Abstract 18993: Statins Reduce Thoracic Aortic Aneurysm Growth in Marfan Syndrome Mice via Inhibition of the RAS Induced ERK Signaling Pathway
Rationale: Aortic root aneurysm formation and subsequent dissection remain the major cause of death in patients with Marfan syndrome (MFS). HMG-CoA reductase inhibitors (statins) have been reported to reduce aneurysm growth in MFS mouse models, although the mechanism is unknown. In addition to reducing cholesterol, statins block both farneslyation and geranylgeranylation, which participate in membrane bound G-protein signaling, including Ras. The Ras signaling pathway (via ERK) has been shown to be important in MFS aneurysm formation.
Objective: Systematically dissect the prenylation pathway to better define the mechanism behind the beneficial effect of statins on aneurysm reduction in MFS and anticipate this will help elucidate the pathophysiology of aneurysm formation.
Method and results: Fbn1C1039G/+ mice (4 week old) were treated subcutaneously with either (a) Pravastatin (PS) (HMG-Co Reductase inhibitor) (100 mg/kg per day); (b) Manumycin A (MA) (FPT inhibitor) (2.5 mg/kg/every other day); (c) Perillyl Alcohol (PA) (GGPT-1 and -2 inhibitor) (5.0 mg/kg/every other day); or (d) vehicle control Fbn1C1039G/+ mice from age 4-8 weeks. PS and MA significantly reduced aneurysm growth compared to vehicle control (PS:1.57 ± 0.03 mm; MA: 1.55 ± 0.06 mm; vehicle: 1.77 ± 0.05 mm, respectively: p < 0.05). There was no significant difference between PS and MA treated groups. In contrast, PA did not significantly decrease aneurysm size (PA: 1.81 ± 0.06 mm). Elastin staining illustrated reduced elastin breakdown in MA treated mice compared to vehicle control treated groups (MA: 2.2 ± 0.3, vehicle: 4.2 ± 0.6, respectively: p < 0.05). After identifying that the Ras pathway is important, we measured the relative expression of pRaf-1 and pErk1/2, downstream enzymes in transforming growth factor- β (TGF-β) signaling pathway with Western blot. Although elevated in control Marfan mice, both pRaf-1 and pErk 1/2 were significantly reduced in MA treated mice, corresponding with a reduction in aneurysm growth (pRaf-1: MA: 5.1 ± 1.3, vehicle: 8.8 ± 0.8, p = 0.08, pErk1/2: MA: 2.3 ± 0.1, vehicle: 3.2 ± 0.1, p < 0.05, respectively).
Conclusion: Statins reduce aortic aneurysm growth in Fbn1C1039G/+ Marfan mice by decreasing both Ras activation and downstream ERK signaling.
Author Disclosures: M. Arakawa: None. T.K. Koyano: None. T. Sato: None. Y. Youn: None. K. Penov: None. A.J. Pedroza: None. A.J. Connoly: None. H. Adachi: None. M. Fischbein: Research Grant; Modest; Marfan Foundation, Americal Heart Association.
- © 2015 by American Heart Association, Inc.