Abstract 1428: Cyclophilin a Promotes Vascular Oxidative Stress and Accelerates Development of Angiotensin II-Induced Aortic Aneurysms

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kimio Satoh ◽  
Patrizia Nigro ◽  
Tetsuya Matoba ◽  
Michael R O’Dell ◽  
Zhaoqiang Cui ◽  
...  
Keyword(s):  
Cell Migration ◽  
Angiotensin Ii ◽  
Rhode Island ◽  
Inflammatory Cell ◽  
Aortic Wall ◽  
Bone Marrow Cells ◽  
Aortic Rupture ◽  
Gelatin Zymography ◽  
Cyclophilin A ◽  
Aortic Aneurysms

Cyclophilin A (CyPA) is a chaperone protein secreted from vascular smooth muscle cells (VSMC) in response to reactive oxygen species (ROS), that stimulates VSMC migration and inflammatory cell migration in vitro. Abdominal aortic aneurysm (AAA) formation involves inflammatory cytokine release, leukocyte recruitment, aortic wall degradation, and neovascularization. We hypothesized that VSMC-derived CyPA contributes to AAA pathogenesis due to its proinflammatory properties. To determine the role of CyPA in AAA formation, ApoE −/− and ApoE −/− CyPA −/− mice were infused with angiotensin II (AngII, 1000 ng/min/kg) for 4 weeks. There were no differences in blood pressure and cholesterol between ApoE −/− and ApoE −/− CyPA −/− mice before and after Ang II treatment. AngII-induced AAA formation and aortic rupture was frequently observed in ApoE −/− mice (89% and 40%). In contrast, ApoE −/− CyPA −/− mice were completely protected from AngII-induced AAA formation and aortic rupture (0% and 0%). ApoE −/− CyPA −/− mice showed decreased levels of monocyte chemoattractant protein (MCP)-1 in the aorta and lacked elastic lamina degradation, microvessel formation, and aortic expansion. In response to AngII, recruitment of leukocytes to the aortic wall was markedly impaired in ApoE −/− CyPA −/− mice compared with ApoE −/− mice (counts/area; 8.6±4.3 vs. 60.0±13.8, P <0.01). The incidence of AAA was 63% in CyPA +/+ marrow-transplanted ApoE −/− mice, while the incidence of AAA in ApoE −/− CyPA −/− mice remained 0% after transplantation of CyPA +/+ bone marrow cells. In situ and gelatin zymography demonstrated that CyPA was required for matrix metalloproteinase (MMP) activation in aortic wall. Treatment of mouse aortic wild-type VSMC with AngII augmented MMP activity, which was significantly less in CyPA −/− VSMC. Treatment of VSMC with 100 nM CyPA augmented MMP activity, suggesting the importance of extracellular CyPA as well as intracellular CyPA. Finally, VSMC-specific CyPA overexpressing mice revealed augmented AngII-induced MMP activity in the vascular wall. Vascular-derived CyPA contributes to AAA pathogenesis in mice by increasing proinflammatory cytokine expression, inflammatory cell migration, and MMP activation. This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).

Abstract 518: Cyclophilin A is a Novel Pro-Inflammatory Cytokine that Accelerates Development of Atherosclerosis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kimio Satoh ◽  
Michael R O’Dell ◽  
Duan-fang Liao ◽  
Zhaoqiang Cui ◽  
Patrizia Nigro ◽  
...  
Keyword(s):  
New York ◽  
Cell Migration ◽  
Rhode Island ◽  
Inflammatory Cytokine ◽  
Inflammatory Cell ◽  
Cyclophilin A ◽  
Heart Association ◽  
List Type ◽  
En Face

