Invited commentary

Abstract

During the past few decades, we have successfully applied minimally invasive endovascular procedures to many vascular diseases, including abdominal aortic aneurysm (AAA). Even after remarkable advancements in this field, we continue to struggle with rare but possible complications as well as with the physical, emotional, and economic burdens of these minimal but still invasive interventions. One of the key objectives of vascular surgery research is to establish effective, noninvasive treatments for vascular disease. Thus, the goal of basic science research for AAA is not only to decipher the complex pathophysiology of the disease process but also to identify modifiable factors so that we can stop the growth and rupture of aortic aneurysm pharmacologically. These endeavors have led us to identify potentially modifiable targets, including proteases, inflammation, angiogenesis, oxidative stress, and macrophage activation. A good example of this translational research is the Non-invasive Treatment for Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT) that is currently ongoing in the United States.1Baxter B.T. Matsumura J. Curci J. McBride R. Blackwelder W.C. Liu X. et al.Non-invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT): design of a phase IIb, placebo-controlled, double-blind, randomized clinical trial of doxycycline for the reduction of growth of small abdominal aortic aneurysm.Contemp Clin Trials. 2016; 48: 91-98Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor that is identified as a master regulator of oxygen homeostasis in mammalian cells. Its fundamental process is largely controlled by its alpha subunit, HIF-1α, which is rapidly degraded by polyubiquitylation and subsequent degradation in normoxia. When oxygen is limited (hypoxia), HIF-1α is no longer degraded and activates survival pathways, including inflammatory responses, energy metabolism, angiogenesis, cell differentiation, and apoptosis pathways.2Liu W. Shen S.M. Zhao X.Y. Chen G.Q. Targeted genes and interacting proteins of hypoxia inducible factor-1.Int J Biochem Mol Biol. 2012; 3: 165-178PubMed Google Scholar In the current issue, Wang et al focused on the role of HIF-1α in AAA. By analyzing human AAA tissue samples and a well-established mouse model of AAA, they have thoroughly tested their hypothesis and demonstrated the involvement of HIF-1α in AAA. More important, the current study has a clear focus on the translational potential of their findings. They tested the effect of pharmacologic inhibition of HIF-1α in the mouse AAA model and showed a suppressive effect with two known inhibitors of HIF-1α, digoxin and 2-methoxyestradiol. One important aspect of the translational research is the feasibility of its approach. Even if the findings are novel and possibly effective, careful consideration of feasibility is crucial for future clinical application. Because the rigorous validation of safety and effectiveness through the multilevel clinical trials is necessary, the economic impact of these processes, especially for a newly identified pharmacologic agent or genetic modification method, might easily delay or even compromise the potential clinical applications. The current study showed the effectiveness of pharmacologic agents that are already used clinically for other indications. Although thorough validation processes will still be required, we hope their findings will lead to new therapies that will benefit patients with AAA in the near future. The opinions or views expressed in this commentary are those of the authors and do not necessarily reflect the opinions or recommendations of the Journal of Vascular Surgery or the Society for Vascular Surgery Hypoxia-inducible factor 1 in clinical and experimental aortic aneurysm diseaseJournal of Vascular SurgeryVol. 68Issue 5PreviewMural angiogenesis and macrophage accumulation are two pathologic hallmarks of abdominal aortic aneurysm (AAA) disease. The heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) is an essential regulator of angiogenesis and macrophage function. In this study, we investigated HIF-1 expression and activity in clinical and experimental AAA disease. Full-Text PDF Open Archive