Long Term Stabilization of Expanding Aortic Aneurysms by a Short Course of Cyclosporine A through Transforming Growth Factor-Beta Induction

Dai, Jianping; Michineau, Stéphanie; Franck, G; Desgranges, Pascal; Becquemin, Jean‐Pierre; Gervais, Marianne; Allaire, Éric

doi:10.1371/journal.pone.0028903

Cited by 48 publications

(53 citation statements)

References 36 publications

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“…34,35 Consistent with our findings on the role of mtROS in AIIinduced activation of the NLRP3 inflammasome, Zhou et al 18 and Nakahira et al 19 recently showed the mitochondria to be the major source of ROS, which activates the inflammasome. Interestingly, Dai et al 36 reported that administration of cyclosporin A protects AAA expansion in the rat elastase and murine calcium chloride models in vivo. Although molecular link between mitochondrial dysfunction and inflammasome activation remains to be determined, these data suggest the critical role of mitochondria-dependent NLRP3 inflammasome activation in progression of AAA formation.…”

Section: Discussionmentioning

confidence: 99%

Inflammasome Activation by Mitochondrial Oxidative Stress in Macrophages Leads to the Development of Angiotensin II–Induced Aortic Aneurysm

Usui

Shirasuna

Kimura

et al. 2015

ATVB

167

128

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A bdominal aortic aneurysm (AAA) is an age-related disease that occurs in ≤9% of adults aged of ≥65 years and is responsible for a significant number of deaths in Western countries.1 Although aggressive management of hypertension and hyperlipidemia is recommended in patients with AAA, these strategies have only little effect on the progression of AAA. Surgery is the only treatment for patients with AAA, but this is costly and associated with high morbidity and mortality.2 Endovascular repair is associated with lower postoperative mortality rates as compared to open surgical repair; however, there are no significant differences in total mortality or AAA-related mortality in the long term, with a higher incidence of reintervention in endovascular repair.3 When surgical treatment is not possible, AAAs typically progress to rupture with high mortality primarily because no effective nonsurgical treatment is currently available. Thus, a better understanding of the underlying mechanisms involved in AAA formation may help in identifying new therapeutic targets that could suppress AAA progression and reduce the risk of rupture.© 2014 American Heart Association, Inc. Objective-Abdominal aortic aneurysm (AAA) is considered a chronic inflammatory disease; however, the molecular basis underlying the sterile inflammatory response involved in the process of AAA remains unclear. We previously showed that the inflammasome, which regulates the caspase-1-dependent interleukin-1β production, mediates the sterile cardiovascular inflammatory responses. Therefore, we hypothesized that the inflammasome is a key mediator of initial inflammation in AAA formation. Approach and Results-Apoptosis-associated speck-like protein containing a caspase recruitment domain is highly expressed in adventitial macrophages in human and murine AAA tissues. Using an established mouse model of AAA induced by continuous infusion of angiotensin II in Apoe -/-mice, NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1 deficiency in Apoe -/-mice were shown to decrease the incidence, maximal diameter, and severity of AAA along with adventitial fibrosis and inflammatory responses significantly, such as inflammatory cell infiltration and cytokine expression in the vessel wall. NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1 deficiency in Apoe -/-mice also reduced elastic lamina degradation and metalloproteinase activation in the early phase of AAA formation. Furthermore, angiotensin II stimulated generation of mitochondria-derived reactive oxygen species in the adventitial macrophages, and this mitochondria-derived reactive oxygen species generation was inhibited by NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1 deficiency. In vitro experiments revealed that angiotensin II stimulated the NLRP3 inflammasome activation and subsequent interleukin-1β release in macrophages,...

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Section: Discussionmentioning

confidence: 99%

Inflammasome Activation by Mitochondrial Oxidative Stress in Macrophages Leads to the Development of Angiotensin II–Induced Aortic Aneurysm

Usui

Shirasuna

Kimura

et al. 2015

ATVB

167

128

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“…When compared with NaCl-treated mice, perivascular application of CaCl 2 to the infrarenal abdominal aorta induced a significant increase of the external aortic diameter from day 2 to day 14 after surgery, with a maximum dilatation reaching 150±19% at day 14 ( Figure 1B), in accordance with previous data. 15 The level of SDF-1α, β, γ, and CXCR4 mRNA increased significantly in mouse aortas after CaCl 2 aneurysmal induction, as early as day 2 and up to day 14 ( Figure 1C). A positive correlation between aortic mRNA content and aortic diameter was only demonstrated for the SDF-1a isoform and CXCR4 transcripts ( Figure 1D).…”

Section: Sdf-1/cxcr4 Axis Is Upregulated In Human and Experimental Aaasmentioning

confidence: 92%

Chemokine (C-X-C Motif) Receptor 4 Blockade by AMD3100 Inhibits Experimental Abdominal Aortic Aneurysm Expansion Through Anti-Inflammatory Effects

Michineau

Franck

Wagner-Ballon

et al. 2014

ATVB

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Objective-Inflammation plays a critical role in the development of abdominal aortic aneurysms (AAAs). Because stromal cell-derived factor 1 (SDF-1) is known for its ability to attract inflammatory cells, we investigated whether SDF-1/ chemokine (C-X-C motif) receptor 4 (CXCR4) axis is expressed in aneurysmal aortic wall and plays a role in AAA physiopathology and asked whether its blockade modulates AAA formation and expansion. Approach and Results-Quantitative real-time polymerase chain reaction analysis showed that SDF-1α and CXCR4 mRNA levels are increased in both human and CaCl 2 -induced mouse AAA wall and are positively correlated to the aortic diameter in mice. ELISA quantification and immunostaining demonstrated that, in mice, aortic SDF-1α is rapidly induced during AAA formation, first by apoptotic vascular smooth muscle cells in the injured media and then by adventitial macrophages once AAA is fully established. Using green fluorescent protein-positive (GFP +/− ) bone marrow transplantation experiments, we demonstrated that aortic SDF-1 overexpression is implicated in the recruitment of bone marrow-derived macrophages within the AAA wall. Furthermore, in mice, blockade of CXCR4 by AMD3100 decreases the infiltration of adventitial macrophages, inhibits AAA formation, and prevents aortic wall destruction. AMD3100 reduces the mRNA levels of MMP-12 and MMP-14 as well as that of inflammatory effectors MCP-1, MIP-1β, MIP-2α, RANTES, IL-1β, IL-6, TNF-α, and E-selectin. Finally, AMD3100 stabilizes the diameter of formed, expanding AAAs in 2 experimental models.