Background - Cyclophilin A (CyPA), a member of the immunophilin family, is highly expressed in vascular smooth muscle cells (VSMC) in mice and humans. CyPA is secreted in response to reactive oxygen species (ROS) and also is a positive regulator of helper T (Th) profile promoting differentiation of Th0 cells into Th1 lymphocytes (increased IFN-γ The development of atherosclerosis involves vascular inflammatory cytokine release, inflammatory cell migration/activation, and altered Th1/Th2 profile. Based on the role of CyPA in ROS signaling and Th profile we hypothesized that CyPA would promote atherosclerosis. Methods and Results - We compared atherosclerosis development in ApoE −/− and ApoE −/− CyPA −/− mice using two different models. In ApoE −/− mice fed a high-fat diet for 16 weeks, atherosclerosis assessed by oil-red O (ORO) staining was significantly greater in ApoE −/− mice compared to ApoE −/− CyPA −/− mice (%ORO, en face aorta; 23.1±5.5 vs. 6.8±3.2, P <0.01). Immunostaining of atherosclerotic lesions in the aortic cusp revealed the co-localization of CyPA, CD45, and MCP-1, suggesting the importance of CyPA for inflammatory cell recruitment and cytokine production. Angiotensin II infusion (AngII, 1000 ng/min/kg, 4 weeks) significantly increased atherosclerosis area in ApoE −/− mice, which was significantly less in ApoE −/− CyPA −/− mice (%ORO, en face aorta; 11.1±4.6 vs. 4.0±2.8, P<0.01). ApoE −/− mice showed significant increases in vascular MCP-1 expression, VCAM-1 expression, and inflammatory cell migration to the aortic wall, all of which were significantly less in ApoE −/− CyPA −/− mice. Cytokine/chemokine array analysis revealed that AngII significantly increased secretion of numerous cytokine/chemokines from ApoE −/− spleno-cytes, which was significantly less in ApoE −/− CyPA −/− splenocytes. Mechanistic studies in vitro revealed that AngII enhanced CyPA secretion from mouse aortic VSMC. Finally, expression of CyPA was significantly increased in atherosclerotic plaques of patients with acute coronary syndromes. Conclusion - CyPA is a novel mediator of atherosclerosis by promoting inflammatory cytokine/chemokine secretion, adhesion molecule expression, and inflammatory cell migration. This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).

Abstract 3551: Cyclophilin a Promotes Angiotensin II-Induced Inflammation and Cardiovascular Hypertrophy in Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kimio Satoh ◽  
Liam Casey ◽  
Michael R O’Dell ◽  
Patrizia Nigro ◽  
Amy Mohan ◽  
...  
Keyword(s):  
Body Weight ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Rhode Island ◽  
Bone Marrow Cells ◽  
Weight Ratio ◽  
Cyclophilin A ◽  
Ros Production ◽  
Body Weight Ratio ◽  
Cardiovascular Hypertrophy

Background - Cyclophilin A (CyPA) is a chaperone protein secreted from vascular smooth muscle cells (VSMC) in response to reactive oxygen species (ROS). We have recently demonstrated that extracellular CyPA stimulates at least 3 signaling pathways (ERK1/2, Akt and JAK) and mediates numerous cellular effects of ROS. Angiotensin II (Ang II) induces ROS through NADPH oxidases and activates matrix metalloproteinase (MMP) in VSMC. ROS and MMPs have been demonstrated to mediate cardiac hypertrophy and remodeling. We hypothesized that VSMC-derived CyPA contributes to AngII-induced cardiovascular hypertrophy in vivo due to its proinflammatory properties. Methods and Results - ApoE −/− and ApoE −/− CyPA −/− mice were treated with AngII (1000 ng/min/kg for 4 weeks) to induce cardiac hypertrophy. Long-term infusion of AngII significantly increased heart/body weight ratio in ApoE −/− mice, which was significantly less in ApoE −/− CyPA −/− mice (6.6±1.0 vs. 4.8±0.7, P <0.01). Echocar-diography confirmed a significantly greater increase in LV mass in ApoE −/− mice compared to ApoE −/− CyPA −/− mice (112% vs. 47%). Perivascular accumulation of inflammatory cells and cardiac myofibroblasts in ApoE −/− mice was significantly greater than in ApoE −/− CyPA −/− mice. Consequently, coronary artery ROS production (DHE fluorescence) and MMP activation (in situ zymography) were markedly increased by AngII in ApoE −/− mice compared to ApoE −/− CyPA −/− mice. To determine the source of CyPA, bone marrow cells (BMCs) transplantation was performed. The heart/body weight ratio was still higher in ApoE −/− mice compared with ApoE −/− CyPA −/− mice after reconstitution with GFP + CyPA +/+ BMCs (6.7±0.6 vs. 5.6±0.9, P <0.01). Recruitment of GFP + BMCs to the heart in chimeric ApoE −/− mice was significantly greater than the chimeric ApoE −/− CyPA −/− mice (count/area; 218±63 vs. 109±43, P <0.01). To prove a vascular source of CyPA was essential, VSMC-specific CyPA overexpressing mice were generated. In these mice there was a significant increase in cardiac MMP activity after AngII infusion (VSMC-Tg > WT > CyPA −/− ). Conclusion - CyPA is a novel mediator of AngII-induced cardiac hypertrophy by stimulating vascular ROS production, MMP activation, and inflammatory cell recruitment. This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).

