Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease (Nov 2018)

Statins Reduce Thoracic Aortic Aneurysm Growth in Marfan Syndrome Mice via Inhibition of the Ras‐Induced ERK (Extracellular Signal‐Regulated Kinase) Signaling Pathway

  • Tetsuya Sato,
  • Mamoru Arakawa,
  • Yasushi Tashima,
  • Eitoshi Tsuboi,
  • Grayson Burdon,
  • Jeffrey Trojan,
  • Tiffany Koyano,
  • Young‐Nam Youn,
  • Kiril Penov,
  • Albert J. Pedroza,
  • Mohammad Shabazzi,
  • Itai Palmon,
  • Marie Noel Nguyen,
  • Andrew J. Connolly,
  • Atsushi Yamaguchi,
  • Michael P. Fischbein

DOI
https://doi.org/10.1161/JAHA.118.008543
Journal volume & issue
Vol. 7, no. 21

Abstract

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Background Statins reduce aneurysm growth in mouse models of Marfan syndrome, although the mechanism is unknown. In addition to reducing cholesterol, statins block farnesylation and geranylgeranylation, which participate in membrane‐bound G‐protein signaling, including Ras. We dissected the prenylation pathway to define the effect of statins on aneurysm reduction. Methods and Results Fbn1C1039G/+ mice were treated with (1) pravastatin (HMG‐CoA [3‐hydroxy‐3‐methylglutaryl coenzyme A] reductase inhibitor), (2) manumycin A (MA; FPT inhibitor), (3) perillyl alcohol (GGPT1 and ‐2 inhibitor), or (4) vehicle control from age 4 to 8 weeks and euthanized at 12 weeks. Histological characterization was performed. Protein analysis was completed on aortic specimens to measure ERK (extracellular signal‐regulated kinase) signaling. In vitro Fbn1C1039G/+ aortic smooth muscle cells were utilized to measure Ras‐dependent ERK signaling and MMP (matrix metalloproteinase) activity. Pravastatin and MA significantly reduced aneurysm growth compared with vehicle control (n=8 per group). In contrast, PA did not significantly decrease aneurysm size. Histology illustrated reduced elastin breakdown in MA‐treated mice compared with vehicle control (n=5 per group). Although elevated in control Marfan mice, both phosphorylated c‐Raf and phosphorylated ERK1/2 were significantly reduced in MA‐treated mice (4–5 per group). In vitro smooth muscle cell studies confirmed phosphorylated cRaf and phosphorylated ERK1/2 signaling was elevated in Fbn1C1039G/+ smooth muscle cells (n=5 per group). Fbn1C1039G/+ smooth muscle cell Ras‐dependent ERK signaling and MMP activity were reduced following MA treatment (n=5 per group). Corroborating in vitro findings, MMP activity was also decreased in pravastatin‐treated mice. Conclusions Aneurysm reduction in Fbn1C1039G/+ mice following pravastatin and MA treatment was associated with a decrease in Ras‐dependent ERK signaling. MMP activity can be reduced by diminishing Ras signaling.

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