Publication: Nitric oxide mediates aortic disease in mice deficient in the metalloprotease Adamts1 and in a mouse model of Marfan syndrome
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2017-02
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Nature Publishing Group
Abstract
Heritable thoracic aortic aneurysms and dissections (TAAD), including Marfan syndrome (MFS), currently lack a cure, and causative mutations have been identified for only a fraction of affected families. Here we identify the metalloproteinase ADAMTS1 and inducible nitric oxide synthase (NOS2) as therapeutic targets in individuals with TAAD. We show that Adamts1 is a major mediator of vascular homeostasis, given that genetic haploinsufficiency of Adamts1 in mice causes TAAD similar to MFS. Aortic nitric oxide and Nos2 levels were higher in Adamts1-deficient mice and in a mouse model of MFS (hereafter referred to as MFS mice), and Nos2 inactivation protected both types of mice from aortic pathology. Pharmacological inhibition of Nos2 rapidly reversed aortic dilation and medial degeneration in young Adamts1-deficient mice and in young or old MFS mice. Patients with MFS showed elevated NOS2 and decreased ADAMTS1 protein levels in the aorta. These findings uncover a possible causative role for the ADAMTS1-NOS2 axis in human TAAD and warrant evaluation of NOS2 inhibitors for therapy.
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ADAMTS1 Protein Adult Aged Aneurysm, Dissecting Animals Aorta Aortic Aneurysm Aortic Aneurysm, Thoracic Disease Models, Animal Enzyme Inhibitors Female Fibrillin-1 Gene Knockdown Techniques Haploinsufficiency Humans Immunoblotting Male Marfan Syndrome Mice Middle Aged NG-Nitroarginine Methyl Ester Nitric Oxide Nitric Oxide Synthase Type II Real-Time Polymerase Chain Reaction
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Bibliographic citation
Nat Med. 2017; 23(2):200-212