Abstract 283: Platelet Inhibition Increases Angiotensin II-induced Abdominal Aortic Aneurysm Incidence and Rupture in Mice

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
A. Phillip Owens ◽  
Yacine Boulaftali ◽  
Wolfgang Bergmeier ◽  
James P Luyendyk ◽  
Nigel Mackman
Keyword(s):  
Angiotensin Ii ◽  
Mouse Model ◽  
Milk Fat ◽  
Aortic Rupture ◽  
Plasma Cholesterol ◽  
Dabigatran Etexilate ◽  
Aortic Aneurysms ◽  
Thrombin Inhibitor ◽  
Drug Bioavailability ◽  
Abdominal Aortic

Objective Platelets play a central role in both hemostasis and thrombosis. The coagulation protease thrombin activates platelets by cleavage of protease-activated receptors (PAR1 and PAR4 in humans, and PAR3 and PAR4 in mice). Circulating thrombin is increased in patients with abdominal aortic aneurysms (AAAs). We recently demonstrated that PAR4 deficiency in mice increased the incidence of aneurysm (P = 0.001) and rupture-induced death (P = 0.003) in an angiotensin II (AngII) infusion model of AAA. Furthermore, platelet depletion significantly increased rupture in this model (P = 0.048). The purpose of this study was to examine clinically used anti-platelet drugs in this mouse model of AAA. Methods and Results Male Ldlr -/- mice (8-12 weeks in age) were fed a fat and cholesterol-enriched diet (21% milk fat, 0.2% cholesterol). Groups of mice received either aspirin (30 mg/L via drinking water [ASA]), or diet supplemented with the direct thrombin inhibitor dabigatran etexilate (10 g/kg chow [DE]) or the P2Y 12 inhibitor clopidogrel (50 mg/kg/day [Plavix]) 1 week prior to and throughout AngII (1,000 ng/kg/min) infusion for 28 days. Drug bioavailability was confirmed with all treatments. Medial diameters in the suprarenal aortic region were increased significantly from baseline to day 28 in all groups infused with AngII, as measured by in vivo ultrasound. Medial diameters were not different in any of the treatment groups compared with placebo controls. However, DE (87% vs. 47%) and Plavix (82% vs. 40%) significantly increased the incidence of AAA versus placebo groups (P < 0.05). ASA also increased the incidence of AAA (93% vs. 70% P = NS). Importantly, all treatments had a significant increase in aortic rupture-induced death versus placebo groups (P < 0.05; DE [67% vs. 7%]; Plavix [41% vs. 0%]; and ASA [64% vs. 10%]). None of the treatments affected total plasma cholesterol, lipoprotein-cholesterol distributions, or AngII-induced increases in systolic blood pressure. Conclusion This study indicates that the presence of functional platelets reduces the formation and rupture of AAA in this mouse model. This suggests that inhibition of platelet function may be detrimental to patients with existing AAAs, a conclusion that will be addressed in future mouse studies.

Abstract 522: TGF-beta Neutralization Augments Development of Angiotensin II-induced Aneurysms in Both Ascending and Abdominal Aortic Regions

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Xiaofeng Chen ◽  
Debra L Rateri ◽  
Deborah A Howatt ◽  
Anju Balakrishnan ◽  
Jessica J Moorleghen ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Transforming Growth Factor Beta ◽  
Neutralizing Antibodies ◽  
Transforming Growth Factor ◽  
Aortic Rupture ◽  
Neutralizing Antibody ◽  
Normal Diet ◽  
Aortic Aneurysms ◽  
Tgf Beta ◽  
Abdominal Aortic

