sirolimus and Aortic-Dissection

Aortic dissection (AD) is a serious clinical condition that is unpredictable and frequently results in fatal outcome. Although rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has been reported to be effective in preventing aortopathies in mouse models, its mode of action has yet to be clarified. A mouse AD model that was created by the simultaneous administration of β-aminopropionitrile (BAPN) and angiotensin II (AngII) for 14 days. Rapamycin treatment was started either at day 1 or at day 7 of BAPN+AngII challenge, and continued throughout the observational period. Rapamycin was effective both in preventing AD development and in suppressing AD progression. On the other hand, gefitinib, an inhibitor of growth factor signaling, did not show such a beneficial effect, even though both rapamycin and gefitinib suppressed cell cycle activation in AD. Rapamycin suppressed cell cycle-related genes and induced muscle development-related genes in an AD-related gene expression network without a major impact on inflammation-related genes. Rapamycin augmented the activation of Akt1, Akt2, and Stat3, and maintained the contractile phenotype of aortic smooth muscle cells. These findings indicate that rapamycin was effective both in preventing the development and in suppressing the progression of AD, indicating the importance of the mTOR pathway in AD pathogenesis.

Topics: Aminopropionitrile; Angiotensin II; Animals; Aortic Dissection; Cell Cycle Checkpoints; Cell Line; Disease Models, Animal; Gefitinib; Gene Expression Regulation; Gene Ontology; Gene Regulatory Networks; Male; Mice; Muscle, Smooth, Vascular; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; STAT3 Transcription Factor; TOR Serine-Threonine Kinases

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; Aortic Aneurysm, Thoracic; Aortic Dissection; Dissection; Mice; Sirolimus

Transforming growth factor-beta is a pleiotropic cytokine having diverse roles in vascular morphogenesis, homeostasis, and pathogenesis. Altered activity of and signaling through transforming growth factor-beta has been implicated in thoracic aortic aneurysms and dissections, conditions characterized by a reduced structural integrity of the wall that associates with altered biomechanics and mechanobiology. We quantify and contrast the passive and active biaxial biomechanical properties of the ascending and proximal descending thoracic aorta in a mouse model of altered transforming growth factor-beta signaling, with and without treatment with rapamycin.. Postnatal disruption of the gene (Tgfbr2) that codes the type II transforming growth factor-beta receptor compromises vessel-level contractility and elasticity. Daily treatment with rapamycin, a mechanistic target of rapamycin inhibitor that protects against aortic dissection in these mice, largely preserves or restores the contractile function while the passive properties remain compromised. Importantly, this increased smooth muscle contractility protects an otherwise vulnerable aortic wall from pressure-induced intramural delaminations in vitro.. Notwithstanding the protection afforded by rapamycin in vivo and in vitro, the residual mechanical dysfunctionality suggests a need for caution if rapamycin is to be considered as a potential therapeutic. There is a need for in vivo evaluations in cases of increased hemodynamic loading, including hypertension or extreme exercise, which could unduly stress a structurally vulnerable aortic wall. Given these promising early results, however, such studies are clearly warranted.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Arterial Pressure; Elasticity; Extracellular Matrix; Genetic Predisposition to Disease; Male; Mice, Knockout; Muscle, Smooth, Vascular; Phenotype; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Sirolimus; Stress, Mechanical; TOR Serine-Threonine Kinases; Vascular Stiffness; Vasoconstriction

Topics: Adult; Aortic Dissection; Cesarean Section; Chest Pain; Coronary Aneurysm; Coronary Angiography; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Postpartum Period; Pregnancy; Risk Assessment; Severity of Illness Index; Sirolimus; Tomography, Optical Coherence; Treatment Outcome

Topics: Adrenergic beta-1 Receptor Antagonists; Adult; Anti-Inflammatory Agents, Non-Steroidal; Aortic Dissection; Aspirin; Clopidogrel; Coronary Aneurysm; Coronary Angiography; Drug Therapy, Combination; Drug-Eluting Stents; Electrocardiography; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Metoprolol; Platelet Aggregation Inhibitors; Risk Factors; Sirolimus; Smoking; Ticlopidine; Treatment Outcome

Topics: Antihypertensive Agents; Antineoplastic Agents; Aortic Aneurysm; Aortic Dissection; Carcinoma, Renal Cell; Combined Modality Therapy; Humans; Hypertension; Indoles; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Nephrectomy; Pyrroles; Sirolimus; Sunitinib

Topics: Aged; Angioplasty, Balloon, Coronary; Aortic Dissection; Cardiovascular Agents; Coronary Aneurysm; Coronary Angiography; Drug-Eluting Stents; Humans; Male; Sirolimus; Treatment Outcome; Ultrasonography, Interventional

The use of bare metal stents to treat symptomatic intracranial stenosis may be associated with significant restenosis rates. The advent of drug-eluting stents (DESs) in the coronary circulation has resulted in a reduction of restenosis rates. We report our technical success rate and short-term restenosis rates after stenting with DESs in the intracranial and extracranial circulation.. This study was a retrospective review of the period between April 1, 2004, and April 15, 2006, of 59 patients with 62 symptomatic intracranial or extracranial atherosclerotic lesions at 2 medical centers (University of Pittsburgh and Borgess Medical Center).. The mean age of our cohort was 61+/-12 years. The location of the 62 lesions was as follows: extracranial vertebral artery 31 (50%), intracranial vertebral artery or basilar artery 18 (29%), extracranial internal carotid artery (ICA) near the petrous bone 5 (8%), and intracranial ICA 8 (13%). There were 2 (3%) periprocedural complications: 1 non-flow-limiting dissection and 1 disabling stroke. Fifty vessels were available for follow-up angiography or computed tomography angiography at a median time of 4.0+/-2 months. A total of 2 of 36 extracranial stents (7%) and 1 of 26 intracranial stents (5%) were found to have restenosis > or = 50% at follow-up.. This report demonstrates that DES delivery in the intracranial and extracranial circulation is technically feasible. A small percentage of patients developed short-term in-stent restenosis. Longer-term follow-up is required in the setting of a prospective study to determine the late restenosis rates for DESs in comparison with bare metal stents.

Topics: Anticoagulants; Aortic Dissection; Calcinosis; Carotid Artery, External; Carotid Artery, Internal; Carotid Stenosis; Catheterization; Cohort Studies; Drug Evaluation; Drug Implants; Feasibility Studies; Female; Follow-Up Studies; Humans; Ischemic Attack, Transient; Male; Middle Aged; Organ Specificity; Paclitaxel; Recurrence; Retrospective Studies; Sirolimus; Stents; Stroke; Vertebrobasilar Insufficiency

Immediate and two month angiographic and intravascular ultrasound examination of sirolimus eluting stents deployed for complex coronary dissection is presented. The findings support the hypothesis that this novel treatment option is both effective and safe.

Topics: Aged; Aortic Dissection; Coronary Restenosis; Coronary Stenosis; Female; Humans; Sirolimus; Stents