Background Aberrant activation of the NLRP 3 (nucleotide‐binding oligomerization domain, leucine‐rich repeat–containing receptor family pyrin domain‐containing 3) inflammasome is thought to play a causative role in atherosclerosis. NLRP 3 is kept in an inactive ubiquitinated state to avoid unwanted NLRP 3 inflammasome activation. This study aimed to test the hypothesis that pharmacologic manipulating of NLRP 3 ubiquitination blunts the assembly and activation of the NLRP 3 inflammasome and protects against vascular inflammation and atherosclerosis. Since genetic studies yielded mixed results about the role for this inflammasome in atherosclerosis in low‐density lipoprotein receptor– or apolipoprotein E–deficient mice, this study attempted to clarify the discrepancy with the pharmacologic approach using both models. Methods and Results We provided the first evidence demonstrating that tranilast facilitates NLRP 3 ubiquitination. We showed that tranilast restricted NLRP 3 oligomerization and inhibited NLRP 3 inflammasome assembly. Tranilast markedly suppressed NLRP 3 inflammasome activation in low‐density lipoprotein receptor– and apolipoprotein E–deficient macrophages. Through reconstitution of the NLRP 3 inflammasome in human embryonic kidney 293T cells, we found that tranilast directly limited NLRP 3 inflammasome activation. By adopting different regimens for tranilast treatment of low‐density lipoprotein receptor– and apolipoprotein E–deficient mice, we demonstrated that tranilast blunted the initiation and progression of atherosclerosis. Mice receiving tranilast displayed a significant reduction in atherosclerotic lesion size, concomitant with a pronounced decline in macrophage content and expression of inflammatory molecules in the plaques compared with the control group. Moreover, tranilast treatment of mice substantially hindered the expression and activation of the NLRP 3 inflammasome in the atherosclerotic lesions. Conclusions Tranilast potently enhances NLRP 3 ubiquitination, blunts the assembly and activation of the NLRP 3 inflammasome, and ameliorates vascular inflammation and atherosclerosis in both low‐density lipoprotein receptor– and apolipoprotein E–deficient mice.
Vagus nerve stimulation (VNS) restores autonomic balance, suppresses inflammation action and minimizes cardiomyocyte injury. However, little knowledge is known about the VNS’ role in cardiomyocyte phenotype, sarcomere organization, and energy metabolism of infarcted hearts. VNS in vivo and acetylcholine (ACh) in vitro optimized the levels of α/β-MHC and α-Actinin positive sarcomere organization in cardiomyocytes while reducing F-actin assembly of cardiomyocytes. Consistently, ACh improved glucose uptake while decreasing lipid deposition in myocytes, correlating both with the increase of Glut4 and CPT1α and the decrease of PDK4 in infarcted hearts in vivo and myocytes in vitro, attributing to improvement in both glycolysis by VEGF-A and lipid uptake by VEGF-B in response to Ach. This led to increased ATP levels accompanied by the repaired mitochondrial function and the decreased oxygen consumption. Functionally, VNS improved the left ventricular performance. In contrast, ACh-m/nAChR inhibitor or knockdown of VEGF-A/B by shRNA powerfully abrogated these effects mediated by VNS. On mechanism, ACh decreased the levels of nuclear translocation of FoxO3A in myocytes due to phosphorylation of FoxO3A by activating AKT. FoxO3A overexpression or knockdown could reverse the specific effects of ACh on the expression of VEGF-A/B, α/β-MHC, Glut4, and CPT1α, sarcomere organization, glucose uptake and ATP production. Taken together, VNS optimized cardiomyocytes sarcomere organization and energy metabolism to improve heart function of the infarcted heart during the process of delaying and/or blocking the switch from compensated hypertrophy to decompensated heart failure, which were associated with activation of both P13K/AKT-FoxO3A-VEGF-A/B signaling cascade.
In Taiwan, chronic kidney disease (CKD) is highly prevalent and traditional Chinese medicine (TCM) is one of the most commonly used complementary medicines. To date, little information is available on the utilization patterns for TCM among CKD patients, particularly those with late stage CKD. We conducted a cross-sectional hospital-based study to investigate this issue. In this study, late stage CKD patients were identified by ICD-9-CM codes: 585 and 586, and only CKD stage 3b, 4 and 5 patients were included in the analysis. Clinical information was retrieved from the electronic medical records database from January, 1, 2006 to December, 31, 2011. Among a total of 8,459 patients, 408 TCM users and 8,051 non-TCM users were identified and their data were analyzed. We found that TCM users were almost four times more likely to be older than 55 years than non-TCM users, after controlling for the other covariates (adjusted odds ratio [aOR]: 3.98, 95% confidence interval [CI]:[2.33, 6.81]). They were also less likely to have diabetes (aOR: 0.48), hypertension (aOR: 0.62) or gout (aOR: 0.62). Among all disease conditions, late stage CKD patients with neoplasms had the highest tendency to seek TCM treatment compared to non-neoplasm CKD patients (aOR: 5.39, 95% CI: [4.64, 6.26]). Among all TCM users, internal medicine outpatient services (providing CHMs only) is more frequently used than acupuncture/massage outpatient services (3,476 vs. 320 visits). Jia-Wei-Xiao-Yao-San (JWXYS) was the most commonly prescribed Chinese herbal medicine (CHM) for late CKD patients (36.2% of 4,494 prescriptions), followed by Bu-Yang-Huan-Wu-Tang (BYHWT)
Atherosclerosis is a maladaptive chronic inflammatory disease, which remains the leading cause of death worldwide. The NLRP3 inflammasome constitutes a major driver of atherosclerosis, yet the mechanism of action is poorly understood. Mitochondrial dysfunction is essential for NLRP3 inflammasome activation. However, whether activated NLRP3 inflammasome exacerbates mitochondrial dysfunction remains to be further elucidated. Herein, we sought to address these issues applying VX765, a well-established inhibitor of caspase 1. VX765 robustly restrains caspase 1-mediated interleukin-1β production and gasdermin D processing. Our study assigned VX765 a novel role in antagonizing NLRP3 inflammasome assembly and activation. VX765 mitigates mitochondrial damage induced by activated NLRP3 inflammasome, as evidenced by decreased mitochondrial ROS production and cytosolic release of mitochondrial DNA. VX765 blunts caspase 1-dependent cleavage and promotes mitochondrial recruitment and phosphorylation of Parkin, a key mitophagy regulator. Functionally, VX765 facilitates mitophagy, efferocytosis and M2 polarization of macrophages. It also impedes foam cell formation, migration and pyroptosis of macrophages. VX765 boosts autophagy, promotes efferocytosis, and alleviates vascular inflammation and atherosclerosis in both ApoE−/− and Ldlr−/− mice. However, these effects of VX765 were abrogated upon ablation of Nlrp3 in ApoE−/− mice. This work provides mechanistic insights into NLRP3 inflammasome assembly and this inflammasome in dictating atherosclerosis. This study highlights that manipulation of caspase 1 paves a new avenue to treatment of atherosclerotic cardiovascular disease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.