scholarly journals Activation of Invariant Natural Killer T Cells by α-Galactosylceramide Attenuates the Development of Angiotensin II-Mediated Abdominal Aortic Aneurysm in Obese ob/ob Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Akimichi Saito ◽  
Naoki Ishimori ◽  
Satoshi Tokuhara ◽  
Tsuneaki Homma ◽  
Mikito Nishikawa ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
T Lymphocytes ◽  
Aortic Aneurysm ◽  
Natural Killer ◽  
M2 Macrophage ◽  
Inkt Cells ◽  
Abdominal Aortic ◽  
Invariant Natural Killer ◽  
Natural Killer T

The infiltration and activation of macrophages as well as lymphocytes within the aorta contribute to the pathogenesis of abdominal aortic aneurysm (AAA). Invariant natural killer T (iNKT) cells are unique subset of T lymphocytes and have a crucial role in atherogenesis. However, it remains unclear whether iNKT cells also impact on the development of AAA. Ob/ob mice were administered angiotensin II (AngII, 1,000 ng/kg/min) or phosphate-buffered saline (PBS) by osmotic minipumps for 4 weeks and further divided into 2 groups; α-galactosylceramide (αGC; PBS-αGC; n = 5 and AngII-αGC; n = 12), which specifically activates iNKT cells, and PBS (PBS-PBS; n = 10, and AngII-PBS; n = 6). Maximal abdominal aortic diameter was comparable between PBS-PBS and PBS-αGC, and was significantly greater in AngII-PBS than in PBS-PBS. This increase was significantly attenuated in AngII-αGC without affecting blood pressure. αGC significantly enhanced iNKT cell infiltration compared to PBS-PBS. The ratio of F4/80-positive macrophages or CD3-positive T lymphocytes area to the lesion area was significantly higher in AngII-PBS than in PBS-PBS, and was significantly decreased in AngII-αGC. Gene expression of M2-macrophage specific markers, arginase-1 and resistin-like molecule alpha, was significantly greater in aortic tissues from AngII-αGC compared to AngII-PBS 1 week after AngII administration, and this increase was diminished at 4 weeks. Activation of iNKT cells by αGC can attenuate AngII-mediated AAA in ob/ob mice via inducing anti-inflammatory M2 polarized state. Activation of iNKT cells by the bioactive lipid αGC may be a novel therapeutic target against the development of AAA.

Activation of invariant natural killer T cells ameliorates doxorubicin-induced cardiotoxicity in mice

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Obata ◽  
N Ishimori ◽  
A Saito ◽  
S Kinugawa ◽  
I Nakano ◽  
...  
Keyword(s):  
Body Weight ◽  
Natural Killer ◽  
Heart Tissue ◽  
M2 Macrophage ◽  
Funding Source ◽  
Inkt Cells ◽  
Arginase 1 ◽  
Relative Ratio ◽  
Invariant Natural Killer ◽  
Natural Killer T

Abstract Objective Doxorubicin (DOX) is one of the most important anticancer agents and widely used to treat cancers but clinical utility of DOX is limited for its dose-dependent cardiotoxicity. The precise mechanism of DOX-induced cardiotoxicity is still not fully understood but it has been reported that cardiac inflammation is involved in the cardiotoxicity. Invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes that recognize glycolipid antigens and secrete a large amount of both Th1 and Th2 cytokines on activation, have been shown to play crucial roles in the regulation of immune responses. However, it remains unclear whether iNKT cells are involved in DOX-induced cardiotoxicity. Methods and results Male C57BL/6J mice were administered DOX (20mg/kg body weight; n=28) or vehicle (Vehicle; n=6). DOX-administered mice were further divided into 2 groups; those treated with α-galactosylceramide (αGC, 0.1μg/g body weight; DOX-αGC; n=14), which specifically activates iNKT cells, or those treated with PBS (DOX-PBS; n=14) by intraperitoneal injections (twice; 4 days before and 3 days after DOX administration).An echocardiography conducted at 14 days after DOX/Vehicle administration revealed that LV fractional shortening was significantly reduced in the DOX-PBS compared to the Vehicle (49.3±0.8% vs. 59.2±1.7%, P<0.05), and this decrease was completely attenuated in the DOX-αGC (57.7±1.3%, P<0.05 vs. DOX-PBS)without affecting LV end-diastolic diameter. Flow cytometric analysis revealed that the ratio of iNKT cells to mononuclear cells infiltrated into the heart tissue was significantly increased in the DOX+αGC compared to the Vehicle and the DOX+PBS (1.00±0.09% vs. 0.54±0.09% and 0.71±0.07%, P<0.05). Immuno-histochemistry revealed that the infiltration number of Iba1+macrophages in the heart tissue was significantly elevated in the DOX+αGC compared to the Vehicle and the DOX+PBS (55.4±3.2 cells/mm2 vs. 21.7±2.0 cells/mm2 and 37.5±5.9 cells/mm2, P<0.05) The ratio of fibrosis area to the heart tissue was markedly higher in the DOX-PBS than in Vehicle (4.3±0.5% vs. 2.2±0.1%, P<0.05), and this increase was completely attenuated in the DOX-αGC (2.8±0.1%, P<0.05 vs.DOX-PBS).Real-time PCR analysis revealed that mRNA expressions of M2 macrophage markers (Arginase 1 and Retnla) and IL-4 were significantly enhanced in the DOX+αGC compared to the DOX+PBS (Arginase 1: 2.5±0.4 vs. 1.6±0.3 [relative ratio to the Vehicle], P=0.08; Retnla: 2.4±0.5 vs. 1.1±0.2 [relative ratio to the Vehicle], P<0.05; IL-4: 1.0±0.3 vs. 8.94±2.8 [relative ratio to the DOX+PBS], P<0.05), while those of M1 macrophage markers (iNOS and MCP-1) did not change among all groups. Conclusions Activation of iNKT cells ameliorates DOX-induced cardiotoxicity in mice via enhanced M2 macrophage polarization with the upregulation of IL-4 and reducing cardiac fibrosis. iNKT cell activation can be a novel preventive strategy against DOX-induced cardiotoxicity. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Japan Agency for Medical Research and Development (18lm0203001j0002) and JSPS KAKENHI (18K15834).

