ACE Inhibitors Potently Reduce Vascular Inflammation, Results of an Open Proof-Of-Concept Study in the Abdominal Aortic Aneurysm

Kortekaas, Kim E.; Meijer, C. Arnoud; Hinnen, Jan Willem; Dalman, Ronald L.; Xu, Baohui; Hamming, Jaap F.; Lindeman, J.

doi:10.1371/journal.pone.0111952

Cited by 52 publications

(45 citation statements)

References 38 publications

(50 reference statements)

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“…A critical question is whether quenching IL-6 has beneficial effect in the clinical context. Our earlier studies show that statins, ACE-inhibitors and doxycycline therapy all profoundly reduce aneurysm wall IL-6 levels [15,38,39], yet this is not followed by attenuation of aneurysm progression [4]. Although one could argue that halving IL-6 hyper-expression in AAA disease is not sufficient to interfere with AAA progression, it remains to be established whether a further suppression is clinically feasible.…”

Section: Discussionmentioning

confidence: 99%

IL-6: A Janus-like factor in abdominal aortic aneurysm disease

et al. 2016

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Section: Discussionmentioning

confidence: 99%

IL-6: A Janus-like factor in abdominal aortic aneurysm disease

et al. 2016

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“…Table 2 Relative mRNA expression of selected inflammatory mediators, proteases, cytokines, and cell activation markers (log transcript level relative to GAPDH (GAPDH = 0)) Vitamin D receptor activation and vascular inflammation AJ Nieuwland et al A critical point is whether the observed effects of VDR activation are beneficial in the context of AAA disease or vascular disease in general (atherosclerosis). Although cathepsin K 29 and L 30 have both been implicated in the process of aneurysm formation, 31 an apparent dominant role in AAA progression is challenged by the observation that reductions in cathepsin K and L expression during, respectively, statin 28 and ACE inhibitor therapy 27 are not followed by an effect on aneurysms growth. It is unclear whether and if the effects of VDR activation on T-helper cell content will influence AAA disease.…”

Section: Discussionmentioning

confidence: 99%

“…We cannot exclude that minor effects on other inflammatory pathways are missed due to a type II statistical error. Yet, if such effects exist, they presumably compare weakly with the effect exerted on the NFAT pathways, and with pleiotropic effects on NFκB and AP-1 signaling exerted by, respectively, statins 28 and ACE inhibitors, 27 and doxycycline. 26 A further limitation of the study is that evaluation of baseline vitamin D status was not included in the study protocol.…”

Section: Discussionmentioning

confidence: 99%

Activation of the vitamin D receptor selectively interferes with calcineurin-mediated inflammation: a clinical evaluation in the abdominal aortic aneurysm

Nieuwland

Kokje

Koning

et al. 2016

Laboratory Investigation

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In vitro and in vivo studies attribute potent immune regulatory properties to the vitamin D receptor (VDR). Yet, it is unclear to what extend these observations translate to the clinical context of (vascular) inflammation. This clinical study evaluates the potential of a VDR agonist to quench vascular inflammation. Patients scheduled for open abdominal aneurysm repair received paricalcitol 1 μg daily during 2-4 weeks before repair. Results were compared with matched controls. Evaluation in a parallel group showed that AAA patients are vitamin D insufficient (median plasma vitamin D: 43 (30-62 (IQR)) nmol/l). Aneurysm wall samples were collected during surgery, and the inflammatory footprint was studied. The brief paricalcitol intervention resulted in a selective 73% reduction in CD4+ T-helper cell content (Po0.024 ) and a parallel 35% reduction in T-cell (CD3+) content (Po0.032). On the mRNA level, paricalcitol reduced expression of T-cell-associated cytokines IL-2, 4, and 10 (Po0.019). No effect was found on other inflammatory mediators. On the protease level, selective effects were found for cathepsin K (Po0.036) and L (Po0.005). Collectively, these effects converge at the level of calcineurin activity. An effect of the VDR agonist on calcineurin activity was confirmed in a mixed lymphocyte reaction. In conclusion, brief course of the VDR agonist paricalcitol has profound effects on local inflammation via reduced T-cell activation. The antiinflammatory potential of VDR activation in vitamin D insufficient patients is highly selective and appears to be mediated by an effect on calcineurin-mediated responses.

