NLRP3 Inflammasome as a Molecular Marker in Diabetic Cardiomyopathy

Luo, Baoming; Huang, Feng; Li, Yanli; Liang, Youcai; Wei, Zhe; Ke, Honghong; Zeng, Zhiyu; Huang, Weiqiang; He, Yan

doi:10.3389/fphys.2017.00519

Cited by 161 publications

(129 citation statements)

References 73 publications

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“…High glucose-induced reactive oxygen species (ROS) can trigger the activation of the NLRP3 inflammasome and promote the production of cleaved caspase-1, thus accelerating the release of IL-1β and IL-18 [28]. This process can induce mitochondrial oxidative stress, promote apoptosis and influence the abnormal metabolism of glucose and adipose tissue [29].…”

Section: Discussionmentioning

confidence: 99%

LncRNA KCNQ1OT1 Mediates Pyroptosis in Diabetic Cardiomyopathy

Yang

Qin

Wang

et al. 2018

Cell Physiol Biochem

144

109

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Background/Aims: Diabetic cardiomyopathy (DCM) is a common complication of diabetes and can cause heart failure, arrhythmia and sudden death. The pathogenesis of DCM includes altered metabolism, mitochondrial dysfunction, oxidative stress, inflammation, cell death and extracellular matrix remodeling. Recently, pyroptosis, a type of programmed cell death related to inflammation, was proven to be activated in DCM. However, the molecular mechanisms underlying pyroptosis in DCM remain elusive. The long non-coding RNA (lncRNA) Kcnq1ot1 participates in many cardiovascular diseases. This study aims to clarify whether Kcnq1ot1 affects cardiac pyroptosis in DCM. Methods: AC16 cells and primary cardiomyocytes were incubated with 5.5 and 50 mmol/L glucose. Diabetic mice were induced with streptozotocin (STZ). Kcnq1ot1 was silenced both in vitro and in vivo. qRT-PCR was used to detect the expression level of Kcnq1ot1. Immunofluorescence, qRT-PCR and western blot analyses were used to detect the degree of pyroptosis. Echocardiography, hematoxylin and eosin staining, and Masson’s trichrome staining were used to detect the cardiac function and morphology in mice. Cell death and function were detected using TUNEL staining, immunofluorescence staining and Ca²⁺ measurements. Results: The expression of Kcnq1ot1 was increased in patients with diabetes, high glucose-induced cardiomyocytes and diabetic mouse cardiac tissue. Silencing Kcnq1ot1 alleviated pyroptosis by targeting miR-214-3p and caspase-1. Furthermore, silencing Kcnq1ot1 reduced cell death, cytoskeletal structure abnormalities and calcium overload in vitro and improved cardiac function and morphology in vivo. Conclusion: Kcnq1ot1 is overexpressed in DCM, and silencing Kcnq1ot1 inhibits pyroptosis by influencing miR-214-3p and caspase-1 expression. We clarified for the first time that Kcnq1ot1 could be a new therapeutic target for DCM.

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Section: Discussionmentioning

confidence: 99%

LncRNA KCNQ1OT1 Mediates Pyroptosis in Diabetic Cardiomyopathy

Yang

Qin

Wang

et al. 2018

Cell Physiol Biochem

144

109

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“…Both priming and activating signal are needed for NLRP3‐inflammasome activation . The priming signal, such as microbial ligands or endogenous molecules, activates NF‐κB signal pathway to induce expression of NLRP3 proteins . However, the increased protein amounts of NLRP3 are insufficient for NLRP3‐inflammasome activation.…”

Section: Discussionmentioning

confidence: 99%

“…41 The priming signal, such as microbial ligands or endogenous molecules, activates NF-κB signal pathway to induce expression of NLRP3 proteins. 42 However, the increased protein amounts of NLRP3 are insufficient for NLRP3-inflammasome activation. The activation signal, such as ATP, is needed to promote the assembly of inflammasomes.…”

Section: Discussionmentioning

confidence: 99%

The effect of NLRP inflammasome on the regulation of AGEs‐induced inflammatory response in human periodontal ligament cells

