NLRP3 (Nucleotide Oligomerization Domain-Like Receptor Family, Pyrin Domain Containing 3)-Caspase-1 Inflammasome Degrades Contractile Proteins: Implications for Aortic Biomechanical Dysfunction and Aneurysm and Dissection Formation.

OBJECTIVE: Increasing evidence suggests that contractile dysfunction in smooth muscle cells (SMCs) plays a critical role in aortic biomechanical dysfunction and aortic aneurysm and dissection (AAD) development. However, the mechanisms underlying SMC contractile dysfunction in sporadic AAD are poorly understood. In this study, we examined the role of the NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3)-caspase-1 inflammasome, a key inflammatory cascade, in SMC contractile dysfunction in AAD. APPROACH AND RESULTS: We observed significant SMC contractile protein degradation in aortas from patients with sporadic thoracic AAD. The contractile protein degradation was associated with activation of the NLRP3-caspase-1 inflammasome cascade. In SMCs, caspase-1 bound and directly cleaved and degraded contractile proteins, leading to contractile dysfunction. Furthermore, Nlrp3 or caspase-1 deficiency in mice significantly reduced angiotensin II-induced contractile protein degradation, biomechanical dysfunction, and AAD formation in both thoracic and abdominal aortas. Finally, blocking this cascade with the inflammasome inhibitor, glyburide (an antidiabetic medication), reduced angiotensin II-induced AAD formation. CONCLUSIONS: Inflammasome-caspase-1-mediated degradation of SMC contractile proteins may contribute to aortic biomechanical dysfunction and AAD development. This cascade may be a therapeutic target in AAD formation. In addition, glyburide may have protective effects against AAD development.

ADAMTS-1 and ADAMTS-4 levels are elevated in thoracic aortic aneurysms and dissections.

BACKGROUND: ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) is a recently identified family of extracellular metalloproteinases that has been shown to participate in tissue destruction. We hypothesized that ADAMTS-1 and ADAMTS-4 expression is increased in aortic tissues from patients with thoracic aortic aneurysms and dissections. METHODS: We examined ADAMTS-1 and ADAMTS-4 expression in human descending thoracic aortic aneurysms (n = 14), chronic descending thoracic aortic dissections (n = 16), and descending thoracic aortas from age-matched control organ donors (n = 12). In these tissues, we also evaluated the degradation of versican, a proteoglycan substrate of ADAMTS-1 and ADAMTS-4. In cultured macrophages, we examined whether ADAMTS-4 functions in macrophage infiltration by using a transwell assay. RESULTS: ADAMTS-1 and ADAMTS-4 protein and mRNA expression was significantly higher in thoracic aortic aneurysm and dissection tissues than in control aortic tissues. Double immunofluorescence staining showed the expression of ADAMTS-1 and ADAMTS-4 in smooth muscle cells and macrophages. Consistent with the upregulation of ADAMTS-1 and ADAMTS-4 in thoracic aortic aneurysm and dissection tissues, versican was degraded significantly more in these tissues than in control aortic tissues. In cultured macrophages, transforming growth factor-ß increased ADAMTS-4 protein levels and induced macrophage invasion, and the knockdown of ADAMTS-4 reduced cell invasion. CONCLUSIONS: Increased expression of ADAMTS proteins may promote thoracic aortic aneurysm progression by degrading versican and facilitating macrophage invasion.