Abstract 11982: Circulating Invariant Natural Killer T Cells are Decreased in Patients With Chronic Heart Failure

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Akimichi Saito ◽  
Naoki Ishimori ◽  
Mikito Nishikawa ◽  
Shintaro Kinugawa ◽  
Hiroyuki Tsutsui
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Ejection Fraction ◽  
Natural Killer ◽  
Left Ventricular ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Inkt Cells ◽  
Lv Ejection Fraction ◽  
Invariant Natural Killer ◽  
Natural Killer T

Objective: Inflammatory mediators play a crucial role in the development of chronic heart failure (HF). Invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes, which recognize glycolipid antigens and secrete a large amount of T helper (Th) 1/Th2 cytokines on activation, function as immunomodulatory cells in the various pathological processes. We have demonstrated that iNKT cells have a protective role against the development of left ventricular (LV) remodeling and failure after myocardial infarction in mice. However, it remains unclear whether iNKT cells are involved in the development of HF in humans. Methods and Results: Nine HF patients (NYHA II or III, LV ejection fraction 26.3±3.0%) and 8 healthy controls were studied. The mean age and male gender were comparable between HF and controls (51.2±5.1 vs. 45.1±4.5 years and 77.8 vs. 75.0%). The causes of HF were idiopathic dilated cardiomyopathy in 3, ischemic in 2, and others in 4 patients. Plasma BNP was significantly higher in HF than in controls (739.4±207.2 vs. 19.8±6.5 pg/mL, P <0.01). The number of circulating iNKT cells, identified by the positive-staining of Vα24-Jα18 T Cell Receptor by flow-cytometric analysis, was significantly lower in HF (747±85 vs. 1058±271 counts/mL, P <0.01). Its ratio to the total lymphocyte was also significantly lower (0.111±0.004 vs. 0.146±0.035%, P <0.01). Plasma interleukin-6 and high-sensitivity CRP were significantly higher in HF (3.99±0.86 vs. 0.78±0.14 pg/mL and 0.28±0.10 vs. 0.06±0.02 mg/dL, respectively, both P <0.01). LV ejection fraction ( r =0.72, P <0.05) and plasma log BNP ( r =-0.70, P <0.05) were significantly correlated to the ratio of iNKT cells among HF patients. Conclusions: Circulating iNKT cells were decreased in HF patients, suggesting that they have a potential role in the development of human HF.

scholarly journals Endothelial Cell Tetrahydrobiopterin Modulates Sensitivity to Ang (Angiotensin) II–Induced Vascular Remodeling, Blood Pressure, and Abdominal Aortic Aneurysm

Hypertension ◽  
2018 ◽  
Vol 72 (1) ◽  
pp. 128-138 ◽  
Author(s):  
Surawee Chuaiphichai ◽  
Victoria S. Rashbrook ◽  
Ashley B. Hale ◽  
Lucy Trelfa ◽  
Jyoti Patel ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Abdominal Aortic Aneurysm ◽  
Endothelial Cell ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Vascular Remodeling ◽  
Abdominal Aortic

Abstract 279: Role of Caveolin-1 in Abdominal Aortic Aneurysm induced by Angiotensin II

