title: Microtubule stabilization attenuates vascular calcification through the inhibition of osteogenic signaling and matrix vesicle release.
abstract: Vascular calcification is a strong predictor of cardiovascular morbidity and mortality, especially in individuals with chronic kidney disease or diabetes. The mechanism of vascular calcification has remained unclear, however, and no effective therapy is currently available. Our study was aimed at identifying the role of dynamic remodeling of microtubule cytoskeletons in hyperphosphatemia-induced vascular calcification. Exposure of primary cultures of mouse vascular smooth muscle cells (VSMCs) to inorganic phosphate (Pi) elicited ectopic calcification that was associated with changes in tubulin dynamics, induction of osteogenic signaling, and increased release of matrix vesicles. A microtubule depolymerizing agent enhanced Pi-dependent calcification, whereas microtubule stabilization by paclitaxel suppressed calcification both in VSMC cultures and in an ex vivo culture system for the mouse aorta. The inhibition of Pi-stimulated calcification by paclitaxel was associated with down-regulation of osteogenic signal and attenuation of matrix vesicle release. Our results indicate that microtubule plays a central role in vascular calcification, and that microtubule stabilization represents a potential new approach to the treatment of this condition.
authors.affiliation: Department of Microbiology and Aging-associated Vascular Disease Research Center, Yeungnam University College of Medicine, Daegu 705-717, Republic of Korea.
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Aging-associated Vascular Disease Research Center, Yeungnam University College of Medicine, Daegu 705-717, Republic of Korea.
authors.forename: Hyunsoo
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Aging-associated Vascular Disease Research Center, Yeungnam University College of Medicine, Daegu 705-717, Republic of Korea. Electronic address: dwjeong@ynu.ac.kr.
authors.forename: Daewon
authors.initials: D
authors.lastname: Jeong
mesh_terms: D000818:Animals; D002114:Calcinosis / Q000517:prevention & control; D003599:Cytoskeleton / Q000502:physiology; D008297:Male; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology; D010710:Phosphates / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation; D061205:Vascular Calcification / Q000517:prevention & control*
chemical_list: D010710:Phosphates; D017239:Paclitaxel
keywords: Ectopic calcification; Hyperphosphatemia; Microtubule; Vascular smooth muscle cell