title: Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models.
abstract: Thoracic aortic diseases, including aneurysms and dissections of the thoracic aorta, are a major cause of morbidity and mortality. Risk factors for thoracic aortic disease include increased hemodynamic forces on the ascending aorta, typically due to poorly controlled hypertension, and heritable genetic variants. The altered genes predisposing to thoracic aortic disease either disrupt smooth muscle cell (SMC) contraction or adherence to an impaired extracellular matrix, or decrease canonical transforming growth factor beta (TGF-β) signaling. Paradoxically, TGF-β hyperactivity has been postulated to be the primary driver for the disease. More recently, it has been proposed that the response of aortic SMCs to the hemodynamic load on a structurally defective aorta is the primary driver of thoracic aortic disease, and that TGF-β overactivity in diseased aortas is a secondary, unproductive response to restore tissue function. The engineering of mouse models of inherited aortopathies has identified potential therapeutic agents to prevent thoracic aortic disease.
authors.affiliation: Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030; email: Dianna.M.Milewicz@uth.tmc.edu.
authors.forename: Dianna M
authors.initials: DM
authors.lastname: Milewicz
authors.affiliation: Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030; email: Dianna.M.Milewicz@uth.tmc.edu.
authors.forename: Siddharth K
authors.initials: SK
authors.lastname: Prakash
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ramirez
mesh_terms: D000784:Aortic Dissection / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D019808:Losartan / Q000627:therapeutic use; D008382:Marfan Syndrome / Q000235:genetics / Q000628:therapy*; D008465:Mechanoreceptors; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000959:Antihypertensive Agents; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D019808:Losartan
keywords: ACTA2; Marfan syndrome; TGF-β; angiotensin receptor; aortopathy; losartan; mutation; phenotype; thoracic aortic disease