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Takehiko Takayanagi ◽  
Kevin Crawford ◽  
Tomonori Kobayashi ◽  
Victor Rizzo ◽  
Satoru Eguchi
Keyword(s):  
Oxidative Stress ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Egf Receptor ◽  
Critical Role ◽  
Membrane Microdomains ◽  
Structural Protein ◽  
Caveolin 1 ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) is a significant cause of mortality for adults aged >60 years. Accumulating evidence suggests that activation of the AT1 receptor by angiotensin II (AngII) in AAA formation. While several downstream signals and target proteins have been identified in this pathway, there is a huge void in our knowledge regarding the AngII-sensitive proximal events primarily responsible for AAA formation. We recently reported that caveolae membrane microdomains in vascular smooth muscle cells (VSMC) mediate a metalloprotease ADAM17-dependent EGF receptor (EGFR) transactivation which linked to vascular remodeling induced by AngII. Given that ADAM17 expression is one of the key features in AAA, we have tested our hypothesis that caveolin-1 (Cav1), a major structural protein of caveolae, in the vasculature plays a critical role for development of AAA via its regulation on ADAM17. 8 week old male Cav1-/- mice and the control C57Bl/6 wild-type (WT) mice were co-infused with AngII and BAPN, a lysyl oxidase inhibitor, to induce AAA. We found that Cav1-/- mice did not develop AAA compared to C57Bl/6 mice in spite of hypertension assessed by telemetry in both groups. This finding suggests that the AngII signaling essential for vascular contraction remains in place in Cav1-/- mice. We found an increased expression of ADAM17 and auto-phosphorylation of EGFR in WT abdominal aortae with aneurysms that were markedly attenuated in Cav1-/- mice infused with AngII+BAPN. Furthermore, Cav1-/- mice with the infusion showed less oxidative stress and ER stress than their WT counterparts as assessed by nitrotyrosine staining and KDEL/p-eIF2a staining, respectively. In conclusion, Cav1 and presumably vascular caveolae micro-domain appear to play a critical role in the formation of AAA in mice via regulation of the ADAM17/EGFR signaling axis and subsequent induction of ER/oxidative stress.

scholarly journals IKK Epsilon Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Inhibiting Inflammation, Oxidative Stress, and Apoptosis

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Hao Chai ◽  
ZhongHao Tao ◽  
YongChao Qi ◽  
HaoYu Qi ◽  
Wen Chen ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Ang Ii ◽  
Elastin Degradation ◽  
Maximal Diameter ◽  
Abdominal Aortic ◽  
Primary Mouse

Abdominal aortic aneurysm (AAA) is a vascular disorder that is considered a chronic inflammatory disease. However, the precise molecular mechanisms involved in AAA have not been fully elucidated. Recently, significant progress has been made in understanding the function and mechanism of action of inhibitor of kappa B kinase epsilon (IKKε) in inflammatory and metabolic diseases. The angiotensin II- (Ang II-) induced or pharmacological inhibitors were established to test the effects of IKKε on AAA in vivo. After mice were continuously stimulated with Ang II for 28 days, morphologically, we found that knockout of IKKε reduced AAA formation and drastically reduced maximal diameter and severity. We also observed a decrease in elastin degradation and medial destruction, which were independent of systolic blood pressure or plasma cholesterol concentrations. Western blot analyses and immunohistochemical staining were carried out to measure IKKε expression in AAA tissues and cell lines. AAA phenotype of mice was measured by ultrasound and biochemical indexes. In zymography, immunohistology staining, immunofluorescence staining, and reactive oxygen species (ROS) analysis, TUNEL assay was used to examine the effects of IKKε on AAA progression in AAA mice. IKKε deficiency significantly inhibited inflammatory macrophage infiltration, matrix metalloproteinase (MMP) activity, ROS production, and vascular smooth muscle cell (VSMC) apoptosis. We used primary mouse aortic VSMC isolated from apolipoprotein E (Apoe) −/− and Apoe−/−IKKε−/− mice. Mechanistically, IKKε deficiency blunted the activation of the ERK1/2 pathway. The IKKε inhibitor, amlexanox, has the same impact in AAA. Our results demonstrate a critical role of IKKε in AAA formation induced by Ang II in Apoe−/− mice. Targeting IKKε may constitute a novel therapeutic strategy to prevent AAA progression.

scholarly journals Caloric Restriction Exacerbates Angiotensin II–Induced Abdominal Aortic Aneurysm in the Absence of p53

Hypertension ◽  
2019 ◽  
Vol 73 (3) ◽  
pp. 547-560 ◽  
Author(s):  
Peng Gao ◽  
Hexuan Zhang ◽  
Qin Zhang ◽  
Xia Fang ◽  
Hao Wu ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Caloric Restriction ◽  
Abdominal Aortic
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