NLRP3 inflammasome expression in peripheral blood monocytes of coronary heart disease patients and its modulation by rosuvastatin

Jian Zhu, Shili Wu, Sigan Hu, Hui Li, Miaonan Li, Xu Geng, Hongju Wang, Jian Zhu, Shili Wu, Sigan Hu, Hui Li, Miaonan Li, Xu Geng, Hongju Wang

Abstract

Nucleotide‑binding oligomerization domain, leucine rich repeat, and pyrin domain‑containing protein 3 (NLRP3) inflammasome has been implicated in a series of physiological and pathological processes. However, its correlation in coronary heart disease (CHD) still remains to be elucidated. The present study aimed to determine the expression of NLRP3 inflammasome in peripheral blood monocytes (PBMCs) of stable angina pectoris (SAP) and acute myocardial infarction (AMI) patients. In addition, the effect of rosuvastatin on their activities was analyzed in vitro. A total of 60 participants with SAP (n=20), AMI (n=20) and non‑CHD controls (n=20) were enrolled. Fluorescence‑activated cell sorting, real‑time PCR, western blotting and enzyme‑linked immunosorbent assay were performed to reveal the role of NLRP3 inflammasome. NLRP3 inflammasome was expressed in the PBMCs, and revealed an increased expression along the downstream interleukin (IL)‑1β and IL‑18 in both SAP and AMI groups, compared to the control group. Moreover, there was a more marked increase in the expression of these indicators in AMI patients when compared to SAP patients. Interference with rosuvastatin in vitro revealed that the expression of NLRP3 inflammasome and its downstream cytokines were significantly downregulated in both SAP and AMI groups in a time‑dependent manner. The activation of NLRP3 inflammasome may be involved in the development of CHD, and rosuvastatin could attenuate the inflammatory process of atherosclerosis by downregulating NLRP3 expression and its downstream mediators. These findings indicated a potential role of NLRP3 in the pathogenesis and management of CHD, and also provided new insights into the mechanistic framework of rosuvastatin activity.

Figures

Figure 1.
Figure 1.
Upregulation of NLRP3 inflammasome mRNA levels in PBMCs in patients with SAP and AMI, compared with non-CHD controls. (A) PBMCs were isolated from peripheral blood and the positive rate of CD14 was calculated to be ≥95% of PBMCs by flow cytometry. RT-PCR assays were performed to quantify the mRNA levels of (B) NLRP3, (C) ASC and (D) caspase-1 in PBMCs of each group. *P

Figure 2.

Increase in protein expression levels…

Figure 2.

Increase in protein expression levels of NLRP3 inflammasome and secretion of its downstream…

Figure 2.
Increase in protein expression levels of NLRP3 inflammasome and secretion of its downstream interleukins in PBMCs of patients with SAP and AMI, compared with non-CHD controls. (A) Western blotting was used to detect the protein expression of NLRP3, ASC and caspase-1 in PBMCs of each group. (B) Quantitative results are illustrated for the three indicators using western blot analysis. (C) Plasma levels of IL-1β and IL-18 from each group were measured by ELISA. *P

Figure 3.

Effect of rosuvastatin on NLRP3…

Figure 3.

Effect of rosuvastatin on NLRP3 inflammasome mRNA levels in PBMCs in vitro .…

Figure 3.
Effect of rosuvastatin on NLRP3 inflammasome mRNA levels in PBMCs in vitro. PBMCs were isolated from the peripheral blood of patients with non-CHD, SAP and AMI, respectively, followed by proliferation and treatment with rosuvastatin at a concentration of 20 µM for the indicated time-points. RT-PCR assay was performed to investigate the influence of rosuvastatin on the mRNA levels of (A) NLRP3, (B) ASC and (C) caspase-1 in PBMCs of each group. *P<0.05; **P<0.01. NLRP3, nucleotide-binding oligomerization domain, leucine rich repeat, and pyrin domain-containing protein 3; PBMCs, peripheral blood monocytes; CHD, coronary heart disease; SAP, stable angina pectoris; AMI, acute myocardial infarction; ASC, apoptosis-associated speck-like protein containing a CARD; NS, not significant.

Figure 4.

Effect of rosuvastatin on protein…

Figure 4.

