NLRP3 (Nucleotide Oligomerization Domain–Like Receptor Family, Pyrin Domain Containing 3)–Caspase-1 Inflammasome Degrades Contractile Proteins

Abstract

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–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. Additionally, glyburide may have protective effects against AAD development.

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…Caspase-1 is responsible for the protein degradation. Thus AAA, TAA, and AD are attenuated in NLRP3Ϫ/Ϫ or caspase-1Ϫ/Ϫ mice treated with ANG II plus high-fat diet (1158). In addition, in a novel model of TAD induced by ANG II infusion with BAPN pretreatment, neutrophil-derived MMP9 is proposed to contribute to TAD (525).…”

Aortic Aneurysms

“…In addition to inflammatory cell accumulation, markers of inflammasomes are present in plasma and AAA. 38–40 Two research groups found that inflammasome activation contributed to AAA in AngII-infused mice. 40,41 …”

“…40,122–124 In contrast to AngII-induced AAA, TAA induced by AngII is independent of hypercholesterolemia. 125 In addition to AngII-induced TAA, co-infusion of AngII and β-aminopropionitrile also induces TAA in mice.…”

“…34,126 Ikonomidis and colleagues developed a mouse model of TAA by applying calcium chloride onto the descending thoracic aortic region. 127 Using these mouse models, recent studies discovered that genetic depletion of AT1 receptor reduced AngII-induced TAA; 128,129 nucleotide oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) caspase-1 inflammasome contributed to AngII-induced TAA; 40 smooth muscle cell-specific deficiency of low-density lipoprotein receptor-related protein 1 augmented AngII-induced TAA; 130 genetic MMP-2 deficiency accelerated AngII-induced TAA, but attenuated calcium chloride-induced TAA; 123 and smooth muscle cell-specific deficiency of hypoxia-inducible factor-1α increased TAA in mice co-infused with AngII and β-aminopropionitrile. 53 …”

Reduced endothelial thioredoxin‐interacting protein protects arteries from damage induced by metabolic stressin vivo

“…In humans, NLRP3 is overexpressed in the aorta of patients with coronary atherosclerosis, and aortic NLRP3 expression is correlated with the severity of coronary artery disease and the atherosclerotic risk factors (32). Recently, the NLRP3‐caspase‐1 inflammasome cascade has been described as promoting the degradation of contractile proteins in smooth muscle cells, which causes aortic contractile dysfunction in a model of aortic aneurysm and dissection (33).…”