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FBN1 and TGFB1: Molecular mechanisms in the pathogenesis of thoracic aortic aneurysms and dissections.

Ramune Sepetiene and Sandrita Simonyte

Thoracic aortic aneurysms (TAAD) develop asymptomatically until occurs aortic rupture or dissection often cause of morbidity. A high mortality is determined by TAAD and complications developing. 15,000 people die every year due to the complications of TAAD in USA. It takes 14th place according to the reasons of mortality among 55 years people and older. The main risk factors for TAAD formation still remain under discussion. Hypertension, atherosclerosis, age, gender and eventually genetic predisposition are on the focus for the research. Only in certain cases it is caused by aortitis, atherosclerosis or inherited as a single gene mutation: in the fibrillin genes - Marfan syndrome, by inherited collagen mutations as in Ehler-Danlos syndrome, by mutations of the transforming growth factor-beta gene causing Loeys-Dietz syndrome or by actin gene mutations. Evidence has shown that FBN1 mutations may predispose TAA in the absence of phenotypic characteristics of Marfan syndrome. Recently published data from the genome-wide association study (GWAS) identified novel associations of FBN1 SNPs: namely, rs1036477, rs2118181, rs10519177, rs4774517, rs755251, with sporadic TAAD. These data extend knowledge on the molecular pathways leading to sporadic thoracic disease and connect it with a model of Marfan syndrome. There are anatomical, histological and molecular findings discussed within pathogenesis of TAA development. Fibrillin -1 (FBN1), transforming growth factor (TGF), matrix metalloproteases (MMP) are analyzed in the TAA molecular background and their importance for clinical determination and individualization are more often valuable. How FBN1 or TGFBR mutations lead to the disease are not well understood at a molecular level, the proposed mechanisms trigger the alterations in calcium binding EGF-like domains and increased bioavailability of transforming growth factor. The purpose of this review is to concentrate the available research information with focus on TAA common development trying to find a key for early diagnostic points.