Invited commentary

Abstract

Autophagy is a tightly regulated, multistep intracellular process by which cytoplasmic components are packed in double-membrane vesicles, delivered to the lysosome, and ultimately degraded for energy production and nutrient recycling to maintain cell survival in unfavorable emergent conditions. Whereas autophagy is critically important for cardiovascular homeostasis, dysregulated autophagy is involved in cardiovascular pathologic processes such as atherosclerosis. Although increased autophagy has been reported in experimental and clinical abdominal aortic aneurysms (AAAs),1Zheng Y.H. Tian C. Meng Y. Qin Y.W. Du Y.H. Du J. et al.Osteopontin stimulates autophagy via integrin/CD44 and p38 MAPK signaling pathways in vascular smooth muscle cells.J Cell Physiol. 2012; 227: 127-135Crossref PubMed Scopus (111) Google Scholar, 2Pan L. Li Y. Jia L. Qin Y. Qi G. Cheng J. et al.Cathepsin S deficiency results in abnormal accumulation of autophagosomes in macrophages and enhances Ang II-induced cardiac inflammation.PLoS One. 2012; 7: e35315Crossref PubMed Scopus (76) Google Scholar the role that autophagy plays in AAAs remains unknown. In this study, Ramadan and colleagues demonstrated that smooth muscle cell (SMC) α-actin-expressing cell-specific ablation of ATG7, a critical autophagy molecule, attenuated cardiac and aortic autophagosome formation, accelerated experimental AAAs and aortic wall inflammation, and led to high mortality due to cardiac rupture in response to a high-dose, long-term angiotensin II infusion. These findings suggest that ATG7-mediated autophagy in SMC α-actin-expressing cells is protective against angiotensin II-induced cardiovascular diseases, such as AAAs. This study raised important questions about the pathogenic and clinical significance of autophagy in cardiovascular conditions, particularly AAAs. It is well known that smoking, hyperlipidemia, and aging promote whereas diabetes attenuates AAA disease. Smoking is associated with increased autophagy,3Li Y. Yu G. Yuan S. Tan C. Xie J. Ding Y. et al.14,15-Epoxyeicosatrienoic acid suppresses cigarette smoke condensate-induced inflammation in lung epithelial cells by inhibiting autophagy.Am J Physiol Lung Cell Mol Physiol. 2016; 311: L970-L980Crossref PubMed Scopus (47) Google Scholar whereas hyperlipidemia, diabetes, and aging are linked to reduced autophagy.4Giricz Z. Koncsos G. Rajtik T. Varga Z.V. Baranyai T. Csonka C. et al.Hypercholesterolemia downregulates autophagy in the rat heart.Lipids Health Dis. 2017; 16: 60Crossref PubMed Scopus (19) Google Scholar, 5Kim J. Cheon H. Jeong Y.T. Quan W. Kim K.H. Cho J.M. et al.Amyloidogenic peptide oligomer accumulation in autophagy-deficient beta cells induces diabetes.J Clin Invest. 2014; 124: 3311-3324Crossref PubMed Scopus (118) Google Scholar, 6LaRocca T.J. Henson G.D. Thorburn A. Sindler A.L. Pierce G.L. Seals D.R. Translational evidence that impaired autophagy contributes to arterial ageing.J Physiol. 2012; 590: 3305-3316Crossref PubMed Scopus (172) Google Scholar Thus, influences of these factors on AAA formation and autophagy are not completely consistent. It warrants further addressing whether, how, and by what mechanisms autophagy-modulating effects of aneurysm risk factors are linked to AAA pathogenesis. Senescence, apoptosis, and synthetic phenotype of SMCs are also pathogenic in AAA disease. Additional studies are needed to determine whether ATG7-mediated basal and induced autophagy prevents SMCs from switching from contractile phenotype toward proaneurysmal pathogenic phenotypes. More important, does pharmacologically augmenting autophagy formation hold translational value for clinical AAA management? In this regard, rapamycin and metformin, two well-known autophagy-enhancing agents, have been shown to suppress experimental AAAs.7Rouer M. Xu B.H. Xuan H.J. Tanaka H. Fujimura N. Glover K.J. et al.Rapamycin limits the growth of established experimental abdominal aortic aneurysms.Eur J Vasc Endovasc Surg. 2014; 47: 493-500Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 8Shirasu T. Koyama H. Miura Y. Hoshina K. Kataoka K. Watanabe T. Nanoparticles effectively target rapamycin delivery to sites of experimental aortic aneurysm in rats.PLoS One. 2016; 11: e0157813Crossref PubMed Scopus (30) Google Scholar, 9Fujimura N. Xiong J. Kettler E.B. Xuan H. Glover K.J. Mell M.W. et al.Metformin treatment status and abdominal aortic aneurysm disease progression.J Vasc Surg. 2016; 64: 46-54.e8Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 10Golledge J. Moxon J. Pinchbeck J. Anderson G. Rowbotham S. Jenkins J. et al.Association between metformin prescription and growth rates of abdominal aortic aneurysms.Br J Surg. 2017; 104: 1486-1493Crossref PubMed Scopus (69) Google Scholar In clinical studies, metformin medication also substantially limited the enlargement of established aortic aneurysms.9Fujimura N. Xiong J. Kettler E.B. Xuan H. Glover K.J. Mell M.W. et al.Metformin treatment status and abdominal aortic aneurysm disease progression.J Vasc Surg. 2016; 64: 46-54.e8Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 10Golledge J. Moxon J. Pinchbeck J. Anderson G. Rowbotham S. Jenkins J. et al.Association between metformin prescription and growth rates of abdominal aortic aneurysms.Br J Surg. 2017; 104: 1486-1493Crossref PubMed Scopus (69) Google Scholar Given the low AAA incidence reported in this study, to validate its therapeutic value, it is crucial to test whether the deficiency of ATG7 in SMC α-actin-expressing cells is protective against AAAs in alternative animal modeling systems, including angiotensin II-induced dissection AAA in spontaneous or high-fat diet-induced hyperlipidemic rodents and elastase infusion-induced nondissection AAA models. Furthermore, the influences of gain and loss of function of autophagy on onset of and further enlargement of established AAAs should be investigated using autophagy-enhancing and autophagy-suppressing agents, respectively, with dose-range experiments. Loss of vascular smooth muscle cell autophagy exacerbates angiotensin II-associated aortic remodelingJournal of Vascular SurgeryVol. 68Issue 3PreviewThe pathophysiologic processes of abdominal aortic aneurysms (AAAs) and atherosclerosis often intersect. Given that anomalies in vascular smooth muscle cell (SMC) autophagy have been noted in models of atherosclerosis, we sought to evaluate the potential role that SMC autophagy may play in the initiation and progression of AAAs. Full-Text PDF Open Archive