| ǥ :
|
ȣ - 490506 105 |
| Activation of Protein Kinase G (PKG) by Exisulind or OSI461 Reduces Neointimal Hyperplasia after Angioplasty |
| 서울대학교 의과대학 내과학교실¹ ,서울대학교병원 임상의학연구소 심혈관연구실² |
| 김주영¹², 양한모¹ ² ,강현재¹ ² ,구본권¹ ² ,정우영¹ ² ,김효수¹ ² ,김철호¹ ² ,손대원¹ ² ,오병희¹ ² ,박영배¹ ² ,최윤식¹ ² |
Background: After angioplasty, vascular smooth muscle cell(VSMC)s undergo phenotypic and proliferative changes in response to balloon injury. Some studies have demonstrated that neointimal formation after injury is associated with reduced vascular cGMP-dependent Protein Kinase(PKG) in VSMCs. This suggests that PKG occupies a central switching role in the modulation of VSMC phenotype in response to injury. In cancer cells, it is well known that Exisulind and OSI461(potent derivatives of NSAID Sulindac) exert antiproliferative effects through PKG activation. Here, We examined the effects of these drugs on neointimal formation after balloon injury and its action mechanism. Methods: In vitro experiments were performed to evalauate the effects of these drugs on PKG pathways and the viability and migration of VSMCs. In vivo experiment examined the effects of Exisulind, OSI461, and vehicle (n=10/group) on neointimal growth after denudation injury of rat carotid arteries. Treatment was started 3 days before injury and continued for 2weeks after injury. Results: In WST-1 assay and incorporation of BrdU, Exisulind and OSI461 reduced the viable and proliferative cell numbers in a dose-dependent manner. In cell cycle and apoptosis FACS, Exisulind arrested the cell cycle at G1 phase. OSI461, however, arrested the cell cycle at G2 phase and showed more increased apoptotic VSMCs than Exisulind. In Western blot and Kinase assay, Exisulind and OSI 461 increased the level of PKG, MEKK and JNK and reduced the level of β-catenin. Gene transfer of Dominant-Negative(DN) PKG reversed the effects of Exisulind and OSI461 on VSMCs viability and migration. At 2 weeks after injury, Exisulind and OSI461 significantly reduced intima-to-media ratio (vehicle vs Exisulind vs OSI461 0.89±0.16 vs 0.58±0.15 vs 0.49±0.13 p<0.05). Conversely, gene delivery of DN-PKG reversed the inhibition of intimal hyperplasia by these drugs. Conclusion: This study demonstrated that Exisulind and OSI461 are potential inhibitors of neointimal formation by activation of PKG and downregulation of β-catenin. Our findings suggest a potential use for Exisulind and OSI461 in the prevention of restenosis after angioplasty as DES.
|
|
|
|
|