Effect of rosuvastatin on protein expression levels of NLRP3 inflammasome in PBMCs and…

Figure 4.
Effect of rosuvastatin on protein expression levels of NLRP3 inflammasome in PBMCs and secretion of its downstream cytokines in supernatants in vitro. PBMCs were isolated from the peripheral blood of patients with non-CHD, SAP and AMI, respectively, followed by proliferation and treatment with rosuvastatin at a concentration of 20 µM for the indicated time-points. (A) Western blotting was conducted to analyze the influence of rosuvastatin on the protein levels of NLRP3, ASC and caspase-1 in PBMCs of each group. (B) Quantitative results for modulating the protein expression of the aforementioned three indicators by rosuvastatin are illustrated. (C) Modulation of IL-1β and IL-18 secretion in the supernatants by rosuvastatin of each group was measured by ELISA. *P<0.05, **P<0.01 and #P<0.05 (compared to the 0-h group); ΔP<0.05 (compared to the 12-h group). NLRP3, nucleotide-binding oligomerization domain, leucine rich repeat, and pyrin domain-containing protein 3; PBMCs, peripheral blood monocytes; CHD, coronary heart disease; SAP, stable angina pectoris; AMI, acute myocardial infarction; ASC, apoptosis-associated speck-like protein containing a CARD; NS, not significant.

Figure 5.

Proposed model for NLRP3 inflammasome…

Figure 5.

Proposed model for NLRP3 inflammasome signaling pathway involved in inflammatory pathogenesis of coronary…

Figure 5.
Proposed model for NLRP3 inflammasome signaling pathway involved in inflammatory pathogenesis of coronary atherosclerosis. Stimulated PBMCs orchestrate activation of NLRP3 inflammasome due to the upregulation of the expression of NLRP3, ASC, caspase-1, and their downstream mediators, leading to atherosclerotic progression. NLRP3, nucleotide-binding oligomerization domain, leucine rich repeat, and pyrin domain-containing protein 3; PBMCs, peripheral blood monocytes; ASC, apoptosis-associated speck-like protein containing a CARD.
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References
    1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, et al. Heart disease and stroke statistics-2017 update: A report from the American heart association. Circulation. 2017;135:e146–e603. doi: 10.1161/CIR.0000000000000485. - DOI - PMC - PubMed
    1. Welsh P, Grassia G, Botha S, Sattar N, Maffia P. Targeting inflammation to reduce cardiovascular disease risk: A realistic clinical prospect? Br J Pharmacol. 2017;174:3898–3913. doi: 10.1111/bph.13818. - DOI - PMC - PubMed
    1. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–1131. doi: 10.1056/NEJMoa1707914. - DOI - PubMed
    1. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–843. doi: 10.1056/NEJM200003233421202. - DOI - PubMed
    1. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nuñez G, Schnurr M, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–1361. doi: 10.1038/nature08938. - DOI - PMC - PubMed
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Figure 2.
Figure 2.
Increase in protein expression levels of NLRP3 inflammasome and secretion of its downstream interleukins in PBMCs of patients with SAP and AMI, compared with non-CHD controls. (A) Western blotting was used to detect the protein expression of NLRP3, ASC and caspase-1 in PBMCs of each group. (B) Quantitative results are illustrated for the three indicators using western blot analysis. (C) Plasma levels of IL-1β and IL-18 from each group were measured by ELISA. *P

Figure 3.

Effect of rosuvastatin on NLRP3…

Figure 3.

Effect of rosuvastatin on NLRP3 inflammasome mRNA levels in PBMCs in vitro .…

Figure 3.
Effect of rosuvastatin on NLRP3 inflammasome mRNA levels in PBMCs in vitro. PBMCs were isolated from the peripheral blood of patients with non-CHD, SAP and AMI, respectively, followed by proliferation and treatment with rosuvastatin at a concentration of 20 µM for the indicated time-points. RT-PCR assay was performed to investigate the influence of rosuvastatin on the mRNA levels of (A) NLRP3, (B) ASC and (C) caspase-1 in PBMCs of each group. *P<0.05; **P<0.01. NLRP3, nucleotide-binding oligomerization domain, leucine rich repeat, and pyrin domain-containing protein 3; PBMCs, peripheral blood monocytes; CHD, coronary heart disease; SAP, stable angina pectoris; AMI, acute myocardial infarction; ASC, apoptosis-associated speck-like protein containing a CARD; NS, not significant.

Figure 4.

Effect of rosuvastatin on protein…

Figure 4.

