K-134, a phosphodiesterase 3 inhibitor, reduces vascular inflammation and hypoxia, and prevents rupture of experimental abdominal aortic aneurysms
Objective: Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease, which frequently results in fatal rupture; however, no pharmacologic treatment exists to inhibit AAA growth and prevent rupture. In this study, we investigated whether K-134, a novel phosphodiesterase 3 inhibitor, could li...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-01-01
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| Series: | JVS - Vascular Science |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666350320300262 |
| _version_ | 1818644208041328640 |
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| author | Naoki Unno, MD Hiroki Tanaka, MD, PhD Tatsuro Yata, MD, PhD Takafumi Kayama, MD Yuta Yamanaka, MD Hajime Tsuyuki, MD Masaki Sano, MD, PhD Kazunori Inuzuka, MD, PhD Ena Naruse, CVT Hiroya Takeuchi, MD, PhD |
| author_facet | Naoki Unno, MD Hiroki Tanaka, MD, PhD Tatsuro Yata, MD, PhD Takafumi Kayama, MD Yuta Yamanaka, MD Hajime Tsuyuki, MD Masaki Sano, MD, PhD Kazunori Inuzuka, MD, PhD Ena Naruse, CVT Hiroya Takeuchi, MD, PhD |
| author_sort | Naoki Unno, MD |
| collection | DOAJ |
| description | Objective: Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease, which frequently results in fatal rupture; however, no pharmacologic treatment exists to inhibit AAA growth and prevent rupture. In this study, we investigated whether K-134, a novel phosphodiesterase 3 inhibitor, could limit the progression and rupture of AAA using multiple experimental models. Methods: A hypoperfusion-induced AAA rat model was developed by inserting of a small catheter and via tight ligation of the infrarenal aorta. Rats were fed with a 0.15% K-134-containing diet (K-134(+) group) or a normal diet (K-134(-) group) from 7 days before the experiment to 28 days after model creation (pretreatment protocol). After the administration period, elastin fragmentation, macrophage infiltration, reactive oxygen species expression, matrix metalloproteinase levels, aneurysmal tissue hypoxia, and adventitial vasa vasorum (VV) stenosis were assessed. In the delayed treatment protocol, rats with AAA >3 mm were randomly divided to K-134(+) or K-134(-) group 7 days after model creation, and the effect of K-134 on suppressing preexisting AAA was examined. Further, elastase-induced rat model and angiotensin II-infused ApoE-/- mouse model were also used to examine the ability of K-134 to prevent rupture. Results: K-134 prevented AAA rupture and significantly improved survival in the pretreatment protocol (P < .01). In the K-134(+) group, elastin degeneration was prevented; macrophage infiltration and reactive oxygen species production were significantly decreased. At 14 days, the enzymatic activity of matrix metalloproteinase-9 was significantly decreased. Further, K-134 inhibited intimal hyperplasia and VV stenosis. Expressions of hypoxic markers, hypoxia-inducible factor-1α, and pimonidazole, in the aneurysmal wall were also attenuated. In the delayed treatment protocol, K-134 also improved survival of rats with preexisting AAA. Similarly, in the elastase-induced rat model and angiotensin II-infused ApoE-/- mouse model, K-134 inhibited rupture and significantly improved survival (P < .01). Conclusions: K-134 prevented the rupture of AAA and improved survival through suppressing inflammatory reaction. The inhibition of intimal hyperplasia in the adventitial VV may be associated with reduced hypoxia in the aneurysmal tissue. (JVS–Vascular Science 2020;1:219-32.) Clinical Relevance: This study shows that K-134, a novel phosphodiesterase 3 inhibitor, suppressed abdominal aortic aneurysm (AAA) rupture. Considering that K-134 had already undergone a phase Ⅱ study in the United States for claudication in peripheral artery occlusive disease patients with good tolerance, K-134 may become a promising new therapeutic option for AAAs and could undergo clinical trials for patients with small AAA. |
| first_indexed | 2024-12-17T00:11:11Z |
| format | Article |
| id | doaj.art-31bb12671e7748ee980cedb9072baa2f |
| institution | Directory Open Access Journal |
| issn | 2666-3503 |
| language | English |
| last_indexed | 2024-12-17T00:11:11Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JVS - Vascular Science |
| spelling | doaj.art-31bb12671e7748ee980cedb9072baa2f2022-12-21T22:10:50ZengElsevierJVS - Vascular Science2666-35032020-01-011219232K-134, a phosphodiesterase 3 inhibitor, reduces vascular inflammation and hypoxia, and prevents rupture of experimental abdominal aortic aneurysmsNaoki Unno, MD0Hiroki Tanaka, MD, PhD1Tatsuro Yata, MD, PhD2Takafumi Kayama, MD3Yuta Yamanaka, MD4Hajime Tsuyuki, MD5Masaki Sano, MD, PhD6Kazunori Inuzuka, MD, PhD7Ena Naruse, CVT8Hiroya Takeuchi, MD, PhD9Division of Vascular Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan; Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan; Division of Vascular Surgery, Hamamatsu Medical Center, Hamamatsu, Japan; Correspondence: Naoki Unno, MD, PhD, Hospital Director, Hamamatsu Medical Center, Professor, Division of Vascular Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, JapanDivision of Vascular Surgery, Hamamatsu University School of Medicine, Hamamatsu, JapanDivision of Vascular Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan; Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, JapanDivision of