Deficiency of IL12p40 (Interleukin 12 p40) Promotes Ang II (Angiotensin II)–Induced Abdominal Aortic Aneurysm

Sharma, Neekun; Belenchia, Anthony; Aroor, Annayya R.; Whaley‐Connell, Adam; Pulakat, Lakshmi; Hans, Chetan P.

doi:10.1161/atvbaha.118.311969

Cited by 35 publications

(34 citation statements)

References 50 publications

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“…In a third experiment, both WT mice and IL-22-knockout mice were pretreated daily with dimethyl sulfoxide (DMSO, 50 μl/mouse, Sigma) or SB203580 (5 mg/kg, Millipore) [ 23 ], a specific inhibitor of the p38 pathway, 3 times; all mice were then given DOX (Part 3). In a fourth experiment, both WT mice and IL-22-knockout mice were treated with clodronate liposomes (FormuMax) to deplete macrophages according to the methods of a previous study [ 24 ]; control WT mice received liposomes. Then, all mice were given DOX (Part 4).…”

Section: Methodsmentioning

confidence: 99%

Interleukin-22 deficiency alleviates doxorubicin-induced oxidative stress and cardiac injury via the p38 MAPK/macrophage/Fizz3 axis in mice

Wang

et al. 2020

Redox Biology

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Several interleukin (IL) family members have been demonstrated to be involved in doxorubicin (DOX)-induced cardiac injury. This study aimed to investigate the role of IL-22 in DOX-induced cardiac injury and explore its possible mechanisms. In this study, mice were given DOX, and the cardiac expression and sources of IL-22 were determined. Then, IL-22 was knocked out to observe the effects on DOX-induced cardiac injury in mice. In addition, the p38 mitogen-activated protein kinase (MAPK) pathway was inhibited, macrophages were depleted and adoptively transferred, and Fizz3 was up-regulated in mice to explore the mechanisms. The results showed that cardiac IL-22 expression was significantly increased by DOX treatment and was mostly derived from cardiac macrophages. IL-22 knockout significantly reduced cardiac vacuolization and the expression of cardiomyocyte injury markers in both serum and left ventricular tissue and improved cardiac function in DOX-treated mice. In addition, IL-22 knockout reversed DOX-induced cardiac M1 macrophage/M2 macrophage imbalance, reduced oxidative stress and protected against cardiomyocyte apoptosis. p38 MAPK pathway inhibition with SB203580 and macrophage depletion further alleviated the above effects in DOX-treated IL-22-knockout mice. The effects were stronger IL-22-knockout mice with adoptive transfer of WT macrophages than in those with adoptive transfer of IL-22-knockout macrophages. Furthermore, increasing the expression of Fizz3 reduced cardiomyocyte apoptosis and alleviated cardiac dysfunction. Our results may suggest that IL-22 knockout alleviate DOX-induced oxidative stress and cardiac injury by inhibiting macrophage differentiation and thereby increasing the expression of Fizz3. Reductions in IL-22 expression may be beneficial for clinical chemotherapy in tumor patients.

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Section: Methodsmentioning

confidence: 99%

Interleukin-22 deficiency alleviates doxorubicin-induced oxidative stress and cardiac injury via the p38 MAPK/macrophage/Fizz3 axis in mice

Wang

et al. 2020

Redox Biology

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“…On the other hand our results also seemingly contradict findings by Sharma et al . suggesting that deficiency of IL-12p40 promotes angiotensin II (Ang II)-induced AAA 37 . The discrepancy may be explained by a complete loss of IL-12p40 from birth, which may directly impact the polarization of macrophages in response to various levels of inflammatory modulators at different stages of disease progression.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-12 and -23 blockade mitigates elastase-induced abdominal aortic aneurysm

