TY - JOUR
T1 - Tolvaptan reduces angiotensin II-induced experimental abdominal aortic aneurysm and dissection
AU - Wu, Tao Cheng
AU - Chang, Wei Hung
AU - Lu, Hsin Ying
AU - Shih, Chun Che
N1 - Funding Information:
This study was partially funded by research grants from the Ministry of Science and Technology of Taiwan ( MOST 109-2314-B-075-092-MY3 ) and Taipei Veterans General Hospital ( V105D1-002-MY3-1 , V105D1-002-MY3-2 and V105D1-002-MY3-3 ) to Tao-Cheng Wu. These funding agencies had no influence on the study design, data analysis, or preparation of the manuscript.
Funding Information:
This study was partially funded by research grants from the Ministry of Science and Technology of Taiwan (MOST 109-2314-B-075-092-MY3) and Taipei Veterans General Hospital (V105D1-002-MY3-1, V105D1-002-MY3-2 and V105D1-002-MY3-3) to Tao-Cheng Wu. These funding agencies had no influence on the study design, data analysis, or preparation of the manuscript.This work was assisted in part by the Division of Experimental Surgery of the Department of Surgery, Taipei Veterans General Hospital.
Publisher Copyright:
© 2022
PY - 2022/6
Y1 - 2022/6
N2 - Tolvaptan has been approved for the treatment of autosomal dominant polycystic kidney disease and heart failure. However, the role of tolvaptan in patients with abdominal aortic aneurysm (AAA) has not been examined. Human aortic smooth muscle cells (HASMCs) were used as the in vitro model. Via Ang II infusion, experimental AAAs were induced in Apo-E knockout mice. In vitro study showed that tolvaptan suppressed matrix metalloproteinase (MMP) expressions (MMP-2 and MMP-9) and apoptosis in Ang II-stimulated HASMCs. In the Apo-E knockout mice with Ang II-induced AAA, the animals exhibited AAA formation with elastic lamina degradation, dilatation of the suprarenal aorta, increased macrophage infiltration and higher expressions of MMPs. Treatment with a high dose of tolvaptan prevented experimental AAA formation while preserving the elastic lamina structure, reducing inflammatory macrophages, and inhibiting gelatinolytic activity, MMP expressions and apoptosis of SMCs in aorta tissue. Specifically, tolvaptan reduced the expression of receptor-interacting protein kinase 3 (RIP3) and decreased apoptosis of SMCs. Our data demonstrated that tolvaptan reduces experimental AAA formation and dissection by inhibiting destruction of the aortic structure integrity and reducing inflammatory macrophage infiltration, MMP-2 and MMP-9 expressions, and apoptosis of vascular SMCs, indicating tolvaptan may have therapeutic potential for AAA and dissection.
AB - Tolvaptan has been approved for the treatment of autosomal dominant polycystic kidney disease and heart failure. However, the role of tolvaptan in patients with abdominal aortic aneurysm (AAA) has not been examined. Human aortic smooth muscle cells (HASMCs) were used as the in vitro model. Via Ang II infusion, experimental AAAs were induced in Apo-E knockout mice. In vitro study showed that tolvaptan suppressed matrix metalloproteinase (MMP) expressions (MMP-2 and MMP-9) and apoptosis in Ang II-stimulated HASMCs. In the Apo-E knockout mice with Ang II-induced AAA, the animals exhibited AAA formation with elastic lamina degradation, dilatation of the suprarenal aorta, increased macrophage infiltration and higher expressions of MMPs. Treatment with a high dose of tolvaptan prevented experimental AAA formation while preserving the elastic lamina structure, reducing inflammatory macrophages, and inhibiting gelatinolytic activity, MMP expressions and apoptosis of SMCs in aorta tissue. Specifically, tolvaptan reduced the expression of receptor-interacting protein kinase 3 (RIP3) and decreased apoptosis of SMCs. Our data demonstrated that tolvaptan reduces experimental AAA formation and dissection by inhibiting destruction of the aortic structure integrity and reducing inflammatory macrophage infiltration, MMP-2 and MMP-9 expressions, and apoptosis of vascular SMCs, indicating tolvaptan may have therapeutic potential for AAA and dissection.
KW - Abdominal aortic aneurysm and dissection
KW - Tolvaptan
KW - Vasopressin type 2 antagonist
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U2 - 10.1016/j.vph.2022.106973
DO - 10.1016/j.vph.2022.106973
M3 - Article
C2 - 35227907
AN - SCOPUS:85125621947
SN - 1537-1891
VL - 144
JO - Vascular Pharmacology
JF - Vascular Pharmacology
M1 - 106973
ER -