title: Inhibition of the mTOR pathway in abdominal aortic aneurysm: implications of smooth muscle cell contractile phenotype, inflammation, and aneurysm expansion.
abstract: The development of effective pharmacological treatment of abdominal aortic aneurysm (AAA) potentially offers great benefit to patients with preaneurysmal aortic dilation by slowing the expansion of aneurysms and reducing the need for surgery. To date, therapeutic targets for slowing aortic dilation have had low efficacy. Thus, in this study, we aim to elucidate possible mechanisms driving aneurysm progression to identify potential targets for pharmacological intervention. We demonstrate that mechanistic target of rapamycin (mTOR) signaling is overactivated in aortic smooth muscle cells (SMCs), which contributes to murine AAA. Rapamycin, a typical mTOR pathway inhibitor, dramatically limits the expansion of the abdominal aorta following intraluminal elastase perfusion. Furthermore, reduction of aortic diameter is achieved by inhibition of the mTOR pathway, which preserves and/or restores the contractile phenotype of SMCs and downregulates macrophage infiltration, matrix metalloproteinase expression, and inflammatory cytokine production. Taken together, these results highlight the important role of the mTOR cascade in aneurysm progression and the potential application of rapamycin as a therapeutic candidate for AAA.NEW & NOTEWORTHYThis study provides novel observations that mechanistic target of rapamycin (mTOR) signaling is overactivated in aortic smooth muscle cells and contributes to mouse abdominal aortic aneurysm (AAA) and that rapamycin protects against aneurysm development. Our data highlight the importance of preservation and/or restoration of the smooth muscle cell contractile phenotype and reduction of inflammation by mTOR inhibition in AAA.
authors.affiliation: Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Guangxin
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Lingfeng
authors.initials: L
authors.lastname: Qin
authors.affiliation: Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut; and.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Caulk
authors.affiliation: Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Chen
authors.affiliation: Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, China; sjxin@cmu.edu.cn.
authors.forename: Shijie
authors.initials: S
authors.lastname: Xin
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D018450:Disease Progression; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D010196:Pancreatic Elastase; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D010196:Pancreatic Elastase; D020782:Matrix Metalloproteinases; D020123:Sirolimus
keywords: abdominal aortic aneurysm; inflammation; mechanistic target of rapamycin; smooth muscle cell