Importin-8 and lysyl oxidase : human and murine insights into the pathogenesis of thoracic aortic aneurysm
Thoracic aortic aneurysm (TAA) is caused by a pathological dilatation of the aorta due to vessel wall weakness. TAA is associated with a high mortality rate as the aneurysm can lead to sudden dissection or rupture (TAAD). Until now, more than 40 genes have been discovered that are associated with TAAD development. Still, most TAAD patients, about 70%, is missing a genetic diagnosis. The discovered genes are involved in extracellular matrix remodeling, vascular smooth muscle cell contraction and TGF- signaling pathway. TAAD is a key characteristic of several genetic syndromes of which the most common disorders are Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). Bi-allelic loss-of-function variants in IPO8 were identified in patients phenotypically characterized by severe early-onset TAAD development, resembling the Loeys-Dietz syndrome phenotype. IPO8 encodes for the ubiquitously expressed transport-receptor Importin-8 which is a member of the importin- family and is involved in the translocation of cargoes such as proteins, RNAs and ribonucleoprotein complexes from the cytosol into the nucleus in a RanGTP-dependent manner. To study the pathogenesis in depth, a C57BL/6N Ipo8 knock-out (Ipo8-/-) mouse model was generated, and the cardiovascular phenotype was investigated. The Ipo8-/- mouse model recapitulates severe early-onset TAA and aortic dissection. Ipo8-/- aortic tissue studies revealed elastic fiber fragmentation, an increase in nuclear pSmad2 levels, increase in downstream transcriptional targets of the TGF- signaling pathway, Ccn2 and Mmp2 and downregulation of Smad6 and Smad7, suggesting a role for TGF- dysregulation in IPO8 deficiency. On the contrary, the Sv129 Ipo8-/- mouse model, mice generated on a different genetic background, did not show aortic aneurysms or dissection/ruptures, indicating the importance of the genetic background of mouse models. Additionally, an embryonic lethality of 50% was observed in C57BL/6N Ipo8-/- mice, whereas no embryonic lethality was observed in Sv129 Ipo8-/- mice. Another gene contributing to the genetic landscape of TAAD is lysyl oxidase, an extracellular matrix crosslinking enzyme, encoded by LOX. Patients carrying LOX LOF variants have heterogeneous phenotype and show a spectrum of connective tissue manifestations, aortic and arterial aneurysmal disease.
Antwerp : University of Antwerp, Faculty of Medicine and Health Sciences , 2023
230 p.
Supervisor: Loeys, Bart [Supervisor]
Supervisor: Verstraeten, Aline [Supervisor]
Supervisor: Van Laer, Lut [Supervisor]
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Creation 06.12.2023
Last edited 20.12.2023
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