Abdominal aortic aneurysms: Signal transduction pathways involved in MT-1 MMP regulation and its role in MMP-2 activation.

摘要

Abdominal aortic aneurysms (AAA) are a leading cause of death and morbidity in the elderly. The vast majority of aneurysms occur in the distal infrarenal aorta, while the proximal thoracic aorta appears to be relatively refractory to this disease. AAA are characterized histologically by degradation of extracellular matrix and by the presence of an inflammatory infiltrate. Proteases, especially members of the matrix metalloproteinase (MMP) family, are thought to play a key role in AAA. The mechanisms of activation of MMPs and intracellular signal transduction mechanisms involved in their regulation are not clearly elucidated. This present study investigated three important aspects of AAA: (1) Regarding the propensity for aneurysms to occur in the distal aorta, mRNA expression between the proximal and distal normal aorta were compared; (2) Since MMP-2 appears to have a central role in AAA, the mechanism of its activation was investigated; (3) After identifying an important role for MT-1 MMP in MMP-2 activation, signal transduction pathways involved in its regulation were determined.; In comparing RNA isolated from proximal and distal human aortic tissue, marked differences in gene transcription were observed between the two aortic regions. One particular cDNA fragment, which was upregulated in the disease-prone distal aorta, contained sequence similarity to a novel membrane glycoprotein. Because of the differential expression of this cDNA and its interesting structural motifs, it may have important implications in aneurysmal disease.; MT-1 MMP protein and RNA were increased in AAA tissue compared with nonaneurysmal aorta with atherosclerotic disease, and normal aortic tissue. Histologically, this protein localized to both invading macrophages and mesenchymal cells in aneurysm tissue. Induction of MT-1 MMP expression correlated with MMP-2 activation. Furthermore, AAA tissue has a greater ability to activate exogenous MMP-2. Finally, both protein tyrosine kinase and protein kinase C signal pathways are involved in the upregulation of MT-1 MMP. These results suggest that MT-1 MMP has an important role in MMP-2 activation and AAA pathogenesis.