Introduction and Objectives Angiotensin II (AngII) infusion induces ascending and abdominal aortic aneurysms (AAs) in mice. In a mouse model of Marfan Syndrome expressing Fbn1 C1039G/+ , ascending AAs were reduced by administration of a transforming growth factor-beta (TGF-beta) neutralizing antibody. In contrast, administration of TGF-beta neutralizing antibodies to AngII-infused mice increased aortic rupture. The purpose of this study was to compare the effects of TGF-beta neutralization on formation and progression of AngII-induced ascending and abdominal AAs. Methods and Results Male C57BL/6 mice were fed a normal diet and infused subcutaneously with AngII (1,000 ng/kg/min). Five days prior to initiating infusion, mice were injected i.p. with either a mouse monoclonal TGF-beta antibody (1D11) or an isotype matched IgG at a dose of either 0.3 or 5 mg/kg x 3/per week. 1D11 administration significantly decreased serum TGF-beta concentrations. TGF-beta neutralization at 5 mg/kg greatly increased the incidence of aortic rupture, which was attributed to rupture in both the ascending and abdominal regions. For mice that remained viable after 28 days of infusion, there were equivalent increases in aortic dilation in both the ascending and abdominal regions. Prior to rupture, aortic diameters determined by ultrasound demonstrated no significant effect on AngII-induced dilation of the ascending or abdominal aorta. We also studied the effects of TGF-beta neutralization in mice with established AngII-induced AAs following AngII-infusion for 28 days. C57BL/6 mice were injected with the mouse TGF-beta neutralizing antibody or IgG control (5 mg/kg x 3/per week, n=10 per group), while AngII infusion was continued for a further 28 days. Although TGF-beta antibody administration significantly decreased serum TGF-beta concentrations in mice with established AAs, there was no effect on aortic rupture or dilation of either the ascending or abdominal aortic region. Conclusion TGF-beta inhibition augmented AngII-induced aortic rupture in both the ascending and abdominal regions but had no effect on dilation. Furthermore, TGF-beta neutralization had no effect on either aortic rupture or expansion in established AAs.

Abstract 667: The Role of Aortic Wall-Nuclear Factor- kappa B (NF-kB) Signaling in Formation of Dissecting Aortic Aneurysms

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Talha Ijaz ◽  
Hong Sun ◽  
Adrian Recinos ◽  
Ronald G Tilton ◽  
Allan R Brasier
Keyword(s):  
Flow Cytometry ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Aortic Wall ◽  
Aortic Rupture ◽  
Aortic Aneurysms ◽  
Tunel Staining ◽  
Abdominal Aortic ◽  
Significant Difference

Introduction: Abdominal aortic aneurysm is a devastating disease since it can lead to aortic rupture and instantaneous death. We previously demonstrated that IL-6 secreted from the aortic wall is necessary for the development of abdominal aortic aneurysm and dissection (AAD). Since IL-6 is a NF-kB/RelA dependant gene, we investigated the role of aortic wall- NF-kB/RelA signaling in the development of AAD. Methods and Results: To test the role of aortic wall-RelA, we utilized Cre-Lox technology to delete RelA from aortic cells. Tamoxifen-inducible, Col1a2-promoter driven Cre mice (Col1a2-Cre) were crossed with mT/mG Cre-reporter mice to determine which aortic cells undergo genetic recombination after Cre activation. Flow cytometry analysis of the aortic wall indicated that 88% of the genetically recombined cells were SMCs and 8% were fibroblasts. Next, RelA floxed (RelA f/f) mice, generated in our lab, were crossed with Col1a2-Cre mice. RelA f/f Cre+ and RelA f/f Cre- were stimulated with tamoxifen for 10 days to generate aortic-RelA deficient (Ao-RelA-/-) or wild-type (Ao-RelA+/+) transgenics. Flow cytometry, qRT-PCR, and immunohistochemistry analysis suggested a depletion of aortic-RelA greater than 60%. To test the role of Ao-RelA in AAD, Ao-RelA -/- (n= 20) and Ao-RelA +/+ (n=14) mice were infused with angiotensin II for 7 days. Surprisingly, 20% of Ao-RelA-/- mice died from development of AAD and aortic rupture while no deaths were observed in Ao-RelA+/+ group. In addition, 40% of Ao-RelA-/- mice developed AAD compared to 14% of Ao-RelA+/+ mice. There was no significant difference in TUNEL staining or ERTR7+ fibroblast population between the two groups. Conclusion: Our studies suggest that aortic wall-RelA may be necessary for protection from AAD.

