K-134, a phosphodiesterase 3 inhibitor, reduces vascular inflammation and hypoxia, and prevents rupture of experimental abdominal aortic aneurysms

Abstract

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.

On vasa vasorum: A history of advances in understanding the vessels of vessels

“…Most recently, the same group reported rapid detection of HIF-1α in medial SMCs and macrophages (within 3 hours after ligation) and, despite an increased number of vasa vasorum, inferred that their hypoperfusion exerts time-dependent effects on aortic wall biology including potential hypoxia-mediated changes in contractile SMCs before onset of AAA ( 156 ). Pretreatment with a phosphodiesterase inhibitor (K-134) was shown to prevent aortic rupture in the hypoperfusion rat model, with noted decreases in vasa vasorum stenosis and medial hypoxia as well as prevention of rupture in elastase- and Ang-II–induced models of AAA ( 157 ). These studies in rat models definitively demonstrate that when vasa vasorum perfusion is physically compromised, wall hypoxia and degeneration ensue, resulting in histological phenomena reminiscent of human aneurysmal pathology.…”