors.

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The work was supported by National Institutes of Health grants U01 NS058030, U01 NS087964 to Dr Boss, and R01 HL132141 to Dr Pilz. Drs Kalyanaraman, Casteel, Boss, and Pilz are coinventors on a patent application entitled “New Treatment for Aortic Aneurysm.” Dr Dretchen is the Chief Scientific Officer of Mesa Science Associates, a company that has interest in licensing cobinamide. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.