PPARα Agonist Stimulated Angiogenesis by Improving Endothelial Precursor Cell Function Via a NLRP3 Inflammasome Pathway

Deng, Yaxiong; Han, Xue; Zheng, Yao; Sun, Ying; Yu, Jiawen; Cai, Jianming; Ren, Guo-Fei; Jiang, Guojun; Han, Feng; Hospital, Zhejiang Xiaoshan

doi:10.1159/000479999

Cited by 53 publications

(36 citation statements)

References 44 publications

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“…In endothelial cells, the NLRP3 inflammasome exhibits a significant initiating mechanism, and its activation may accelerate the development of endothelial dysfunction or atherogenic pathology by inducing plasma trimethylamine-Noxide (TMAO) [38]. The repression of the NLRP3 inflammasome is a critical factor in I/R or inflammation by correlation with SIRT1, which was proved to be involved in both preventing cells from injury induced by various stress and improving endothelial precursor cell function [39,40]. Activating the NLRP3 inflammasome signaling can promote atherosclerosis pathogenesis via the overexpression of inducible endothelial-specific GPR124 [41].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-495 Ameliorates Cardiac Microvascular Endothelial Cell Injury and Inflammatory Reaction by Suppressing the NLRP3 Inflammasome Signaling Pathway

Zhou¹,

Xiang²,

Li³

et al. 2018

Cell Physiol Biochem

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Background/Aims: In recent years, microRNA-495 (miR-495) has been reported to be a tumor-suppressor miR that is down-modulated in cancers. However, its potential mechanism remains unknown. Therefore, this study aimed to demonstrate the role of miR-495 in cardiac microvascular endothelial cell (CMEC) injury and inflammatory reaction by mediating the pyrin domain-containing 3 (NLRP3) inflammasome signaling pathway. Methods: Overall, 40 mice were assigned into myocardial ischemia/reperfusion injury (MIR) and sham groups. After model establishment, the levels of troponin T (TnT), troponin I (TnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP), creatine kinase isoenzyme MB (CK-MB), myoglobin (MYO), tumor necrosis factor-alpha (TNF-α), and interleukin 1beta (IL-1β) were detected by Enzyme-Linked Immunosorbent Assay (ELISA). Apoptosis was evaluated using Terminal deoxy (d)-UTP nick end labeling (TUNEL) staining, the level of NLRP3 protein was determined by immunohistochemical assay, and miR-495 was detected by in situ hybridization (ISH). The infarct size was determined using 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. The expression of miR-495 and the mRNA and protein levels of NLRP3, TNF-α, IL-1β, IL-18 and caspase-1 were evaluated by RT-qPCR and western blot analysis. After transfection, the cells were treated with a miR-495 mimic, a miR-495 inhibitor, or siNLRP3. Cell proliferation was measured by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and cell cycle and apoptosis by flow cytometry. Results: Mice with myocardial I/R injury had elevated levels of TnT, TnI, NT-proBNP, CK-MB, MYO, TNF-α and IL-1β; enhanced cell apoptosis; increased expression of NLRP3, TNF-α, IL-1β, IL-18 and caspase-1; and decreased miR-495 expression. MiR-495 was confirmed to target NLRP3. Moreover, miR-495 reduced the mRNA and protein levels of NLRP3, TNF-α, IL-1β, IL-18 and caspase-1, inhibited cell apoptosis and decreased cells at the G₀/G₁ phase while improving cell proliferation and increasing cells at the S phase. However, the effects of NLRP4 were proved to be reciprocal. Conclusion: In conclusion, the current study indicated that miR-495 improved CMEC injury and inflammation by suppressing the NLRP3 inflammasome signaling pathway.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-495 Ameliorates Cardiac Microvascular Endothelial Cell Injury and Inflammatory Reaction by Suppressing the NLRP3 Inflammasome Signaling Pathway

Zhou¹,

Xiang²,

Li³

et al. 2018

Cell Physiol Biochem

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“…Fenofibrate is a selective agonist of peroxisome proliferator-activated receptor α (PPARα) that prevents the progression of microvascular complications in T2DM. Deng et al found that fenofibrate promotes wound healing via alleviating EPC dysfunction and stimulating angiogenesis in diabetic mice induced by streptozotocin (STZ), the effects of which are attributed to the inhibition of NLRP3 inflammasome pathway 101 .…”

