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SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II–infused mice via activation of iNOS

หน่วยงาน Nanyang Technological University, Singapore

รายละเอียด

ชื่อเรื่อง : SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II–infused mice via activation of iNOS
นักวิจัย : Tan, Chek Kun , Tan, Eddie H. , Luo, Baiwen , Huang, Charlotte Liwen , Loo, Say Chye Joachim , Choong, Cleo Swee Neo , Tan, Nguan Soon
คำค้น : DRNTU::Science::Biological sciences.
หน่วยงาน : Nanyang Technological University, Singapore
ผู้ร่วมงาน : -
ปีพิมพ์ : 2556
อ้างอิง : Tan, C. K., Tan, E. H., Luo, B., Huang, C. L, Loo, S. C. J., Choong, C. S. N., & Tan, N. S. (2013). SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II–infused mice via activation of iNOS. Journal of the american heart association, 2(3). , 2047-9980 , http://hdl.handle.net/10220/10649 , http://dx.doi.org/10.1161/JAHA.113.000269 , 172891
ที่มา : -
ความเชี่ยวชาญ : -
ความสัมพันธ์ : Journal of the American heart association
ขอบเขตของเนื้อหา : -
บทคัดย่อ/คำอธิบาย :

Ninety percent of the patients carrying distinct SMAD3 mutations develop aortic aneurysms and dissections, called aneurysms-osteoarthritis syndrome (AOS). However, the etiology and molecular events downstream of SMAD3 leading to the pathogenesis of aortic aneurysms in these patients still remain elusive. Therefore, we aimed to investigate the vascular phenotypes of SMAD3-knockout mice. Methods and Results‒We showed that angiotensin II-induced vascular inflammation, but not hypertension, leads to aortic aneurysms and dissections, ultimately causing aortic rupture and death in these mice. Lipopolysaccharide-triggered inflammation confirmed that enhanced aortic macrophage recruitment was essential for aneurysm formation in angiotensin II-infused SMAD3-knockout mice. In contrast, phenylephrine-triggered hypertension alone was insufficient to induce aortic aneurysms in these mice. Using uniaxial tensile and contractility tests, we showed that SMAD3 deficiency resulted in defective aortic biomechanics and physiological functions, which caused weakening of the aortic wall and predisposed these mice to aortic aneurysms. Chromatin immunoprecipitation (ChIP) and re-ChIP assays revealed that the underlying mechanism involved an aberrant upregulation of inducible nitric oxide synthase (iNOS)-derived nitric oxide production and an activation of elastolytic matrix metalloproteinases 2 and 9. Administration of clodronate-liposomes and iNOS inhibitor completely abrogated these aortic conditions, thereby identifying iNOS-mediated nitric oxide secretion from macrophages as the downstream event of SMAD3 that drives this severe pathology. Conclusions‒Macrophage depletion and iNOS antagonism represent two promising approaches for preventing aortic aneurysms related to SMAD3 mutations and merit further investigation as adjunctive strategies for the life-threatening manifestations of AOS.

บรรณานุกรม :
Tan, Chek Kun , Tan, Eddie H. , Luo, Baiwen , Huang, Charlotte Liwen , Loo, Say Chye Joachim , Choong, Cleo Swee Neo , Tan, Nguan Soon . (2556). SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II–infused mice via activation of iNOS.
    กรุงเทพมหานคร : Nanyang Technological University, Singapore.
Tan, Chek Kun , Tan, Eddie H. , Luo, Baiwen , Huang, Charlotte Liwen , Loo, Say Chye Joachim , Choong, Cleo Swee Neo , Tan, Nguan Soon . 2556. "SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II–infused mice via activation of iNOS".
    กรุงเทพมหานคร : Nanyang Technological University, Singapore.
Tan, Chek Kun , Tan, Eddie H. , Luo, Baiwen , Huang, Charlotte Liwen , Loo, Say Chye Joachim , Choong, Cleo Swee Neo , Tan, Nguan Soon . "SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II–infused mice via activation of iNOS."
    กรุงเทพมหานคร : Nanyang Technological University, Singapore, 2556. Print.
Tan, Chek Kun , Tan, Eddie H. , Luo, Baiwen , Huang, Charlotte Liwen , Loo, Say Chye Joachim , Choong, Cleo Swee Neo , Tan, Nguan Soon . SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II–infused mice via activation of iNOS. กรุงเทพมหานคร : Nanyang Technological University, Singapore; 2556.