Pioglitazone attenuates progression of aortic valve calcification via down-regulating receptor for advanced glycation end products.
Receptor for advanced glycation end products (RAGE) is associated with inflammation and the progression of cardiovascular diseases. The current study tested the hypothesis that RAGE is involved in the pathogenesis of aortic valve (AV) calcification. Pioglitazone attenuated AV calcification in experimental hypercholesterolemic rabbits via down-regulation of RAGE. Male New Zealand rabbits weighing 2.5-3.0 kg were randomly divided into three groups: control group, high cholesterol + vitamin D(2) (HC + vitD(2)) group and HC + vitD(2) supplemented with pioglitazone group. Compared with HC + vitD(2) group, pioglitazone significantly inhibited the progression of AV calcification assessed by echocardiography. HC + vitD(2) diet markedly increased RAGE expression, oxidative stress, inflammatory cells infiltration and osteopontin expression. These changes were also significantly attenuated by administration of pioglitazone. Cultured porcine aortic valve interstitial cells (VICs) were used as in vitro model. We found that advanced glycation end products of bovine serum albumin markedly increased the expression of RAGE, induced high levels of production of pro-inflammatory cytokines and promoted osteoblastic differentiation of VICs. However, these effects were found to be remarkably suppressed by siRNA silencing of RAGE and pioglitazone as well. Our data provide evidence that RAGE activation-induced inflammation promotes AV calcification in hypercholesterolemic rabbits, which can be attenuated by pioglitazone treatment. This beneficial effect is associated with remarkable down-regulation of RAGE expression.
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Fei
F
Li
Zhejun
Z
Cai
Fang
F
Chen
Xucong
X
Shi
Qiao
Q
Zhang
Si
S
Chen
Jiawei
J
Shi
Dao Wen
DW
Wang
Nianguo
N
Dong
D000818:Animals; D001021:Aortic Valve / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001024:Aortic Valve Stenosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002114:Calcinosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004452:Echocardiography; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008297:Male; D010006:Osteoblasts / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists; D000077205:Pioglitazone; D011817:Rabbits; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D045162:Thiazolidinediones; D000077205:Pioglitazone