Vascular Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan; Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, JapanDivision of Vascular Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan; Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, JapanDivision of Vascular Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan; Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, JapanDivision of Vascular Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan; Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, JapanDivision of Vascular Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan; Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, JapanDivision of Vascular Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan; Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, JapanSecond Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, JapanObjective: Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease, which frequently results in fatal rupture; however, no pharmacologic treatment exists to inhibit AAA growth and prevent rupture. In this study, we investigated whether K-134, a novel phosphodiesterase 3 inhibitor, could limit the progression and rupture of AAA using multiple experimental models. Methods: A hypoperfusion-induced AAA rat model was developed by inserting of a small catheter and via tight ligation of the infrarenal aorta. Rats were fed with a 0.15% K-134-containing diet (K-134(+) group) or a normal diet (K-134(-) group) from 7 days before the experiment to 28 days after model creation (pretreatment protocol). After the administration period, elastin fragmentation, macrophage infiltration, reactive oxygen species expression, matrix metalloproteinase levels, aneurysmal tissue hypoxia, and adventitial vasa vasorum (VV) stenosis were assessed. In the delayed treatment protocol, rats with AAA >3 mm were randomly divided to K-134(+) or K-134(-) group 7 days after model creation, and the effect of K-134 on suppressing preexisting AAA was examined. Further, elastase-induced rat model and angiotensin II-infused ApoE-/- mouse model were also used to examine the ability of K-134 to prevent rupture. Results: K-134 prevented AAA rupture and significantly improved survival in the pretreatment protocol (P < .01). In the K-134(+) group, elastin degeneration was prevented; macrophage infiltration and reactive oxygen species production were significantly decreased. At 14 days, the enzymatic activity of matrix metalloproteinase-9 was significantly decreased. Further, K-134 inhibited intimal hyperplasia and VV stenosis. Expressions of hypoxic markers, hypoxia-inducible factor-1α, and pimonidazole, in the aneurysmal wall were also attenuated. In the delayed treatment protocol, K-134 also improved survival of rats with preexisting AAA. Similarly, in the elastase-induced rat model and angiotensin II-infused ApoE-/- mouse model, K-134 inhibited rupture and significantly improved survival (P < .01). Conclusions: K-134 prevented the rupture of AAA and improved survival through suppressing inflammatory reaction. The inhibition of intimal hyperplasia in the adventitial VV may be associated with reduced hypoxia in the aneurysmal tissue. (JVS–Vascular Science 2020;1:219-32.) Clinical Relevance: This study shows that K-134, a novel phosphodiesterase 3 inhibitor, suppressed abdominal aortic aneurysm (AAA) rupture. Considering that K-134 had already undergone a phase Ⅱ study in the United States for claudication in peripheral artery occlusive disease patients with good tolerance, K-134 may become a promising new therapeutic option for AAAs and could undergo clinical trials for patients with small AAA.http://www.sciencedirect.com/science/article/pii/S2666350320300262Abdominal aortic aneurysmPhosphodiesterase 3 inhibitorHypoxiaAtherosclerosisK-134 |
| spellingShingle | Naoki Unno, MD Hiroki Tanaka, MD, PhD Tatsuro Yata, MD, PhD Takafumi Kayama, MD Yuta Yamanaka, MD Hajime Tsuyuki, MD Masaki Sano, MD, PhD Kazunori Inuzuka, MD, PhD Ena Naruse, CVT Hiroya Takeuchi, MD, PhD K-134, a phosphodiesterase 3 inhibitor, reduces vascular inflammation and hypoxia, and prevents rupture of experimental abdominal aortic aneurysms JVS - Vascular Science Abdominal aortic aneurysm Phosphodiesterase 3 inhibitor Hypoxia Atherosclerosis K-134 |
| title | K-134, a phosphodiesterase 3 inhibitor, reduces vascular inflammation and hypoxia, and prevents rupture of experimental abdominal aortic aneurysms |
| title_full | K-134, a phosphodiesterase 3 inhibitor, reduces vascular inflammation and hypoxia, and prevents rupture of experimental abdominal aortic aneurysms |
| title_fullStr | K-134, a phosphodiesterase 3 inhibitor, reduces vascular inflammation and hypoxia, and prevents rupture of experimental abdominal aortic aneurysms |
| title_full_unstemmed | K-134, a phosphodiesterase 3 inhibitor, reduces vascular inflammation and hypoxia, and prevents rupture of experimental abdominal aortic aneurysms |
| title_short | K-134, a phosphodiesterase 3 inhibitor, reduces vascular inflammation and hypoxia, and prevents rupture of experimental abdominal aortic aneurysms |
| title_sort | k 134 a phosphodiesterase 3 inhibitor reduces vascular inflammation and hypoxia and prevents rupture of experimental abdominal aortic aneurysms |
| topic | Abdominal aortic aneurysm Phosphodiesterase 3 inhibitor Hypoxia Atherosclerosis K-134 |
| url | http://www.sciencedirect.com/science/article/pii/S2666350320300262 |
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