Inhibition of Aortic Elastolysis by Adenoviral Gene Transfer of the Tissue-Inhibitor of Matrixmetalloproteinase-1 in Fibrillin-1 Deficient Gene Targeted Mice

• Applicant: Professor Dr. Matthias Karck
• Subject Area: Cardiac and Vascular Surgery
• Term: from 2006 to 2009
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 18857040

The vascular component of the Marfan syndrome is characterized by an abnormal increase in activity of matrix-metalloproteinases (MMPs) in smooth muscle cells of the aortic wall. This group of enzymes causes elastolysis in the aortic media resulting in a progressive destabilization of the vessel wall. Therefore, life-threatening aortic aneurysms and aortic dissections may develop early in life of patients with Marfan syndrome. The homozygote Fibrillin-1 deficient gene targeted mouse represents an accepted small animal model for the Marfan syndrome. Similar to patients with Marfan syndrome, this model expresses an increased MMP activity in smooth muscle cells of the aortic wall with an age dependent increase in fragmentation of elastic fibers. Using this model, aim of the project is the reduction of MMP activity in transplanted aortic grafts by in vitro gene transfer resulting in overexpression of the tissue inhibitor of matrix-metalloproteinase 1 (TIMP-1). Up to six weeks after infrarenal aortic transplantation of gene targeted donor animals into gene targeted recipient animals, the grafts will be evaluated by morphometrical, histological, and zymographical techniques, whether the elastolysis in the vessel¿s media can be attenuated. Proof of this concept may allow a causal treatment option of the vascular component of the Marfan syndrome for the first time.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Klaus Kallenbach