Yan

Akk

et al. 2019

Sci Rep

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Macrophages play an important role in the inflammatory process that contributes to the development of abdominal aortic aneurysm (AAA). Studies of human and mouse AAA tissue reveal expanded populations of macrophages producing an abundance of pro-inflammatory cytokines, including TNF-α, IL-12p40 and high level of metalloprotease 9 (MMP-9) at the late stages of disease. Herein, we show that blockade of IL-12p40 in the early phase of aneurysm development suppresses macrophage expansion, inflammatory cytokine and MMP-9 production and mitigates AAA development. Since IL-12 and IL-23 are related cytokines that share the common p40 subunit, we also evaluate the effect of direct IL-23 blockade on the development of AAA. Specific IL-23p19 blockade prevents AAA progression with the same efficiency as IL-12p40 antagonism, suggesting that the efficacy of anti-IL-12p40 treatment may reflect IL-23 blockade. IL-12p40 and IL-23p19 are also abundantly expressed in human AAA tissue. Our findings have potential translational value since IL-12p40 and IL-23p19 antagonists already exist as FDA-approved therapeutics for various chronic inflammatory conditions.

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“…Aortic stiffening is an early change generating aortic wall stress that triggers aneurysmal growth, and remodeling 29 . Measurement of PWV is a reliable and reproducible approach to determine aortic stiffness and seems to be independent of arterial pressure 30,31 . Our novel findings that Notch inhibitor provides stability to the established AAAs by improving the aortic stiffness as primary outcome, have potential therapeutic implications.…”

Section: Discussionmentioning

confidence: 99%

“…40 MHz high-frequency array transducer (Vevo MS550D) was used to collect B-mode, M-Mode, ECG-based kilohertz Visualization (EKV) mode images as well as Power Doppler measurements by the imaging system (Vevo 2100, VisualSonics) 30,48 . In vivo aortic stiffness was measured locally in the abdominal aorta by PWV technique by analyzing EKV data collected at various days of AngII infusion using Vevo Vasc software as described previously 30,51 . The measurements for all PWV, distensibility and radial strains were conducted following the two-man principle who were blinded to the study groups.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological inhibition of Notch signaling regresses pre-established abdominal aortic aneurysm

Sharma

Ruíz-Rosado

Partida-Sánchez

et al. 2019

Sci Rep

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Abdominal aortic aneurysm (AAA) is characterized by transmural infiltration of myeloid cells at the vascular injury site. Previously, we reported preventive effects of Notch deficiency on the development of AAA by reduction of infiltrating myeloid cells. In this study, we examined if Notch inhibition attenuates the progression of pre-established AAA and potential implications. Pharmacological Notch inhibitor (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester; DAPT) was administered subcutaneously three times a week starting at day 28 of angiotensin II (AngII) infusion. Progressive increase in pulse wave velocity (PWV), maximal intra-luminal diameter (MILD) and maximal external aortic diameter (MEAD) were observed at day 56 of the AngII. DAPT prevented such increase in MILD, PWV and MEAD (P < 0.01). Histologically, the aortae of DAPT-treated Apoe−/− mice had significant reduction in inflammatory response and elastin fragmentation. Naked collagen microfibrils and weaker banded structure observed in the aortae of Apoe−/− mice in response to AngII, were substantially diminished by DAPT. A significant decrease in the proteolytic activity in the aneurysmal tissues and vascular smooth muscle cells (vSMCs) was observed with DAPT (P < 0.01). In human and mouse AAA tissues, increased immunoreactivity of activated Notch signaling correlated strongly with CD38 expression (R2 = 0.61). Collectively, we propose inhibition of Notch signaling as a potential therapeutic target for AAA progression.

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Deficiency of IL12p40 (Interleukin 12 p40) Promotes Ang II (Angiotensin II)–Induced Abdominal Aortic Aneurysm

Cited by 35 publications

References 50 publications

Interleukin-22 deficiency alleviates doxorubicin-induced oxidative stress and cardiac injury via the p38 MAPK/macrophage/Fizz3 axis in mice

Interleukin-22 deficiency alleviates doxorubicin-induced oxidative stress and cardiac injury via the p38 MAPK/macrophage/Fizz3 axis in mice

Interleukin-12 and -23 blockade mitigates elastase-induced abdominal aortic aneurysm

Pharmacological inhibition of Notch signaling regresses pre-established abdominal aortic aneurysm

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