Zhang

et al. 2019

J of Periodontal Research

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Background and Objective Diabetes influences the frequency and development of periodontitis. Inflammation of human periodontal ligament cells (HPDLCs) participates in this pathologic process. Hence, this study aims to explore whether advanced glycation end products (AGEs), by‐products of diabetes, could exaggerate inflammation induced by muramyl dipeptide (MDP) in HPDLCs, and whether nucleotide‐binding oligomerization domain‐like receptors (NLRs) signaling pathway was involved. Material and Methods Human periodontal ligament cells were pre‐treated with 100 μg/mL AGEs for 24 hours and stimulated with 10 μg/mL MDP for 24 hours. IL‐6, IL‐1β, and RAGE were detected, and the activation of NF‐κB signaling pathway was observed. The expression of NLRs was evaluated with or without silencing RAGE or blocking NF‐κB pathway under AGEs stimulation. Statistical analyses were performed by using independent sample t test. Results Advanced glycation end products induced significant increase of inflammatory cytokines in HPDLCs (P < 0.05). Results of western blot (WB) showed that after 45 minutes stimulation of AGEs, p‐p65/p65 ratio peaked; AGEs promoted the expression of NLRP1, NLRP3, and apoptosis‐associated speck‐like protein containing a CARD (ASC). After silencing RAGE or blocking NF‐κB pathway, the up‐regulation of NLRs protein caused by AGEs was attenuated. Additionally, AGEs pre‐treatment could enhance the inflammatory response of MDP and the expression of NLRs, which were demonstrated by more expression of IL‐6, IL‐1β, NOD2, NLRP1, NLRP3, and ASC. Conclusion Advanced glycation end products induced inflammatory response in HPDLCs via NLRP1‐inflammasome and NLRP3‐inflammasome activation in which NF‐κB signal pathway was involved. Besides, AGEs promoted the inflammatory response of MDP via NOD2, NLRP1‐inflammasome, and NLRP3‐inflammasome.

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“…By a currently unknown cellular process, likely involving additional factors such as transforming growth factor beta‐1, the NLRP3 receptor binds to mitochondria, increasing ATP hydrolysis and ROS production . Meanwhile, mitochondria can also promote NLRP3 inflammasome activation through local ROS production, cytosolic mitophagy‐induced mtDNA accumulation and binding to cardiolipin . What the causes and consequences are of this mitochondrial binding is currently unknown.…”

Section: Pathophysiology Of Disturbances In Mitochondrial Metabolismmentioning

confidence: 99%

“…Together with long-chain saturated FAs (eg palmitate), ceramides, modified low-density lipoprotein and glycaemia (which are all elevated in T2DM), this can activate the cardiac NLRP3 inflammasome, 100 although it remains uncertain whether FAs alone can also promote activation of the NLRP3 inflammasome. 101 By a currently unknown cellular process, likely involving additional factors such as transforming growth factor beta-1, the NLRP3 receptor binds to mitochondria, increasing ATP hydrolysis and ROS production. 102 Meanwhile, mitochondria can also promote NLRP3 inflammasome activation through local ROS production, cytosolic mitophagy-induced mtDNA accumulation and binding to cardiolipin.…”

Section: Systemic Inflammation and Cardiac Mitochondrial Function Imentioning

confidence: 99%

Altered mitochondrial metabolism in the insulin‐resistant heart

et al. 2019

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Obesity‐induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA‐induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.

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NLRP3 Inflammasome as a Molecular Marker in Diabetic Cardiomyopathy

Cited by 161 publications

References 73 publications

LncRNA KCNQ1OT1 Mediates Pyroptosis in Diabetic Cardiomyopathy

LncRNA KCNQ1OT1 Mediates Pyroptosis in Diabetic Cardiomyopathy

The effect of NLRP inflammasome on the regulation of AGEs‐induced inflammatory response in human periodontal ligament cells

Altered mitochondrial metabolism in the insulin‐resistant heart

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