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

Author

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

Subjects
Cardiovascular, Rare Diseases, Animals, Aortic Aneurysm, Thoracic, Extracellular Signal-Regulated MAP Kinases, Female, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Marfan Syndrome, Mice, Mice, Inbred C57BL, Pravastatin, Signal Transduction, Marfan syndrome, aneurysm, cell signaling, vascular biology, Cardiorespiratory Medicine and Haematology
Abstract

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 ( GGPT 1 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 ERK 1/2 were significantly reduced in MA -treated mice (4-5 per group). In vitro smooth muscle cell studies confirmed phosphorylated cR af and phosphorylated ERK 1/2 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.

Published
2018

17. Global patterns in genomic diversity underpinning the evolution of insecticide resistance in the aphid crop pest Myzuspersicae

Author

Singh, Kumar Saurabh, Cordeiro, Erick M. G., Troczka, Bartlomiej J., Pym, Adam, Mackisack, Joanna, Mathers, Thomas C., Duarte, Ana, Legeai, Fabrice, Robin, Stéphanie, Bielza, Pablo, Burrack, Hannah J., Charaabi, Kamel, Denholm, Ian, Figueroa, Christian C., ffrench-Constant, Richard H., Jander, Georg, Margaritopoulos, John T., Mazzoni, Emanuele, Nauen, Ralf, Ramírez, Claudio C., Ren, Guangwei, Stepanyan, Ilona, Umina, Paul A., Voronova, Nina V., Vontas, John, Williamson, Martin S., Wilson, Alex C. C., Xi-Wu, Gao, Youn, Young-Nam, Zimmer, Christoph T., Simon, Jean-Christophe, Hayward, Alex, and Bass, Chris

Published
2021
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