Rapamycin Limits the Growth of Established Experimental Abdominal Aortic Aneurysms (original) (raw)
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Dose-dependent inhibition of myointimal hyperplasia by orally administered rapamycin
Annals of vascular surgery, 2004
Myointimal hyperplasia (MIH) after vascular intervention is a major problem. Recent reports describing elimination of within-stent restenosis by means of rapamycin-eluting stents prompted us to examine the effect of systemic oral rapamycin on MIH induced by arterial trauma. We studied the effect of oral rapamycin on MIH after rabbit aorta balloon injury. Thirty-five New Zealand white rabbits (2.5-3 kg) had aortic injury and were given either no rapamycin (control), 0.1 (low dose) rapamycin mg/kg/day, or 0.4 mg/kg/day (high dose). Rapamycin was started 1 week before injury and continued for 3 (4 weeks total) or 6 weeks (7 weeks total) post-injury. Sections were analyzed to measure aortic intima/media area ratios (I:M) at either 3 or 6 weeks. At 3 weeks, the I:M (mean +/- SD) for controls was 0.53 +/- 0.1; for low dose, 0.17 +/- 0.13; and for high dose, 0.24 +/- 0.07 (p < 0.001 vs. control). At 6 weeks, the I:M for controls was 0.52 +/- 0.12; for low dose-4 weeks, 0.29 +/- 0.15; lo...
Atherosclerosis, 2009
Recently, atherosclerosis has been considered to be the result of inflammation. Interestingly, hydroxymethylglutaryl-coenzyme (HMG-Co) A inhibitors (statins), which are clinically used as lipid-lowering agents, have been reported to have various anti-inflammatory effects. As abdominal aortic aneurysm (AAA) is a common degenerative condition associated with atherosclerosis, this study was designed to investigate the inhibitory effect of a statin, atorvastatin, on aneurysm formation apart from its lipid-lowering effect. We employed an elastase-induced rat AAA model, as statins do not lower cholesterol in rats. Mean aneurysm diameter was significantly smaller in the atorvastatin treatment group as compared to control at 4 weeks after surgery (P < 0.05). Interestingly, atorvastatin inhibited the expression of ICAM and MCP-1, followed by the suppression of macrophage recruitment into the aortic wall at 1 week after operation. A significant reduction in MMP-12, but not MMP-2,-3 and-9, expression was also observed by treatment with atorvastatin at 1 week after surgery. In addition, synthesis of collagen and elastin in the vascular wall were significantly increased by atorvastatin. Here, the present study demonstrated a direct effect of atorvastatin to inhibit the progression of aortic aneurysm, independent of its lipid-lowering effect. This study suggests new therapeutic aspects of statins to inhibit the progression of aneurysms.
Journal of Vascular Surgery, 2001
Background: Abdominal aortic aneurysms (AAAs) are associated with chronic inflammation, disruption of medial elastin, and increased local production of elastolytic matrix metalloproteinases (MMPs). The purpose of this study was to investigate how treatment with a hydroxamate-based MMP antagonist (RS 132908) might affect the development of experimental AAAs. Methods: Male Wistar rats underwent intraluminal perfusion of the abdominal aorta with 50 units of porcine pancreatic elastase followed by treatment for 14 days with RS 132908 (100 mg/kg/day subcutaneously; n = 8) or with vehicle alone (n = 6). The external aortic diameter (AD) was measured in millimeters before elastase perfusion and at death, with AAA defined as an increase in AD (∆AD) of at least 100%. Aortic wall elastin and collagen concentrations were measured with assays for desmosine and hydroxyproline, and fixed aortic tissues were examined by light microscopy. Results: AAAs developed in all vehicle-treated rats, with a mean AD (± SE) that increased from 1.60 ± 0.03 mm before perfusion to 5.98 ± 1.02 mm on day 14 (∆AD = 276.4 ± 67.7%). AAAs developed in only five of eight animals (62.5%) after MMP inhibition, with a mean AD that increased from 1.56 ± 0.05 mm to 3.59 ± 0.34 mm (∆AD = 128.1 ± 18.7%; P < .05, vs vehicle). The overall inhibition of aortic dilatation attributable to RS 132908 was 53.6 ± 6.8%. Aortic wall desmosine fell by 85.4% in the vehicle-treated rats (1210.6 ± 87.8 pmol/sample to 176.7 ± 33.4 pmol/sample; P < .05) but only by 65.6% in the animals treated with RS 312908 (416.2 ± 120.5 pmol/sample). In contrast, hydroxyproline was not significantly affected by either elastase perfusion or drug treatment. Microscopic examination revealed the preservation of pericellular elastin and a greater degree of fibrocollagenous wall thickening after MMP inhibition, with no detectable difference in the extent of inflammation.
