Andrographolide Ameliorates Abdominal Aortic Aneurysm Progression by Inhibiting Inflammatory Cell Infiltration through Downregulation of Cytokine and Integrin Expression

Ren, Jun; Liu, Zhenjie; Wang, Qiwei; Giles, Jasmine; Greenberg, Jason W.; Kent, K. Craig; Liu, Bo

doi:10.1124/jpet.115.227934

Cited by 27 publications

(17 citation statements)

References 48 publications

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“…It is demonstrated that infiltration and accumulation of macrophages in the aorta wall are early events in the apoE -/mouse model and human AAA [27][28][29][30]. Whether through cytokine inhibition or macrophage depletion, reduced macrophage accumulation in the aneurysm wall leads to lower MMP activity and attenuates aneurysm formation in mouse models of AAA [28,29]. Similarly, we also found macrophage accumulation in the media and adventitia of AAA mice in this study, which is more significant in MRS2578-treated groups.…”

Section: Discussionsupporting

confidence: 74%

“…Chronic inflammation of the vessel wall is considered to be initially and constantly responsible for aneurysmal degeneration and expansion [9,25,26] . It is demonstrated that infiltration and accumulation of macrophages in the aorta wall are early events in the apoE -/mouse model and human AAA [27][28][29][30]. Whether through cytokine inhibition or macrophage depletion, reduced macrophage accumulation in the aneurysm wall leads to lower MMP activity and attenuates aneurysm formation in mouse models of AAA [28,29].…”

Section: Discussionmentioning

confidence: 99%

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The Role of a Selective P2Y₆ Receptor Antagonist, MRS2578, on the Formation of Angiotensin II-Induced Abdominal Aortic Aneurysms

Zhang

Xiang

et al. 2020

BioMed Research International

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Objective. The P2Y 6 receptor has been shown to be involved in many cardiovascular diseases, including hypertension and atherosclerosis. The study is aimed at exploring the role of the P2Y 6 receptor in Ang II-induced abdominal aortic aneurysm (AAA) formation in apolipoprotein E-deficient (apoE -/-) mice by using its selective antagonist. Methods. Male apoE -/mice were fed with high-fat diet and infused with angiotensin (Ang) II (1000 ng/kg/min) for 4 weeks to induce AAA or saline as controls. Mice were divided into four groups: normal saline (NS, placebo control) group (n = 8), Ang II+vehicle (Ang II) group (n = 14), Ang II-low dose MRS2578 (Ang II+MRS-16 mg) group (n = 14), and Ang II-high dose MRS2578 (Ang II+MRS-32 mg) group (n = 14). Daily intraperitoneal injection with vehicle or MRS2578 was pretreated one week before Ang II infusion. On postoperative day 10, aorta imaging of each group was taken by ultrasonography. After 4 weeks of Ang II infusion, the excised aortas were processed for diameter measurement and quantification of aneurysm severity and tissue characteristics; the blood samples were collected for measurement of the lipid profile and levels of cytokines. Verhoeff's Van Gieson (EVG) staining and immunochemistry staining were performed to evaluate disruption of the extracellular matrix (ECM) and infiltration of macrophages. Expression and activity of matrix metalloproteinases (MMPs) was measured by gelatin zymography. Results. Treatment with MRS2578 made no significant difference in AAA formation, and maximal aortic diameter yet caused higher AAA rupture-induced mortality from 7% (Ang II) to 21.4% (Ang II+MRS-16 mg) or 42.9% (Ang II+MRS-32 mg), respectively (p < 0:05). Consistently, the severity of aneurysm tended to be more deteriorated in MRS2578-treated groups, especially the high-dosage group. The ratios of type III and IV aneurysm were much higher in the MRS2578-coadministered groups (p < 0:05). Furthermore, histological analyses showed that administration of MRS2578 significantly increased infiltration of macrophages, expression of monocyte chemotactic protein 1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1), and activities of MMP-2 and MMP-9 followed by aggravating degradation elastin in vivo (p < 0:05). However, the multiple effects of MRS2578 on the development of AAA are independent of changes in systolic blood pressure and lipid profiles. Conclusions. The present study demonstrated that administration of MRS2578 exacerbated the progression and rupture of experimental AAA through promoting proinflammatory response and MMP expression and activity, which indicated a crucial role of the P2Y 6 receptor in AAA development. Clinical Relevance. Purinergic P2Y receptors have attracted much attention since the P2Y 12 receptor antagonist had been successfully applied in clinical practice. Elucidating the underlying mechanisms of AAA and exploring potential therapeutic strategies are essential to prevent its progression and reduce the mortality rate.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

The Role of a Selective P2Y₆ Receptor Antagonist, MRS2578, on the Formation of Angiotensin II-Induced Abdominal Aortic Aneurysms

Zhang

Xiang

et al. 2020

BioMed Research International

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“…AGL is evident to inhibit the arterial NF-κB activation and reduce the production of pro-inflammatory cytokines [chemokine (C–C motif) ligand (CCL2), C-X-C CXCL10, TNF-α, and IFN-γ] in the rodent model. Moreover, AGL is evident to suppress a α4 integrin expression and attenuated the ability of monocytes/macrophages adhering with the activated endothelial cells ( Ren et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

Andrographolide, a New Hope in the Prevention and Treatment of Metabolic Syndrome

Islam

2017

Front. Pharmacol.

