sirolimus and Dilatation--Pathologic

The purpose of this study was to investigate whether rapamycin inhibits the development of thoracic aortic aneurysm and dissection (TAAD) in mice.. Three-week-old C57BL/6J male mice were fed a normal diet and randomized into a control group (n = 6), β-aminopropionitrile fumarate (BAPN) group (Gp A; n = 15), BAPN plus rapamycin (5 mg) group (Gp B; n = 8), and BAPN plus rapamycin (10 mg) group (Gp C; n = 8). Gp A, Gp B, and Gp C were administered BAPN (1 g/kg/d) for 4 weeks. One week after BAPN administration, Gp B and Gp C were treated with rapamycin (5 mg/kg/d or 10 mg/kg/d) through gavage for 21 days. Thoracic aortas were harvested for Western blot and immunofluorescence staining at day 14 and for morphologic and histologic analyses at day 28.. BAPN treatment induced TAAD formation in mice. The incidence of TAAD in control, Gp A, Gp B, and Gp C mice was 0%, 80%, 25%, and 37.5%, respectively. Smaller thoracic aortic diameters (ascending aorta and arch) were observed in Gp B and Gp C mice than in Gp A mice (Gp B vs Gp A: ascending aorta, ex vivo, 1.07 ± 0.21 mm vs 1.80 ± 0.67 mm [P < .05]; aortic arch, ex vivo, 1.51 ± 0.40 mm vs 2.70 ± 1.06 mm [P < .05]; Gp C vs Gp A: ascending aortas, ex vivo, 1.10 ± 0.33 mm vs 1.80 ± 0.67 mm [P < .05]; aortic arch, ex vivo, 1.55 ± 0.56 mm vs 2.70 ± 1.06 mm [P < .05]). TAAD mice exhibited elastin fragmentation, abundant inflammatory cell infiltration, and significantly increased matrix metalloproteinase production in the aorta, and rapamycin treatment alleviated these changes. The protein levels of p-S6K and p-S6 in TAAD aortic tissues increased significantly, whereas they were suppressed by rapamycin.. Rapamycin suppressed TAAD formation, probably by inhibition of mechanistic target of rapamycin signaling and reduction of inflammatory cell infiltration and matrix metalloproteinase 9 production. Targeting of the mechanistic target of rapamycin signaling pathway using rapamycin may be a favorable modulation for the clinical treatment of TAAD.

Topics: Aminopropionitrile; Animals; Anti-Inflammatory Agents; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Dilatation, Pathologic; Disease Models, Animal; Male; Matrix Metalloproteinase 9; Mice, Inbred C57BL; Phosphorylation; Protein Kinase Inhibitors; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Vascular Remodeling

Topics: Animals; Anti-Inflammatory Agents; Aorta; Aortic Aneurysm, Abdominal; Cytokines; Dilatation, Pathologic; Disease Models, Animal; Disease Progression; Inflammation Mediators; Macrophages; Male; Matrix Metalloproteinases; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Pancreatic Elastase; Phenotype; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Vasoconstriction

Topics: Adult; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Artery Disease; Cytoreduction Surgical Procedures; Dilatation, Pathologic; Drug-Eluting Stents; Humans; Male; Myocardial Infarction; Plaque, Atherosclerotic; Prosthesis Design; Sirolimus

A 55-year-old man had undergone successful percutaneous intervention with a sirolimus-eluting stent, placed in the right coronary artery (2.5 x 33 mm) and distal left circumflex artery (3.0 x 28 mm) without high pressure ballooning. Twelve months later he presented with unstable angina. Angiography revealed two fracture sites on the right coronary artery-deployed stent, with a large aneurysm and an aneurysmal dilatation of the left circumflex artery without stent fracture. Due to the potential risk of aneurysmal rupture, he underwent coronary artery bypass grafting and ligation of the aneurysm.

Topics: Coronary Aneurysm; Coronary Artery Bypass; Coronary Vessels; Dilatation, Pathologic; Drug-Eluting Stents; Humans; Immunosuppressive Agents; Ligation; Male; Middle Aged; Prosthesis Failure; Sirolimus

Topics: Acetylcholine; Coronary Angiography; Coronary Stenosis; Dilatation, Pathologic; Drug Implants; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Sirolimus; Stents; Ultrasonography, Interventional; Vasoconstrictor Agents