scholarly journals Acute aortic rupture in a dog with spirocercosis following the administration of medetomidine : clinical communication

2005 ◽  
Vol 76 (3) ◽  
Author(s):  
K.E. Joubert ◽  
M.J. McReynolds ◽  
F. Strydom
Keyword(s):  
Aortic Wall ◽  
Aortic Rupture ◽  
Clinical Signs ◽  
Diagnostic Procedures ◽  
Definitive Diagnosis ◽  
Aortic Aneurysms ◽  
Post Mortem ◽  
Clinical Communication ◽  
Acute Rupture ◽  
Strong Suspicion

Spirocercosis is an emerging disease in veterinary medicine. A strong suspicion of spirocercosis is usually evident after a thorough clinical examination and radiography of the chest has been performed. Lesions seen on radiography include an oesophageal mass, spondylitis and oesophageal air. Unfortunately, radiography is not diagnostic and additional diagnostic procedures are required to confirm the diagnosis. Endoscopy is commonly performed to diagnose the condition. The dog presented in this study had radiographic and clinical signs consistent with spirocercosis and definitive diagnosis was required. Shortly after sedation with medetomidine, the dog went into cardiac arrest and failed to respond to resuscitative measures. On post mortem, the diagnosis of spirocercosis was confirmed and the cause of death was identified as acute aortic rupture. Aortic aneurysms are not an uncommon finding and cause of acute death in dogs with spirocercosis. The acute rupture of the aorta in this case is most probably the result of cardiovascular changes associated with the administration of medetomidine. Medetomidine causes an acute rise in systemic vascular resistance with hypertension. The increase in shear stress across the weakened aortic wall resulted in rupture. Caution with the use of medetomidine in patients with spirocercosis is advised.

scholarly journals Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II–induced aortic aneurysms

2009 ◽  
Vol 15 (6) ◽  
pp. 649-656 ◽  
Author(s):  
Kimio Satoh ◽  
Patrizia Nigro ◽  
Tetsuya Matoba ◽  
Michael R O'Dell ◽  
Zhaoqiang Cui ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Cyclophilin A ◽  
Aortic Aneurysms ◽  
Vascular Oxidative Stress

scholarly journals Systemic delivery of targeted nanotherapeutic reverses angiotensin II-induced abdominal aortic aneurysms in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiaoying Wang ◽  
Vaideesh Parasaram ◽  
Saphala Dhital ◽  
Nasim Nosoudi ◽  
Shahd Hasanain ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cause Of Death ◽  
Targeted Delivery ◽  
Aortic Rupture ◽  
Aortic Aneurysms ◽  
Systemic Delivery ◽  
Effective Treatment Option ◽  
Abdominal Aortic ◽  
Pentagalloyl Glucose ◽  
Elastic Lamina

AbstractAbdominal aortic aneurysm (AAA) disease causes dilation of the aorta, leading to aortic rupture and death if not treated early. It is the 14th leading cause of death in the U.S. and 10th leading cause of death in men over age 55, affecting thousands of patients. Despite the prevalence of AAA, no safe and efficient pharmacotherapies exist for patients. The deterioration of the elastic lamina in the aneurysmal wall is a consistent feature of AAAs, making it an ideal target for delivering drugs to the AAA site. In this research, we conjugated nanoparticles with an elastin antibody that only targets degraded elastin while sparing healthy elastin. After induction of aneurysm by 4-week infusion of angiotensin II (Ang II), two biweekly intravenous injections of pentagalloyl glucose (PGG)-loaded nanoparticles conjugated with elastin antibody delivered the drug to the aneurysm site. We show that targeted delivery of PGG could reverse the aortic dilation, ameliorate the inflammation, restore the elastic lamina, and improve the mechanical properties of the aorta at the AAA site. Therefore, simple iv therapy of PGG loaded nanoparticles can be an effective treatment option for early to middle stage aneurysms to reverse disease progression and return the aorta to normal homeostasis.

scholarly journals Significance of Hemodynamics Biomarkers, Tissue Biomechanics and Numerical Simulations in the Pathogenesis of Ascending Thoracic Aortic Aneurysms