Pharmacological Approaches to Prevent Abdominal Aortic Aneurysm Enlargement and Rupture
Annals of the New York Academy of Sciences, 2006
Current efforts to limit the mortality from abdominal aortic aneurysm (AAA) are dependent on detection and elective repair. Even by conservative estimates, there are more than 300,000 undetected AAAs in the United States, most of which are small and would not require immediate intervention. Current practice following detection of a small AAA includes education, risk factor management, and serial observation. This approach, based on the statistical probability of death from rupture compared to the morbidity and mortality of repair, can be unsettling to patients and lead to a decline in perceived quality of life. While the pathophysiology of AAA is not completely understood, observations from human tissues and animal studies have identified a number of potential targets for inhibiting aneurysm expansion. It is clear that the prominent inflammatory response identified in aneurysm tissue has a role in promoting aortic expansion. This inflammatory response is thought to account for increased expression of proteolytic enzymes. Recent work has suggested a unifying hypothesis centered on the MAP kinase family affecting both the regulation of matrix synthesis and the expression of proteolytic enzymes. The tetracycline antibiotics and antihypertensive medications that affect the angiotensin-converting enzyme system can inhibit proteolysis. There are adequate preliminary data to support a large prospective randomized trial of doxycycline to prevent aneurysm expansion.
Rapamycin inhibits vascular smooth muscle cell migration
Journal of Clinical Investigation, 1996
Abnormal vascular smooth muscle cell (SMC) proliferation and migration contribute to the development of restenosis after percutaneous transluminal coronary angioplasty and accelerated arteriopathy after cardiac transplantation. Previously, we reported that the macrolide antibiotic rapamycin, but not the related compound FK506, inhibits both human and rat aortic SMC proliferation in vitro by inhibiting cell cycle-dependent kinases and delaying phosphorylation of retinoblastoma protein (Marx, S.O., T. Jayaraman, L.O. Go, and A.R. Marks. 1995. Circ. Res. 362:801). In the present study the effects of rapamycin on SMC migration were assayed in vitro using a modified Boyden chamber and in vivo using a porcine aortic SMC explant model. Pretreatment with rapamycin (2 ng/ml) for 48 h inhibited PDGFinduced migration (PDGF BB homodimer; 20 ng/ml) in cultured rat and human SMC ( n ϭ 10; P Ͻ 0.0001), whereas FK506 had no significant effect on migration. Rapamycin administered orally (1 mg/kg per d for 7 d) significantly inhibited porcine aortic SMC migration compared with control ( n ϭ 15; P Ͻ 0.0001). Thus, in addition to being a potent immunosuppressant and antiproliferative, rapamycin also inhibits SMC migration. ( J. Clin. Invest. 1996. 98:2277-2283.) Key words: immunophilin • restenosis • atherosclerosis • FK506 • FKBP12 M. Poon and S.O. Marx contributed equally to this paper.
A novel chronic advanced stage abdominal aortic aneurysm murine model
Journal of vascular surgery, 2017
The purpose of this study was to establish a reliable, chronic model of abdominal aortic aneurysm (AAA). Wild-type 8-week-old C56BL/6 male mice (n = 120) were equally divided into three groups: (1) BAPN group: 0.2% 3-aminopropionitrile fumarate salt (BAPN) drinking water was provided to mice 2 days before surgery until the end of study. Sham aneurysm induction surgery was performed using 5 μL of heat deactivated elastase. (2) Elastase group: mice were given regular drinking water without BAPN. During aneurysm induction surgery, 5 μL of the active form of elastase (10.3 mg protein/mL, 5.9 U/mg protein) was applied on top of the infrarenal abdominal aorta adventitia for 5 minutes. (3) BAPN+elastase group: mice were given BAPN drinking water and the active form of elastase application, as above. On postoperative days 7, 14, 21, 28, and 100, aortic samples were collected for histology, cytokine array, and gelatin zymography after aortic diameter measurement. Compared with the elastase g...
Arteriosclerosis, Thrombosis, and Vascular Biology, 2013
Objective-Patients with elastin deficiency attributable to gene mutation (supravalvular aortic stenosis) or chromosomal microdeletion (Williams syndrome) are characterized by obstructive arteriopathy resulting from excessive smooth muscle cell (SMC) proliferation, mural expansion, and inadequate vessel size. We investigated whether rapamycin, an inhibitor of the cell growth regulator mammalian target of rapamycin (mTOR) and effective against other SMC proliferative disorders, is of therapeutic benefit in experimental models of elastin deficiency. Approach and Results-As previously reported, Eln −/− mice demonstrated SMC hyperplasia and severe stenosis of the aorta, whereas Eln +/− mice exhibited a smaller diameter aorta with more numerous but thinner elastic lamellae. Increased mTOR signaling was detected in elastin-deficient aortas of newborn pups that was inhibited by maternal administration of rapamycin. mTOR inhibition reduced SMC proliferation and aortic obstruction in Eln −/− pups and prevented medial hyperlamellation in Eln +/− weanlings without compromising aortic size. However, rapamycin did not prolong the survival of Eln −/− pups, and it retarded the somatic growth of juvenile Eln +/− and Eln +/+ mice. In cell cultures, rapamycin inhibited prolonged mTOR activation and enhanced proliferation of SMC derived from patients with supravalvular aortic stenosis and with Williams syndrome. Conclusions-mTOR inhibition may represent a pharmacological strategy to treat diffuse arteriopathy resulting from elastin deficiency.