Macrophage inflammasome mediates hyperhomocysteinemia-aggravated abdominal aortic aneurysm

Sun, Weiliang; Pang, Yanli; Liu, Ziyi; Sun, Lulu; Liu, Bo; Xu, Mingjiang; Dong, Yongqiang; Feng, Juan; Jiang, Changtao; Kong, Wei; Wang, Xian

doi:10.1016/j.yjmcc.2015.02.005

Cited by 63 publications

(51 citation statements)

References 44 publications

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“…These studies examined the role of the inflammasome in macrophage activation and aortic inflammation in AAA development. 26,27 Here, we proposed a novel role of the inflammasome in SMC contractile protein degradation, aortic contractile dysfunction, and biomechanical failure. We also showed that NLRP3 and caspase-1 deficiency reduced aortic enlargement and AAD development in both the abdominal and thoracic aortic regions and also explored the mechanism of this protection.…”

Section: Discussionmentioning

confidence: 96%

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

Ren

Zheng

et al. 2017

ATVB

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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.

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Section: Discussionmentioning

confidence: 96%

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

Ren

Zheng

et al. 2017

ATVB

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“… 20 Wang et al recently demonstrated that HHcy activated NLRP3 inflammasomes in an abdominal aortic aneurysm mouse model on top of regular diet, which indicates that Hcy alone induced activation of the NLRP3 inflammasome in vivo . 28 As it is hard to induce prominent spontaneous atherosclerosis in mice even with apoE gene deficiency, we therefore set up an HHcy mice model with HF+HM diet to examine whether HHcy can activate NLRP3 inflammasome and promote atherogenesis. It was widely accepted to investigate HHcy-related atherogenesis and mechanisms on top of HF diet.…”

Section: Discussionmentioning

confidence: 99%

Activation of NLRP3 inflammasomes contributes to hyperhomocysteinemia-aggravated inflammation and atherosclerosis in apoE-deficient mice

Wang

et al. 2017

Laboratory Investigation

113

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Hyperhomocysteinemia (HHcy) has been shown to promote vascular inflammation and atherosclerosis, but the underlying mechanisms remain largely unknown. The NLRP3 inflammasome has been identified as the cellular machinery responsible for activation of inflammatory processes. In this study, we hypothesized that the activation of NLRP3 inflammasomes contributes to HHcy-induced inflammation and atherosclerosis. ApoE−/− mice were fed regular chow, high-fat (HF) diet, or HF plus high methionine diet to induce HHcy. To assess the role of NLRP3 inflammasomes in HHcy-aggravated atherosclerosis, NLRP3 shRNA viral suspension was injected via tail vein to knock down the NLRP3 gene. Increased plasma levels of IL-1β and IL-18, aggravated macrophage infiltration into atherosclerotic lesions, and accelerated development of atherosclerosis were detected in HHcy mice as compared with control mice, and were associated with the activation of NLRP3 inflammasomes. Silencing the NLRP3 gene significantly suppressed NLRP3 inflammasome activation, reduced plasma levels of proinflammatory cytokines, attenuated macrophage infiltration and improved HHcy-induced atherosclerosis. We also examined the effect of homocysteine (Hcy) on NLRP3 inflammasome activation in THP-1-differentiated macrophages in the presence or absence of NLRP3 siRNA or the caspase-1 inhibitor Z-WEHD-FMK. We found that Hcy activated NLRP3 inflammasomes and promoted subsequent production of IL-1β and IL-18 in macrophages, which were blocked by NLRP3 gene silencing or Z-WEHD-FMK. As reactive oxygen species (ROS) may have a central role in NLRP3 inflammasome activation, we next investigated whether antioxidant N-acetyl-l-cysteine (NAC) prevented Hcy-induced NLRP3 inflammasome activation in macrophages. We found Hcy-induced NLRP3 inflammasome activation was abolished by NAC. Treatment with NAC in HHcy mice also suppressed NLRP3 inflammasome activation and improved HHcy-induced atherosclerosis. These data suggest that the activation of NLRP3 inflammasomes contributes to HHcy-aggravated inflammation and atherosclerosis in apoE−/− mice. Hcy activates NLRP3 inflammasomes in ROS-dependent pathway in macrophages. These results may have implication for the treatment of HHcy-associated cardiovascular diseases.

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“…Specifically, increased glycolytic metabolism is a prerequisite for robust osteoblast differentiation and mineralized matrix formation. Recently, ApoE has been reported to alter cellular metabolism in hematopoietic cells (30,31). Here, we characterized the metabolic impact of rApoE on differentiating osteoblasts incubated with and without rApoE.…”

Section: Loss Of Apoe Increases Bone Deposition In the Fracture Callusmentioning

confidence: 99%

Lowering circulating apolipoprotein E levels improves aged bone fracture healing

Ron¹,

Zong²,

Nadesan³

et al. 2019

JCI Insight

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Macrophage inflammasome mediates hyperhomocysteinemia-aggravated abdominal aortic aneurysm

Cited by 63 publications

References 44 publications

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

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

Activation of NLRP3 inflammasomes contributes to hyperhomocysteinemia-aggravated inflammation and atherosclerosis in apoE-deficient mice

Lowering circulating apolipoprotein E levels improves aged bone fracture healing

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