2020 ◽  
Vol 26 ◽  
Author(s):  
Salvatore Campisi ◽  
Raja Jayendiran ◽  
Francesca Condemi ◽  
Magalie Viallon ◽  
Pierre Croisille ◽  
...  
Keyword(s):  
Aortic Wall ◽  
Aortic Rupture ◽  
Scientific Evidence ◽  
Aortic Disease ◽  
Aortic Aneurysms ◽  
Imaging Biomarkers ◽  
Aortic Tissue ◽  
Thoracic Aortic Aneurysms ◽  
Non Invasive ◽  
Valve Function

Abstract:: Guidelines for the treatment of aortic wall diseases are based on measurements of maximum aortic diameter. However aortic rupture or dissections do occur for small aortic diameters. Growing scientific evidence underlines the importance of biomechanics and hemodynamics in aortic disease development and progression. Wall shear stress (WWS) is an important hemodynamics marker which depends on aortic wall morphology and on the aortic valve function. WSS could be helpful to interpret aortic wall remodeling and define personalized risk criteria. The complementarity of Computational Fluid Dynamics and 4D Magnetic Resonance Imaging as tools for WSS assessment is a promising reality. The potentiality of these innovative technologies will provide maps or atlases of hemodynamics biomarkers to predict aortic tissue dysfunction. Ongoing efforts should focus on the correlation between these non-invasive imaging biomarkers and clinico-pathologic situations for the implementation of personalized medicine in current clinical practice.

scholarly journals Reduced Nhe1 (Na + -H + Exchanger-1) Function Protects ApoE-Deficient Mice From Ang II (Angiotensin II)–Induced Abdominal Aortic Aneurysms

Hypertension ◽  
2020 ◽  
Vol 76 (1) ◽  
pp. 87-100
Author(s):  
Cong-Lin Liu ◽  
Xin Liu ◽  
Yunzhe Wang ◽  
Zhiyong Deng ◽  
Tianxiao Liu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cell Apoptosis ◽  
Near Infrared ◽  
Gelatin Zymography ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
Ige Mediated ◽  
Human And Mouse

IgE-mediated activation of Nhe1 (Na + -H + exchanger-1) induces aortic cell extracellular acidification and promotes cell apoptosis. A pH-sensitive probe pHrodo identified acidic regions at positions of macrophage accumulation, IgE expression, and cell apoptosis in human and mouse abdominal aortic aneurysm (AAA) lesions. Ang II (angiotensin II)–induced AAA in Nhe1-insufficient Apoe −/− Nhe1 +/− mice and Apoe −/− Nhe1 +/+ littermates tested Nhe1 activity in experimental AAA, because Nhe1 −/− mice develop ataxia and epileptic-like seizures and die early. Nhe1 insufficiency reduced AAA incidence and size, lesion macrophage and T-cell accumulation, collagen deposition, elastin fragmentation, cell apoptosis, smooth muscle cell loss, and MMP (matrix metalloproteinase) activity. Nhe1 insufficiency also reduced blood pressure and the plasma apoptosis marker TCTP (translationally controlled tumor protein) but did not affect plasma IgE. While pHrodo localized the acidic regions to macrophage clusters, IgE expression, and cell apoptosis in AAA lesions from Apoe −/− Nhe1 +/+ mice, such acidic areas were much smaller in lesions from Apoe −/− Nhe1 +/− mice. Nhe1-FcεR1 colocalization in macrophages from AAA lesions support a role of IgE-mediated Nhe1 activation. Gelatin zymography, immunoblot, and real-time polymerase chain reaction analyses demonstrated that Nhe1 insufficiency reduced the MMP activity, cysteinyl cathepsin expression, IgE-induced apoptosis, and NF-κB activation in macrophages and blocked IgE-induced adhesion molecule expression in endothelial cells. A near-infrared fluorescent probe (LS662) together with fluorescence reflectance imaging of intact aortas showed reduced acidity in AAA lesions from Nhe-1-insufficient mice. This study revealed extracellular acidity at regions rich in macrophages, IgE expression, and cell apoptosis in human and mouse AAA lesions and established a direct role of Nhe1 in AAA pathogenesis.

Sign in / Sign up

Export Citation Format

Share Document