Increased JNK in Males Compared with Females in a Rodent Model of Abdominal Aortic Aneurysm

DiMusto, Paul D.; Lu, Guanyi; Ghosh, Abhijit; Roelofs, Karen J.; Sadiq, Omar; McEvoy, Brendan; Su, Gang; Laser, Adriana; Bhamidipati, Castigliano M.; Ailawadi, Gorav; Henke, Peter K.; Eliason, Jonathan L.; Upchurch, Gilbert R.

doi:10.1016/j.jss.2011.11.1024

Cited by 33 publications

(27 citation statements)

References 19 publications

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“…The protective effect of JNK inactivation can be explained by reducing the levels of the (active) proteases in the vessel wall and thus better preserved extracellular matrix. 24,36 Along this line, we observe a reduction of MMP2 and MMP9 protein in the vessel wall and AAA of Aza-treated mice.…”

Section: Discussionsupporting

confidence: 55%

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: 55%

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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“…66 Testosterone upregulated JNK, a protein which stimulates apoptosis signaling pathway. 67 Androgens increased the incidence of AngII-induced AAA in mice and had the ability to stimulate MMP2 expression. 75 The effects of androgens on AAA formation include stimulation of components of the renineangiotensin system producing either increased synthesis or responsiveness to AngII.…”

Section: Discussionmentioning

confidence: 99%

“…DiMusto et al 67 examined sex differences in the c-Jun-N-terminal kinase (Jnk) production, an intracellular signaling molecule with important upstream regulation of several enzymes in AAA formation, inflammation, and cellular death, and found that significantly more Jnk1 or mitogenactivated protein kinase 8 (Mapk8) resulting in increase of pro-and active-MMP2 as well as pro-MMP9 in male versus female mice. In another study, the same group examined the role of plasminogen activator inhibitor 1 now known as Serpine1 in Serpine1 À/À mice and found that overexpression of Serpine1 prevented AAA development in female compared with male mice.…”

Section: Sex Differences In Aaa Animal Models the Role Of Endogenous mentioning

confidence: 99%

Sex Differences in Abdominal Aortic Aneurysm: The Role of Sex Hormones

Makrygiannis

Courtois

Drion

et al. 2014

Annals of Vascular Surgery

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Abdominal aortic aneurysm (AAA) is a complex multifactorial disease with genetic and environmental components. AAA is more common in men, whereas women have a greater risk of rupture and more frequently have concomitant thoracic aortic aneurysms. Moreover, women are diagnosed with AAA about 10 years later and seem to be protected by female sex hormones. In this MEDLINE-based review of literature, we examined human and animal in vivo and in vitro studies to further deepen our understanding of the sexual dimorphism of AAA. We focus on the role of sex hormones during the formation and growth of AAA. Endogenous estrogens and exogenous 17b-estradiol were found to exert favorable actions protecting from AAA in animal models, whereas exogenous hormone replacement therapy in humans had inconclusive results. Androgens, known to have detrimental effects in the vasculature, in sufficient levels maintain the integrity of the aortic wall through their anabolic actions and act differentially in men and women, whereas lower levels of testosterone have been associated with AAA in humans. In conclusion, sex differences remain an important area of AAA research, but further studies especially in humans are needed. Furthermore, differential molecular mechanisms of sex hormones constitute a potential therapeutic target for AAA.

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“…Male gender is a well-known risk factor for AAA development (24–26). Experiments with rodent AAA models have demonstrated that male animals develop a positive AAA phenotype compared with female animals (19, 27–28). In the present study, gender-related differences in AAA phenotype between the two groups of mice on minimal phytoestrogen diet (M− versus F− group) were clearly demonstrated (109.3 ± 37.6% versus 52.9 ± 11.5%, P<0.001).…”

Section: Discussionmentioning

confidence: 99%

Dietary phytoestrogens inhibit experimental aneurysm formation in male mice

Zhao

et al. 2014

Journal of Surgical Research

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Objective The purpose of these experiments was to test the hypothesis that dietary phytoestrogens would diminish experimental aortic aneurysm formation. Materials and methods Six-week old C57BL/6 mice were divided into groups, fed either a diet with minimal phytoestrogen content or a regular commercial rodent diet with high phytoestrogen content for two weeks. At the eight week, aortic aneurysms were induced by infusing the isolated infra-renal abdominal aorta with 0.4% elastase for five minutes. Mice were recovered and the diameter of the infused aorta was measured at post-operative days 3, 7 and 14. Abdominal aorta samples were collected for histology, cytokine array and gelatin zymography after aortic diameter measurement. Blood samples were also collected to determine serum phytoestrogens and estradiol levels. Multiple-group comparisons were done using ANOVA with post hoc Tukey tests. Results Compared to mice on minimal phytoestrogen diet, mice on regular rodent diet had higher levels of serum phytoestrogens (male 1138±846 ng/dL, female 310±295 ng/dL). These serum phytoestrogen levels were also much higher than their own endogenous estradiol level (109 fold higher for males, and 35.5 fold higher for females). While aortic diameters of female mice were unaffected by the phytoestrogen concentration in the diets, male mice on regular rodent diet (M+ group) developed smaller aortic aneurysms than male mice on minimal phytoestrogen diet (M− group)on post-operative day 14 (M+ 54.8±8.8% versus M− 109.3±37.6%, P<0.001). During aneurysm development (post-operative days 3 and 7), there were fewer neutrophils, macrophages and lymphocytes in the aorta from the M+ group than from the M− group. Concentrations of multiple pro-inflammatory cytokines (MMPs, IL-1β, IL-6, IL-17, IL-23, MCP-1, RANTES, INF-γ, TNF-α) from aortas of M+ group were also lower than those from the aortas of M− group. Zymography also demonstrated that M+ group had lower levels of aortic MMP-9s than M− group on post-operative day 14 (P<0.001 for pro-MMP-9, P<0.001 for active MMP-9). Conclusions These results suggest that dietary phytoestrogens inhibit experimental aortic aneurysm formation in male mice via a reduction of the inflammatory response in the aorta wall. The protective effect of dietary phytoestrogens on aneurysm formation warrants further investigation.

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Increased JNK in Males Compared with Females in a Rodent Model of Abdominal Aortic Aneurysm

Cited by 33 publications

References 19 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

Sex Differences in Abdominal Aortic Aneurysm: The Role of Sex Hormones

Dietary phytoestrogens inhibit experimental aneurysm formation in male mice

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