In search of a new therapeutic target for the treatment of genetically triggered thoracic aortic aneurysms and cardiovascular conditions: insights from human and animal lathyrism.
Lathyrism, or the effect of certain plants on connective tissue disruption, particularly involving the vascular and skeletal systems, especially aortic dissection/rupture, has been well documented in animals. Its impact on the pathogenesis of connective tissue diseases in humans is still unclear. An extensive review of the scientific literature from the 1800s until the present time was performed to examine the common pathways between animal and human lathyrism and genetically triggered thoracic aortic aneurysms and cardiovascular conditions in humans, with special focus on the identification of potential therapeutic targets. Search areas covered the following subjects: lathyrism/spontaneous aortic dissection/rupture in animals; beta-aminopropionitrile, semicarbazide and their effects; collagen and elastin synthesis and cross-linking; genetic and molecular biology characteristics of the genetically triggered thoracic aortic conditions. Search results demonstrate Marfan syndrome as a model for the genetically triggered thoracic aortic aneurysms, has been linked to mutations of the fibrillin-1 gene, via transforming growth factor beta-1. Several other conditions do not share this mutation. Inhibition of semicarbazide-sensitive amine oxidase [vascular adhesion protein-1 (VAP-1)] in animals has been shown to result in aortic dilatation due to disruption of elastin cross-linking. Significantly low activity of this enzyme was identified in annulo-aortic ectasia; a condition similar to Marfan syndrome. In conclusion, the precise molecular and genetic pathways responsible for the clinical findings in Marfan syndrome and related conditions remain unclear. Observational and experimental findings relating to the vascular and systemic effects of molecular pathways implicated in the phenomenon of animal and human lathyrism suggest that VAP-1 seems to be involved in the molecular and developmental pathways of the genetically triggered thoracic aortic diseases and thus could be a potential therapeutic target for these conditions.
Sherif
Hisham M F
HM
Department of Cardiac Surgery, Christiana Hospital, Christiana Care Health System, 4755 Ogletown-Stanton Road, Suite 1E50, Newark, DE 19718, USA. hsherif@christianacare.org
D006631:Amine Oxidase (Copper-Containing) / Q000378:metabolism; D000818:Animals; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D007842:Lathyrism / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008382:Marfan Syndrome / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D009154:Mutation; D015398:Signal Transduction; D016896:Treatment Outcome
D016326:Extracellular Matrix Proteins; D006631:Amine Oxidase (Copper-Containing)