Lowering plasma cholesterol levels halts progression of aortic valve disease in mice.
Lowering plasma cholesterol levels halts progression of aortic valve disease in mice.
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DOI：
10.1161/circulationaha.108.834614
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发表时间：
2009-05-26
期刊：
影响因子：
37.8
通讯作者：
Heistad DD
中科院分区：
文献类型：
--
作者：
Miller JD;Weiss RM;Serrano KM;Brooks RM 2nd;Berry CJ;Zimmerman K;Young SG;Heistad DD
高脂血症的治疗可改善动脉粥样硬化血管的功能和结构。然而，治疗高脂血症对主动脉瓣结构和功能的影响一直存在争议，任何影响都可能被降脂治疗的多效性作用所混淆。本研究的目的是确定在 Reversa 小鼠 (Ldlr−/−/Apob100/100/Mttpfl/fl/Mx1Cre+/+) 中通过“基因开关”降低升高的血浆脂质水平是否可以减少氧化应激、减少促骨信号传导并延缓主动脉瓣疾病的进展。高胆固醇血症 6 个月后，Reversa 小鼠表现出主动脉瓣中超氧化物、脂质沉积、肌成纤维细胞活化、钙沉积和促成骨蛋白表达的增加。通过超声心动图判断，主动脉瓣尖瓣最大分离度没有改变。在另外 6 个月的高胆固醇血症期间，超氧化物水平、瓣膜脂质沉积和肌成纤维细胞活化仍然升高。此外，钙沉积和促成骨基因表达变得更加明显，主动脉瓣尖间距从 0.85 ± 0.04 减小至 0.70 ± 0.04 mm（平均值 ± SE；p < 0.05）。 6月龄时胆固醇水平快速正常化（通过诱导Cre重组酶的表达）使主动脉瓣超氧化物水平正常化，减少肌成纤维细胞活化，减少瓣膜钙负荷，抑制促骨信号级联，并防止主动脉瓣瓣尖分离减少。总的来说，这些数据表明，在患有早期主动脉瓣疾病的高胆固醇血症小鼠中，通过基因失活 mttp 基因来降低血浆脂质水平，可以使氧化应激正常化，减少促骨信号传导，并阻止主动脉瓣狭窄的进展。
Treatment of hyperlipidemia produces functional and structural improvements in atherosclerotic vessels. However, the effects of treating hyperlipidemia on the structure and function of the aortic valve has been controversial, and any effects could be confounded by pleiotropic effects of hypolipidemic treatment. The goal of this study was to determine whether reducing elevated plasma lipid levels with a “genetic switch” in Reversa mice (Ldlr−/−/Apob100/100/Mttpfl/fl/Mx1Cre+/+) reduces oxidative stress, reduces proosteogenic signaling, and retards the progression of aortic valve disease. After 6 months of hypercholesterolemia, Reversa mice exhibited increases in superoxide, lipid deposition, myofibroblast activation, calcium deposition, and pro-osteogenic protein expression in the aortic valve. Maximum aortic valve cusp separation, as judged by echocardiography, was not altered. During an additional 6 months of hypercholesterolemia, superoxide levels, valvular lipid deposition, and myofibroblast activation remained elevated. Furthermore, calcium deposition and pro-osteogenic gene expression became more pronounced and the aortic cusp separation decreased from 0.85 ± 0.04 to 0.70 ± 0.04 mm (mean ± SE; p < 0.05). Rapid normalization of cholesterol levels at 6 months of age (by inducing expression of Cre recombinase) normalized aortic valve superoxide levels, decreased myofibroblast activation, reduced valvular calcium burden, suppressed pro-osteogenic signaling cascades, and prevented the reductions in aortic valve cusp separation. Collectively, these data indicate that reducing plasma lipid levels by genetic inactivation of the mttp gene in hypercholesterolemic mice with early aortic valve disease normalizes oxidative stress, reduces pro-osteogenic signaling, and halts the progression of aortic valve stenosis.