Effect of rosuvastatin on protein expression levels of NLRP3 inflammasome in PBMCs and…

Figure 4.
Effect of rosuvastatin on protein expression levels of NLRP3 inflammasome in PBMCs and secretion of its downstream cytokines in supernatants in vitro. PBMCs were isolated from the peripheral blood of patients with non-CHD, SAP and AMI, respectively, followed by proliferation and treatment with rosuvastatin at a concentration of 20 µM for the indicated time-points. (A) Western blotting was conducted to analyze the influence of rosuvastatin on the protein levels of NLRP3, ASC and caspase-1 in PBMCs of each group. (B) Quantitative results for modulating the protein expression of the aforementioned three indicators by rosuvastatin are illustrated. (C) Modulation of IL-1β and IL-18 secretion in the supernatants by rosuvastatin of each group was measured by ELISA. *P<0.05, **P<0.01 and #P<0.05 (compared to the 0-h group); ΔP<0.05 (compared to the 12-h group). NLRP3, nucleotide-binding oligomerization domain, leucine rich repeat, and pyrin domain-containing protein 3; PBMCs, peripheral blood monocytes; CHD, coronary heart disease; SAP, stable angina pectoris; AMI, acute myocardial infarction; ASC, apoptosis-associated speck-like protein containing a CARD; NS, not significant.

Figure 5.

Proposed model for NLRP3 inflammasome…

Figure 5.

Proposed model for NLRP3 inflammasome signaling pathway involved in inflammatory pathogenesis of coronary…

Figure 5.
Proposed model for NLRP3 inflammasome signaling pathway involved in inflammatory pathogenesis of coronary atherosclerosis. Stimulated PBMCs orchestrate activation of NLRP3 inflammasome due to the upregulation of the expression of NLRP3, ASC, caspase-1, and their downstream mediators, leading to atherosclerotic progression. NLRP3, nucleotide-binding oligomerization domain, leucine rich repeat, and pyrin domain-containing protein 3; PBMCs, peripheral blood monocytes; ASC, apoptosis-associated speck-like protein containing a CARD.
Figure 3.
Figure 3.
Effect of rosuvastatin on NLRP3 inflammasome mRNA levels in PBMCs in vitro. PBMCs were isolated from the peripheral blood of patients with non-CHD, SAP and AMI, respectively, followed by proliferation and treatment with rosuvastatin at a concentration of 20 µM for the indicated time-points. RT-PCR assay was performed to investigate the influence of rosuvastatin on the mRNA levels of (A) NLRP3, (B) ASC and (C) caspase-1 in PBMCs of each group. *P<0.05; **P<0.01. NLRP3, nucleotide-binding oligomerization domain, leucine rich repeat, and pyrin domain-containing protein 3; PBMCs, peripheral blood monocytes; CHD, coronary heart disease; SAP, stable angina pectoris; AMI, acute myocardial infarction; ASC, apoptosis-associated speck-like protein containing a CARD; NS, not significant.
Figure 4.
Figure 4.
Effect of rosuvastatin on protein expression levels of NLRP3 inflammasome in PBMCs and secretion of its downstream cytokines in supernatants in vitro. PBMCs were isolated from the peripheral blood of patients with non-CHD, SAP and AMI, respectively, followed by proliferation and treatment with rosuvastatin at a concentration of 20 µM for the indicated time-points. (A) Western blotting was conducted to analyze the influence of rosuvastatin on the protein levels of NLRP3, ASC and caspase-1 in PBMCs of each group. (B) Quantitative results for modulating the protein expression of the aforementioned three indicators by rosuvastatin are illustrated. (C) Modulation of IL-1β and IL-18 secretion in the supernatants by rosuvastatin of each group was measured by ELISA. *P<0.05, **P<0.01 and #P<0.05 (compared to the 0-h group); ΔP<0.05 (compared to the 12-h group). NLRP3, nucleotide-binding oligomerization domain, leucine rich repeat, and pyrin domain-containing protein 3; PBMCs, peripheral blood monocytes; CHD, coronary heart disease; SAP, stable angina pectoris; AMI, acute myocardial infarction; ASC, apoptosis-associated speck-like protein containing a CARD; NS, not significant.
Figure 5.
Figure 5.
Proposed model for NLRP3 inflammasome signaling pathway involved in inflammatory pathogenesis of coronary atherosclerosis. Stimulated PBMCs orchestrate activation of NLRP3 inflammasome due to the upregulation of the expression of NLRP3, ASC, caspase-1, and their downstream mediators, leading to atherosclerotic progression. NLRP3, nucleotide-binding oligomerization domain, leucine rich repeat, and pyrin domain-containing protein 3; PBMCs, peripheral blood monocytes; ASC, apoptosis-associated speck-like protein containing a CARD.

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