Cariporide, a specific Na/H(+) exchanger 1 blocker, inhibits neointimal proliferation induced by advanced glycation end products in a balloon injury rat model.
OBJECTIVE
The association between diabetes and neointimal expansion after vascular injury has been attributed to the accumulation of advanced glycation end products (AGEs). Here we investigated the inhibitory effect of cariporide, a specific Na(+)/H(+) exchanger 1 blocker, on neointimal proliferation induced by AGEs in a balloon injury model.


METHODS
Expression of cyclooxygenase-2 (COX-2) and matrix metalloproteinase (MMP) was monitored by reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR. The level of reactive oxygen species (ROS) was determined by specific fluorescent probe. The phosphorylation of the nuclear factor-ĸB (NF-ĸB) system was studied by Western blot.


RESULTS
Cariporide significantly suppressed AGE-induced neointimal hyperplasia, vascular smooth muscle cell (VSMC) proliferation, COX-2, MMP-2 and MMP-9 expression. In addition, cariporide decreased AGE-induced ROS, malondiadehyde level and increased the superoxide dismutase and glutathione peroxidase activity. We also found that cariporide blocked AGE-induced NF-ĸB activation and inhibitor-ĸB degradation.


CONCLUSIONS
The results indicated that cariporide inhibited AGE-induced neointimal formation by suppressing the VSMC proliferation and the up-regulation of COX-2, MMP-2, MMP-9 via inhibiting ROS and NF-ĸB activation.
Department of Pharmacy, Gan Su Province Hospital, Lan Zhou, China.
Shujin
S
Wu
Qingshan
Q
Yang
Qianqian
Q
Liu
Tao
T
Song
Shouhong
S
Zhou
Yuhui
Y
Liu
Liying
L
Liu
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D020212:Carotid Artery Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics; D017127:Glycation End Products, Advanced; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D058426:Neointima / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use
D017127:Glycation End Products, Advanced; D006146:Guanidines; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat