Doxycycline for Stabilization of Abdominal Aortic Aneurysms

Meijer, C. Arnoud; Stijnen, Theo; Mn, Wasser; Jf, Hamming; Jh, van Bockel; Lindeman, J.H.

doi:10.7326/0003-4819-159-12-201312170-00007

Cited by 186 publications

(91 citation statements)

References 39 publications

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“…An informative example is the antibiotic doxycycline that has been demonstrated to effectively prevent aneurysm development in multiple aortic aneurysm mouse models, [47][48][49][50] beneficial effect of doxycycline therapy on aneurysm progression or repair. 51 This clinical observation is, however, in line with a recent progression study in mice, in which doxycycline did not show any effect on aneurysm progression, 52 suggesting that aneurysm initiation and progression involve more and different processes. The mouse JNK study by Yoshimura et al 24 does comprise a progression study in which JNK inhibitors indeed provoke aneurysm regression.…”

Section: Discussionsupporting

confidence: 66%

Immunosuppressive Drug Azathioprine Reduces Aneurysm Progression Through Inhibition of Rac1 and c-Jun-Terminal-N-Kinase in Endothelial Cells

Marinković

Hibender

Hoogenboezem

et al. 2013

ATVB

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Objective— In aortic aneurysms the arterial vessel wall is dilated because of destruction of its integrity, which may lead to lethal vessel rupture. Chronic infiltration of inflammatory cells into the vessel wall is fundamental to aneurysm pathology. We aim to limit aneurysm growth by inhibition of inflammation and reducing endothelial cell (EC) activation with immunosuppressive drug azathioprine (Aza). Approach and Results— Aza and its metabolite 6-mercaptopurine have anti-inflammatory effects on leukocytes. We here demonstrate that treatment of ECs with 6-mercaptopurine inhibits cell activation as illustrated by reduced expression of interleukin-12, CCL5, CCL2, and vascular cell adhesion molecule-1 and inhibition of monocyte–EC adhesion. The underlying mechanism of 6-mercaptopurine involves suppression of GTPase Rac1 activation, resulting in reduced phosphorylation of c-Jun-terminal-N-kinase and c-Jun. Subsequently, the effect of Aza was investigated in aneurysm formation in the angiotensin II aneurysm mouse model in apolipoprotein E–deficient mice. We demonstrated that Aza decreases de novo aortic aneurysm formation from an average aneurysm severity score of 2.1 (control group) to 0.6 (Aza group), and that Aza effectively delays aorta pathology in a progression experiment, resulting in a reduced severity score from 2.8 to 1.7 in Aza-treated mice. In line with the in vitro observations, Aza-treated mice showed less c-Jun-terminal-N-kinase activation in ECs and reduced leukocyte influx in the aortic wall. Conclusions— The immunosuppressive drug Aza has an anti-inflammatory effect and in ECs inhibits Rac1 and c-Jun-terminal-N-kinase activation, which may explain the protective effect of Aza in aneurysm development and, most importantly for clinical implications, aneurysm severity.

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Section: Discussionsupporting

confidence: 66%

Immunosuppressive Drug Azathioprine Reduces Aneurysm Progression Through Inhibition of Rac1 and c-Jun-Terminal-N-Kinase in Endothelial Cells

Marinković

Hibender

Hoogenboezem

et al. 2013

ATVB

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“…In conclusion, doxycycline may reduce aortic dilatation rate in Marfan mice by inhibiting TGF-β-induced MMP production and by inhibiting MMP-induced release of TGF-β, rather than by reducing inflammation. However, in the only trial in patients with aneurysms, doxycycline presented an unexpected increase in aortic diameter of 0.8 mm after 18 months, when compared to the placebo AAA patients [43].…”

Section: Discussionmentioning

confidence: 84%

No Beneficial Effect of General and Specific Anti-Inflammatory Therapies on Aortic Dilatation in Marfan Mice