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Recently, the use of plant-derived medicines is increasing interest in the prevention and treatment of a variety of disorders including metabolic syndromes. Metabolic syndrome is one of the major risk factors for cardiovascular diseases (CVDs) and incidence of mortality worldwide. Scientific evidence suggests that Andrographis paniculata and its derived components, especially andrographolide (AGL) and its analogs/derivatives have a broad spectrum of biological activities. This review aims to sketch the activity of AGL and its analogs/derivatives against the components of metabolic syndromes such as diabetes, hyperlipidemia, hypertension, and obesity. Additionally, AGL activity against CVDs is also summarized. The finding suggests that AGL and its analogs/derivatives have a potential role in the management of metabolic syndrome; however, more studies should be conducted to evaluate their effectiveness.

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“…Immune cell infiltration and cytokine production are crucial pathogenic processes in the early stage of cardiovascular diseases. Persistent increases in circulating or local levels of the cytokines are associated with the pathogenesis of vascular dysfunction and cardiovascular diseases, such as atherosclerosis, aortic aneurysm, and hypertension (22)(23)(24). Although cytokines are important mediators of vascular immune responses, they also promote endothelial cell dysfunction and alter VSMC phenotype, which contribute to vascular pathologies (13,25).…”

Section: Discussionmentioning

confidence: 99%

TNF-α elicits phenotypic and functional alterations of vascular smooth muscle cells by miR-155-5p–dependent down-regulation of cGMP-dependent kinase 1

Choi

Park

Kim

et al. 2018

Journal of Biological Chemistry

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cGMP-dependent protein kinase 1 (PKG1) plays an important role in nitric oxide (NO)/cGMP-mediated maintenance of vascular smooth muscle cell (VSMC) phenotype and vasorelaxation. Inflammatory cytokines, including tumor necrosis factor-α (TNFα), have long been understood to mediate several inflammatory vascular diseases. However, the underlying mechanism of TNFα-dependent inflammatory vascular disease is unclear. Here, we found that TNFα treatment decreased PKG1 expression in cultured VSMCs, which correlated with NF-κB-dependent biogenesis of miR-155-5p that targeted the 3'-UTR of PKG1 mRNA. TNFα induced VSMC phenotypic switching from a contractile to a synthetic state through the down-regulation of VSMC marker genes, suppression of actin polymerization, alteration of cell morphology, and elevation of cell proliferation and migration. All of these events were blocked by treatment with an inhibitor of miR-155-5p or PKG1, whereas transfection with miR-155-5p mimic or PKG1 siRNA promoted phenotypic modulation, similar to the response to TNFα. In addition, TNFα-induced miR-155-5p inhibited the vasorelaxant response of de-endothelialized mouse aortic vessels to 8-Br-cGMP by suppressing phosphorylation of myosin phosphatase and myosin light chain, both of which are downstream signal modulators of PKG1. Moreover, TNFα-induced VSMC phenotypic alteration and vasodilatory dysfunction were blocked by NF-κB inhibition. These results suggest that TNFα impairs NO/cGMP-mediated maintenance of the VSMC contractile phenotype and vascular relaxation by down-regulating PKG1 through NF-κB-dependent biogenesis of miR-155-5p. Thus, the NF-κB/miR-155-5p/PKG1 axis may be crucial in the pathogenesis of inflammatory vascular diseases, such as atherosclerotic intimal hyperplasia and preeclamptic hypertension.

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Andrographolide Ameliorates Abdominal Aortic Aneurysm Progression by Inhibiting Inflammatory Cell Infiltration through Downregulation of Cytokine and Integrin Expression

Cited by 27 publications

References 48 publications

The Role of a Selective P2Y₆ Receptor Antagonist, MRS2578, on the Formation of Angiotensin II-Induced Abdominal Aortic Aneurysms

The Role of a Selective P2Y₆ Receptor Antagonist, MRS2578, on the Formation of Angiotensin II-Induced Abdominal Aortic Aneurysms

Andrographolide, a New Hope in the Prevention and Treatment of Metabolic Syndrome

TNF-α elicits phenotypic and functional alterations of vascular smooth muscle cells by miR-155-5p–dependent down-regulation of cGMP-dependent kinase 1

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Andrographolide Ameliorates Abdominal Aortic Aneurysm Progression by Inhibiting Inflammatory Cell Infiltration through Downregulation of Cytokine and Integrin Expression

Cited by 27 publications

References 48 publications

The Role of a Selective P2Y6 Receptor Antagonist, MRS2578, on the Formation of Angiotensin II-Induced Abdominal Aortic Aneurysms

The Role of a Selective P2Y6 Receptor Antagonist, MRS2578, on the Formation of Angiotensin II-Induced Abdominal Aortic Aneurysms

Andrographolide, a New Hope in the Prevention and Treatment of Metabolic Syndrome

TNF-α elicits phenotypic and functional alterations of vascular smooth muscle cells by miR-155-5p–dependent down-regulation of cGMP-dependent kinase 1

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Product

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The Role of a Selective P2Y₆ Receptor Antagonist, MRS2578, on the Formation of Angiotensin II-Induced Abdominal Aortic Aneurysms

The Role of a Selective P2Y₆ Receptor Antagonist, MRS2578, on the Formation of Angiotensin II-Induced Abdominal Aortic Aneurysms