Pioglitazone attenuates valvular calcification induced by hypercholesterolemia.
Pioglitazone attenuates valvular calcification induced by hypercholesterolemia.
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DOI：
10.1161/atvbaha.112.300794
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Heistad DD
中科院分区：
文献类型：
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作者：
Chu Y;Lund DD;Weiss RM;Brooks RM;Doshi H;Hajj GP;Sigmund CD;Heistad DD
钙化性主动脉瓣狭窄（CAVS）的发生发展涉及多条信号通路，其中过氧化物酶体增殖物激活受体γ（PPARγ）可能参与调控。本研究验证了吡格列酮（一种PPARγ配体）抑制高脂血症小鼠主动脉瓣钙化的假设。对LDLr-/-/ApoB 100/100小鼠喂食含或不含吡格列酮（20 mg/kg/天）的西式饮食6个月。吡格列酮可减弱主动脉瓣的脂质沉积和钙化，但对主动脉无影响。在主动脉瓣中，吡格列酮降低了活性caspase-3和TUNEL染色的水平。吡格列酮显著改善了瓣膜功能（超声心动图）。为了确定基因表达的变化是否与吡格列酮对主动脉瓣与主动脉的差异效应相关，将Reversa小鼠喂食含或不含吡格列酮的西方饮食2个月。在主动脉瓣，而不是主动脉中，西方饮食增加了几个促钙化基因，吡格列酮减弱了这种增加。吡格列酮可减轻高胆固醇血症小鼠主动脉瓣中的脂质沉积、钙化和凋亡，改善主动脉瓣功能，并对主动脉瓣的作用优于主动脉。我们认为吡格列酮可以预防CAVS，吡格列酮或其他PPARγ配体可能有助于早期干预以预防或减缓主动脉瓣狭窄。
Development of calcific aortic valve stenosis (CAVS) involves multiple signaling pathways, which may be modulated by peroxisome proliferator-activated receptor-gamma (PPARγ). This study tested the hypothesis that pioglitazone, a ligand for PPARγ, inhibits calcification of the aortic valve in hypercholesteremic mice. LDLr-/-/ApoB100/100 mice were fed a Western-type diet with or without pioglitazone (20 mg/kg/day) for 6 months. Pioglitazone attenuated lipid deposition and calcification in the aortic valve, but not aorta. In the aortic valve, pioglitazone reduced levels of active caspase-3 and TUNEL staining. Valve function (echocardiography) was significantly improved by pioglitazone. To determine whether changes in gene expression are associated with differential effects of pioglitazone on aortic valves vs. aorta, Reversa mice were fed Western diet with or without pioglitazone for 2 months. Several pro-calcific genes were increased by Western diet, and the increase was attenuated by pioglitazone, in aortic valve, but not aorta. Pioglitazone attenuates lipid deposition, calcification, and apoptosis in aortic valves of hypercholesterolemic mice, improves aortic valve function, and exhibits preferential effects on aortic valves vs. aorta. We suggest that pioglitazone protects against CAVS, and pioglitazone or other PPARγ ligands may be useful for early intervention to prevent or slow stenosis of aortic valves.