OBJECTIVE: Age-dependent increase in vascular smooth muscle cell (VSMC) proliferation is thought to contribute to the pathology of atherosclerotic diseases. In this study, we investigated the role of mitogen-activated protein kinases (MAPKs) on VSMC proliferation and neointimal formation in the context of aging. METHODS AND RESULTS: VSMCs were isolated from the aorta of young and old rabbits. The proliferative index after serum stimulation was significantly increased in old versus young VSMCs. This was associated with a significant and specific age-dependent increase in p44/p42 MAPK activation. Treatment with MEK inhibitor PD98059 successfully inhibited p44/p42 MAPK activities and VSMC proliferation. These results were confirmed in vivo using a model of balloon injury in rabbit iliac arteries. p44/p42 MAPK activities were rapidly induced by angioplasty in young and old animals. However, the levels of p44/p42 MAPK activities achieved in arteries of old rabbits were significantly higher than those of young rabbits. This was associated with a higher cellular proliferative index and a significant increase in neointimal formation in old animals. Local delivery of PD98059 in old rabbits successfully inhibited p44/p42 MAPK activities after angioplasty, which led to a significant reduction in cellular proliferation and neointimal formation in treated animals. CONCLUSIONS: Our study suggests for the first time that increased p44/p42 MAPK activation contributes to augmented VSMC proliferation and neointimal formation with aging. p44/p42 MAPK inhibition could represent a novel therapeutic avenue against atherosclerotic diseases.
OBJECTIVE: Age-dependent increase in vascular smooth muscle cell (VSMC) proliferation is thought to contribute to the pathology of atherosclerotic diseases. In this study, we investigated the role of mitogen-activated protein kinases (MAPKs) on VSMC proliferation and neointimal formation in the context of aging. METHODS AND RESULTS: VSMCs were isolated from the aorta of young and old rabbits. The proliferative index after serum stimulation was significantly increased in old versus young VSMCs. This was associated with a significant and specific age-dependent increase in p44/p42 MAPK activation. Treatment with MEK inhibitor PD98059 successfully inhibited p44/p42 MAPK activities and VSMC proliferation. These results were confirmed in vivo using a model of balloon injury in rabbit iliac arteries. p44/p42 MAPK activities were rapidly induced by angioplasty in young and old animals. However, the levels of p44/p42 MAPK activities achieved in arteries of old rabbits were significantly higher than those of young rabbits. This was associated with a higher cellular proliferative index and a significant increase in neointimal formation in old animals. Local delivery of PD98059 in old rabbits successfully inhibited p44/p42 MAPK activities after angioplasty, which led to a significant reduction in cellular proliferation and neointimal formation in treated animals. CONCLUSIONS: Our study suggests for the first time that increased p44/p42 MAPK activation contributes to augmented VSMC proliferation and neointimal formation with aging. p44/p42 MAPK inhibition could represent a novel therapeutic avenue against atherosclerotic diseases.
Authors: Roger A O'Neill; Arunashree Bhamidipati; Xiahui Bi; Debabrita Deb-Basu; Linda Cahill; Jason Ferrante; Erik Gentalen; Marc Glazer; John Gossett; Kevin Hacker; Celeste Kirby; James Knittle; Robert Loder; Catherine Mastroieni; Michael Maclaren; Thomas Mills; Uyen Nguyen; Nineveh Parker; Audie Rice; David Roach; Daniel Suich; David Voehringer; Karl Voss; Jade Yang; Tom Yang; Peter B Vander Horn Journal: Proc Natl Acad Sci U S A Date: 2006-10-19 Impact factor: 11.205
Authors: Zhong-Dong Shi; Xin-Ying Ji; Danielle E Berardi; Henry Qazi; John M Tarbell Journal: Am J Physiol Heart Circ Physiol Date: 2009-10-30 Impact factor: 4.733
Authors: Scott R Johnstone; Brett M Kroncke; Adam C Straub; Angela K Best; Clarence A Dunn; Leslie A Mitchell; Yelena Peskova; Robert K Nakamoto; Michael Koval; Cecilia W Lo; Paul D Lampe; Linda Columbus; Brant E Isakson Journal: Circ Res Date: 2012-05-31 Impact factor: 17.367
Authors: Judy M Muller-Delp; Kazuki Hotta; Bei Chen; Bradley J Behnke; Joshua J Maraj; Michael D Delp; Tiffani R Lucero; Jeremy A Bramy; David B Alarcon; Hannah E Morgan; Morgan R Cowan; Anthony D Haynes Journal: J Appl Physiol (1985) Date: 2017-10-12