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“…These data are supported by similar findings from other studies showing inflammatory cell infiltration in the absence of TGF-β1. 10,11,48 Recently, Dai et al 9 showed that Cyclosporine A induced TGF-β1 in samples of human AAAs in vitro and in animal models of AAA in vivo. Administration of Cyclosporine A for 7 days stabilized already formed AAAs with concomitant downregulation of vascular wall inflammation, suggesting that pharmacological induction of TGF-β1 is a potential approach to induce AAA stabilization.…”

Section: Downloaded Frommentioning

confidence: 99%

“…quantification of atherosclerosis by en face staining is a rapid method [9,10]. Hence 135 atherosclerosis was determined in the aortic arch by Sudan IV staining as described 136 previously [1].…”

Section: Downloaded Frommentioning

confidence: 99%

“…6,7 Data from animal experiments examining AAA in a range of models, such as rat transplant, rat elastase, mouse calcium chloride, and mouse angiotensin II (AngII), however, suggest that TGF-β1 inhibits AAA development. [8][9][10][11] TGF-β1 activation is a multistep process. The TGF-β1 precursor interacts with a latency-associated peptide and forms a complex called small latent complex.…”

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confidence: 99%

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A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

Krishna

Seto

Jose

et al. 2015

ATVB

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This activation was observed to be dependent on the interaction between a specific TSP-1 sequence (lysine-argininephenylalanine-lysine; KRFK) and a conserved sequence (leucine-serine-lysine-leucine [LSKL]) near the amino terminus in the latency-associated peptide.14 The lysine--arginine-phenylalanine-lysine sequence interacts with the © 2014 American Heart Association, Inc.Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.114.304732Objective-Interaction of the activating sequence in thrombospondin-1 (TSP-1) with the conserved sequence (leucine-serinelysine-leucine [LSKL]) in the latency-associated peptide region of latent transforming growth factor (TGF)-β complex is important in regulating TGF-β1 activity. We aimed to assess the effect of blocking peptide LSKL on the progression of pre-established abdominal aortic aneurysm in angiotensin II-infused apolipoprotein E-deficient (ApoE −/− ) mice. Approach and Results-Abdominal aortic aneurysm was established in 3-month-old male ApoE −/− mice with subcutaneous infusion of angiotensin II for 28 days. After this, mice received LSKL peptide or control SLLK (serine-leucine-leucinelysine) peptide (4 mg/kg) via daily intraperitoneal injection for an additional 2 weeks. Administration of LSKL peptide promoted larger suprarenal aortic diameter, as determined by ultrasound and morphometric analysis, and stimulated more severe atherosclerosis within the aortic arch. In addition, mice receiving LSKL peptide exhibited elevated circulating proinflammatory cytokine levels and greater inflammatory cells within the suprarenal aorta compared with controls. Mice receiving LSKL peptide showed low plasma TGF-β1 activity and low levels of aortic tissue phosphorylated to total Smad2/3. Aortic gene expression of TGF-β receptor 1 (TGFBRI) and receptor 2 (TGFBRII), but not TGF-β1 and thrombospondin-1, were lower in mice receiving LSKL peptide than controls. LSKL peptide administration was associated with greater aortic elastin fragmentation and lower expression and activity of the TGF-β1-target gene lysyl oxidase like 1 (LOXL1). LSKL sequence to displace the latency-associated peptide and make the TGF-β1 accessible to its receptors, TGFBR I and II. 15 Previous studies have indicated that the conserved sequence (LSKL) is required for activation of TGF-β1 and that mimetic peptides of the sequence act as selective antagonists of TSP-1-mediated TGF-β1 activation in vitro and in vivo. [16][17][18] Previous reports suggest that LSKL peptide-mediated attenuation of TGF-β1 activation can prevent the progression of cardiac, hepatic, and renal interstitial fibrosis. 15,17,19 Complete deficiency of TGF-β1 pathway proteins has marked pathological effects, leading to in utero death. Conclusions-Attenuation 20,21Because TSP-1 provides only one of the means by which TGF-β1 is activated, targeting this protein could have clinical relevance as a less severe strategy with potential to be applied to patients. [22][23][24][25] We are aware of no previous studies whi...

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Long Term Stabilization of Expanding Aortic Aneurysms by a Short Course of Cyclosporine A through Transforming Growth Factor-Beta Induction

Cited by 48 publications

References 36 publications

Inflammasome Activation by Mitochondrial Oxidative Stress in Macrophages Leads to the Development of Angiotensin II–Induced Aortic Aneurysm

Inflammasome Activation by Mitochondrial Oxidative Stress in Macrophages Leads to the Development of Angiotensin II–Induced Aortic Aneurysm

Chemokine (C-X-C Motif) Receptor 4 Blockade by AMD3100 Inhibits Experimental Abdominal Aortic Aneurysm Expansion Through Anti-Inflammatory Effects

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

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