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“…(Steinmetz et al, 2005, Xiong et al, 2014 Clinical evaluation showed the interference of statins, ACE inhibitors and doxycycline with vascular inflammation and protease activity. (van der Meij et al, 2013, Kortekaas et al, 2014, Lindeman et al, 2009) A number of small retrospective reports demonstrated that statins decrease aneurysmal expansion rate (Mosorin et al, 2008, Schouten et al, 2006), yet analysis in much larger cohort failed to confirm this. (Ferguson et al, 2010) The effects of ACE inhibitors on aneurysmal progression are inconsistent, whereas a population-based case-control study showed that patients with AAA were less likely to rupture.…”

Section: Sphingolipid Metabolites -Ceramide and Sphingo-1-phosphatementioning

confidence: 99%

Targeting vascular remodeling in abdominal aortic aneurysm : To identify novel treatment strategies and drug candidates

Vorkapić¹

2016

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Abdominal aortic aneurysm (AAA) is a degenerative weakening of the aortic wall, mainly affecting elderly men with a prevalence of 4.4-7.7 %. AAA is characterized by medial and adventitial inflammatory cell infiltration associated with vascular remodeling of the extracellular matrix proteins such as collagen and elastin and with phenotypic modulation and loss of vascular smooth muscle cells (VSMCs). Although much research has been performed, the precise cellular and molecular pathways behind these processes are still poorly understood. The overall aim of this thesis was to target signaling pathways that affect vascular remodeling of AAA to potentially identify novel strategies and drug candidates for future treatment of aneurysmal diseases. In order to develop our understanding of the pathophysiology of AAA, we used the angiotensin (Ang) II-induced AAA animal model and human biopsies taken at end-stage of disease to recapitulate key aspects of disease formation.Innate immune receptors such as toll-like receptors (TLRs) are known to regulate immunological processes leading to the formation and progression of vascular disease including AAA. In paper I, we aimed to investigate the role of TLR signaling under the control of the TRIF adaptor protein in the formation of AAA. Human, aneurysmal aortas displayed increased expression of TLR3 and TLR4 in surface of macrophages and T lymphocytes. AngII-induced aneurysm formation was attenuated in mice lacking the Trif gene (ApoE −/− Trif −/− ), and these knockout mice presented with a more intact medial layer together with a reduced inflammatory response by macrophages and T lymphocytes and reduced levels of pro-inflammatory cytokines, chemokines, and proteases. Our results suggest an involvement of TRIF in the pathophysiology of AAA.Current management of AAA fully depends on imaging and surgical techniques, and drugbased therapies are still mostly ineffective. In paper II, we aimed to investigate the potential protective role of the tyrosine kinase inhibitor imatinib on the molecular mechanism involved in AAA formation. In AngII-infused ApoE −/− mice, 10 mg/kg imatinib per day affected several key features important in aneurysmal formation, including preservation of the medial layer of the VSMCs, reduced infiltration of CD3ε-positive T lymphocytes, and reduced gene expression of mast cell chymase, resulting in decreased aortic diameter and vessel wall thickness. These results highlight the importance of the tyrosine kinase inhibitor imatinib as a VI potential drug in the treatment of pathological vascular inflammation and remodeling in conditions such as AAA.In paper III, we aimed to investigate the role of adiponectin in experimentally induced AAA formation in mice. In mice with elevated adiponectin levels, AAA development was inhibited, and this was associated with reduced inflammatory cell infiltration, reduced medial degeneration of VSMCs and of elastin in the aortic vessel wall together with an improved systemic cytokine profile and the attenuation of periaorti...

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ACE Inhibitors Potently Reduce Vascular Inflammation, Results of an Open Proof-Of-Concept Study in the Abdominal Aortic Aneurysm

Cited by 52 publications

References 38 publications

IL-6: A Janus-like factor in abdominal aortic aneurysm disease

IL-6: A Janus-like factor in abdominal aortic aneurysm disease

Activation of the vitamin D receptor selectively interferes with calcineurin-mediated inflammation: a clinical evaluation in the abdominal aortic aneurysm

Targeting vascular remodeling in abdominal aortic aneurysm : To identify novel treatment strategies and drug candidates

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