Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

Chen

et al. 2018

British J Pharmacology

Background and Purpose Abdominal aortic aneurysm (AAA) is a degenerative disease affecting human health, but there are no safe and effective medications for AAA therapy. Cycloastragenol (CAG), derived from Astragali Radix, has various pharmacological effects. However, whether CAG can protect against AAA remains elusive. In this study, we investigated whether CAG has an inhibitory effect on AAA and its related mechanism. Experimental Approach The AAA mouse model was induced by incubating the abdominal aorta with elastase. CAG was administered by gavage at different doses beginning on the same day or 14 days after inducing AAA to explore its preventive or therapeutic effects respectively. The preventive effects of CAG on AAA were verified in another AAA mouse model induced by angiotensin II in ApoE−/− mouse. In vitro experiments were implemented on rat vascular smooth muscle cells (VSMCs) stimulated by TNF‐α. Key Results Compared to the control AAA model group, CAG (125 mg·kg−1 body weight day−1) reduced the incidence of AAA, the dilatation of aorta and elastin degradation in media in both mouse models of AAA. CAG suppressed the inflammation, oxidation, phenotype switch and apoptosis in TNF‐α‐stimulated VSMCs, ameliorated the expression and activity of MMPs and decreased the activation of the ERK/JNK signalling pathway. CAG also inhibited the degradation of elastin in TNF‐α‐stimulated VSMCs. Conclusion and Implications CAG presents protective effects against AAA through down‐regulation of the MAPK signalling pathways and thus attenuates inflammation, oxidation, VSMC phenotype switch and apoptosis and the expression of MMPs as well as increasing elastin biosynthesis.

Section: Discussionmentioning

confidence: 99%

Inhibitory effects of cycloastragenol on abdominal aortic aneurysm and its related mechanisms

Chen

et al. 2018

British J Pharmacology

Journal of Pharmacy and Pharmacology

“…All statins possess a 3‐hydroxy‐3‐methylglutaryl (HMG)–like moiety that has high affinity to HMG‐CoA reductase so sterically block this enzyme thereby inhibiting the production of mevalonate, the first step in the cholesterol biosynthesis . Moreover, statins are used in the treatment of aortic aneurysms, inflammatory colitis, chronic renal disease, nasal polyp disease and chronic lymphocytic leukaemia …”

Section: Introductionmentioning

confidence: 99%

Statins anticancer targeted delivery systems: re-purposing an old molecule

Safwat

Ishak

Hathout

et al. 2017

Objectives Exploring the use of statins as anticancer agents and exploiting different drug delivery systems in targeting these molecules to cancerous sites. Literature review was performed to investigate the use of statins in cancer treatment in one hand, and the different pharmaceutical approaches to deliver and target these drugs to their site of action. Key findings Statins were used for decades as antihypercholestrolemic drugs but recently have been proven potential for broad anticancer activities. The incorporation of statins in nanoparticulate drug delivery systems not only augmented the cytotoxicity of statins but also overcame the resistance of cancerous cells against the traditional chemotherapeutic agents. Statins-loaded nanoparticles could be easily tampered to target the cancerous cells and consequently minimal drug amount could be utilized. Summary This review reconnoitered the different endeavors to incorporate statins in various nanoparticles and summarized the successful effects in targeting cancerous cells and reducing their proliferation without the side effects of commonly used chemotherapeutic agents.

“… 3 Experimental studies using animal models of aortic aneurysms have obtained promising results, and several drugs have been tested in clinical trials. These drugs are categorized as antihypertensive (eg, calcium channel blockers, 4 propranolol, 5 angiotensin-converting enzyme inhibitor [perindopril 6 ], angiotensin receptor blocker [telmisartan 7 ], antibiotics [doxycycline 8 ] antiplatelet agent [ticagrelor 9 ], aldosterone antagonist [ephlerenone 10 ], antilipidemic agent [fenofibrate 11 , 12 ], and anti-inflammatory agents, including anti-IL-1β antibody agent [canakinumab 13 ], mast cell inhibitor [pemirolast 14 ], and immunosuppressant [cyclosporine 15 ]). 16 Unfortunately, favorable results have not been obtained to date.…”

mentioning

confidence: 99%

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

Unno

Tanaka

Yata

et al. 2020

JVS-Vascular Science

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.