Section: Hypoglycemic Agentsmentioning

confidence: 99%

NLRP3 inflammasome in endothelial dysfunction

et al. 2020

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Inflammasomes are a class of cytosolic protein complexes. They act as cytosolic innate immune signal receptors to sense pathogens and initiate inflammatory responses under physiological and pathological conditions. The NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome is the most characteristic multimeric protein complex. Its activation triggers the cleavage of pro-interleukin (IL)-1β and pro-IL-18, which are mediated by caspase-1, and secretes mature forms of these mediators from cells to promote the further inflammatory process and oxidative stress. Simultaneously, cells undergo pro-inflammatory programmed cell death, termed pyroptosis. The danger signals for activating NLRP3 inflammasome are very extensive, especially reactive oxygen species (ROS), which act as an intermediate trigger to activate NLRP3 inflammasome, exacerbating subsequent inflammatory cascades and cell damage. Vascular endothelium at the site of inflammation is actively involved in the regulation of inflammation progression with important implications for cardiovascular homeostasis as a dynamically adaptable interface. Endothelial dysfunction is a hallmark and predictor for cardiovascular ailments or adverse cardiovascular events, such as coronary artery disease, diabetes mellitus, hypertension, and hypercholesterolemia. The loss of proper endothelial function may lead to tissue swelling, chronic inflammation, and the formation of thrombi. As such, elimination of endothelial cell inflammation or activation is of clinical relevance. In this review, we provided a comprehensive perspective on the pivotal role of NLRP3 inflammasome activation in aggravating oxidative stress and endothelial dysfunction and the possible underlying mechanisms. Furthermore, we highlighted the contribution of noncoding RNAs to NLRP3 inflammasome activation-associated endothelial dysfunction, and outlined potential clinical drugs targeting NLRP3 inflammasome involved in endothelial dysfunction. Collectively, this summary provides recent developments and perspectives on how NLRP3 inflammasome interferes with endothelial dysfunction and the potential research value of NLRP3 inflammasome as a potential mediator of endothelial dysfunction.

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“…For example, fibrates, which are PPARα ligands, are used widely to ameliorate the microvascular risks associated with metabolic syndrome [26]. This class of exogenous PPARα ligands includes clofibrate, gemfibrozil, fenofibrate, bezafibrate, and ciprofibrate [27][28][29][30][31][32]. Furthermore, the synthetic compounds GW501516, GW0742, L-165041, and GW2433 have been defined as selective PPARβ/δ ligands [33,34].…”

Section: General Characteristics and Roles Of Pparα Pparγ And Pparβ/δmentioning

confidence: 99%

Targeting PPARα for the Treatment and Understanding of Cardiovascular Diseases

Yang

et al. 2018

Cell Physiol Biochem

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Three members of the peroxisome proliferator-activated receptor (PPAR) family, PPARα, PPARγ, and PPARβ/δ, have been investigated widely over the past few decades. Although the roles of these PPARs and their agonists/antagonists were defined in clinical and basic studies, the conflicting results from these studies indicate that more analysis is needed to understand the roles of PPARs. PPARα is a ligand-activated transcription factor that contributes to the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. In this review, we focus on the function and mechanisms of PPARα in the cardiovascular system under various pathological conditions, including vascular and heart injury, blood pressure regulation, and lipid disorder-related cardiovascular injury, as well as its polymorphisms and pharmacogenetic associations with cardiovascular diseases. The anti-inflammatory effect of PPARα in cardiovascular injury is mainly through inhibition of pro-inflammatory signaling pathways and improvement of the lipid profile. Moreover, PPARα also modulates the activity of endothelial nitric oxide synthase and resets the renin-angiotensin system to regulate vascular tone. PPARα gene variants appear to be associated with some cardiovascular risk factors, such as higher plasma lipid levels, cardiac growth, and increased risk of coronary artery disease. Nowadays, novel PPARα drugs with broad safety margins and therapeutic potential for metabolic syndrome and cardiovascular diseases are being developed and applied in the clinical setting. The insights from the current review shed new light on areas of further study and provide a better understanding of the role of PPARα in cardiovascular diseases.

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PPARα Agonist Stimulated Angiogenesis by Improving Endothelial Precursor Cell Function Via a NLRP3 Inflammasome Pathway

Cited by 53 publications

References 44 publications

MicroRNA-495 Ameliorates Cardiac Microvascular Endothelial Cell Injury and Inflammatory Reaction by Suppressing the NLRP3 Inflammasome Signaling Pathway

MicroRNA-495 Ameliorates Cardiac Microvascular Endothelial Cell Injury and Inflammatory Reaction by Suppressing the NLRP3 Inflammasome Signaling Pathway

NLRP3 inflammasome in endothelial dysfunction

Targeting PPARα for the Treatment and Understanding of Cardiovascular Diseases

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