et al. 2014

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AimsPatients with Marfan syndrome have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. In the FBN1 C1039G/+ Marfan mouse model, losartan decreases aortic root dilatation. We recently confirmed this beneficial effect of losartan in adult patients with Marfan syndrome. The straightforward translation of this mouse model to man is reassuring to test novel treatment strategies. A number of studies have shown signs of inflammation in aortic tissue of Marfan patients. This study examined the efficacy of anti-inflammatory therapies in attenuating aortic root dilation in Marfan syndrome and compared effects to the main preventative agent, losartan.Methods and ResultsTo inhibit inflammation in FBN1 C1039G/+ Marfan mice, we treated the mice with losartan (angiotensin II receptor type 1 inhibitor), methylprednisolone (corticosteroid) or abatacept (T-cell-specific inhibitor). Treatment was initiated in adult Marfan mice with already existing aortic root dilatation, and applied for eight weeks. Methylprednisolone- or abatacept-treated mice did not reveal a reduction in aortic root dilatation. In this short time frame, losartan was the only treatment that significantly reduced aorta inflammation, transforming growth factor-beta (TGF-β) signaling and aortic root dilatation rate in these adult Marfan mice. Moreover, the methylprednisolone-treated mice had significantly more aortic alcian blue staining as a marker for aortic damage.ConclusionAnti-inflammatory agents do not reduce the aortic dilatation rate in Marfan mice, but possibly increase aortic damage. Currently, the most promising therapeutic drug in Marfan syndrome is losartan, by blocking the angiotensin II receptor type 1 and thereby inhibiting pSmad2 signaling.

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“…Although the recent, large, double-blind, placebo-controlled Dutch clinical trial found that a single daily dose of 100 mg of doxycycline did not reduce aneurysm growth [103], we believe that further investigations are justified. A vital demand for success is a permanent serum level of doxycycline at a concentration that effectively inhibits mitochondrial protein synthesis; twice a day a moderate dose may suffice.…”

Section: Direct and Indirect Effects Of Doxycyclinementioning

confidence: 90%

“…Recently a trial assessing the efficacy of 100 mg doxycycline daily in 286 patients with small AAAs was reported [103]. This study included approximately 8 times the number of patients involved in previous small positive trials (Table 3).…”

Section: Doxycycline In Clinical Trials Of Aaa Patientsmentioning

confidence: 99%

“…This study included approximately 8 times the number of patients involved in previous small positive trials (Table 3). The investigators reported no benefit of doxycycline administered at this dose over 18 months; in fact, AAA growth was significantly greater in patients randomised to the active agent [103]. The dose of doxycycline used in this recent trial was less than in a number of previous investigations [86,99,100,101].…”

Section: Doxycycline In Clinical Trials Of Aaa Patientsmentioning

confidence: 99%

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Clonal Expansion of T Cells in Abdominal Aortic Aneurysm: A Role for Doxycycline as Drug of Choice?

Kroon

Taanman

2015

IJMS

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Most reported studies with animal models of abdominal aortic aneurysm (AAA) and several studies with patients have suggested that doxycycline favourably modifies AAA; however, a recent large long-term clinical trial found that doxycycline did not limit aneurysm growth. Thus, there is currently no convincing evidence that doxycycline reduces AAA expansion. Here, we critically review the available experimental and clinical information about the effects of doxycycline when used as a pharmacological treatment for AAA. The view that AAA can be considered an autoimmune disease and the observation that AAA tissue shows clonal expansion of T cells is placed in the light of the well-known inhibition of mitochondrial protein synthesis by doxycycline. In T cell leukaemia animal models, this inhibitory effect of the antibiotic has been shown to impede T cell proliferation, resulting in complete tumour eradication. We suggest that the available evidence of doxycycline action on AAA is erroneously ascribed to its inhibition of matrix metalloproteinases (MMPs) by competitive binding of the zinc ion co-factor. Although competitive binding may explain the inhibition of proteolytic activity, it does not explain the observed decreases of MMP mRNA levels. We propose that the observed effects of doxycycline are secondary to inhibition of mitochondrial protein synthesis. Provided that serum doxycycline levels are kept at adequate levels, the inhibition will result in a proliferation arrest, especially of clonally expanding T cells. This, in turn, leads to the decrease of proinflammatory cytokines that are normally generated by these cells. The drastic change in cell type composition may explain the changes in MMP mRNA and protein levels in the tissue samples.

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Doxycycline for Stabilization of Abdominal Aortic Aneurysms

Abstract: The Netherlands Organisation for Health Research and Development, and the NutsOhra Fund.

Cited by 186 publications

References 39 publications

Immunosuppressive Drug Azathioprine Reduces Aneurysm Progression Through Inhibition of Rac1 and c-Jun-Terminal-N-Kinase in Endothelial Cells

Immunosuppressive Drug Azathioprine Reduces Aneurysm Progression Through Inhibition of Rac1 and c-Jun-Terminal-N-Kinase in Endothelial Cells

No Beneficial Effect of General and Specific Anti-Inflammatory Therapies on Aortic Dilatation in Marfan Mice

Clonal Expansion of T Cells in Abdominal Aortic Aneurysm: A Role for Doxycycline as Drug of Choice?

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