Smooth muscle LDL receptor-related protein-1 deletion induces aortic insufficiency and promotes vascular cardiomyopathy in mice.
Smooth muscle LDL receptor-related protein-1 deletion induces aortic insufficiency and promotes vascular cardiomyopathy in mice.
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DOI：
10.1371/journal.pone.0082026
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Rubinstein J
中科院分区：
文献类型：
--
作者：
Basford JE;Koch S;Anjak A;Singh VP;Krause EG;Robbins N;Weintraub NL;Hui DY;Rubinstein J
瓣膜病在马凡氏综合征患者中很常见，可导致心肌病。然而，一些患者在没有明显的血流动力学瓣膜功能障碍的情况下发展为心肌病，这表明疾病进展的其他机制。平滑肌细胞中LDL受体相关蛋白-1 （Lrp1）的破坏已被证明可引起类似马凡氏综合征的血管病变，包括平滑肌细胞的激活、血管功能障碍和主动脉瘤。本研究在小鼠模型中采用超声心动图和血压监测来确定血管平滑肌中Lrp1失活是否导致心肌病，如果是，其机制是否是瓣膜疾病的结果。卡托普利治疗期间的血流动力学变化也被评估。在lrp1基因敲除的幼鼠中观察到主动脉根部扩张，并随着年龄的增长而发展，而在野生型幼鼠中没有发现明显的主动脉扩张。lrp1基因敲除小鼠舒张压降低，脉压升高，经卡托普利治疗后恢复正常。主动脉扩张之后是主动脉功能不全和瓣膜疾病引起的扩张性心肌病。因此，平滑肌细胞Lrp1缺乏导致主动脉扩张和功能不全，导致继发性心肌病，卡托普利可改善这种情况。这些发现为心肌病与血管激活相关的机制提供了新的见解，并提供了一种新的瓣膜性心肌病模型。
Valvular disease is common in patients with Marfan syndrome and can lead to cardiomyopathy. However, some patients develop cardiomyopathy in the absence of hemodynamically significant valve dysfunction, suggesting alternative mechanisms of disease progression. Disruption of LDL receptor-related protein-1 (Lrp1) in smooth muscle cells has been shown to cause vascular pathologies similar to Marfan syndrome, with activation of smooth muscle cells, vascular dysfunction and aortic aneurysms. This study used echocardiography and blood pressure monitoring in mouse models to determine whether inactivation of Lrp1 in vascular smooth muscle leads to cardiomyopathy, and if so, whether the mechanism is a consequence of valvular disease. Hemodynamic changes during treatment with captopril were also assessed. Dilation of aortic roots was observed in young Lrp1-knockout mice and progressed as they aged, whereas no significant aortic dilation was detected in wild type littermates. Diastolic blood pressure was lower and pulse pressure higher in Lrp1-knockout mice, which was normalized by treatment with captopril. Aortic dilation was followed by development of aortic insufficiency and subsequent dilated cardiomyopathy due to valvular disease. Thus, smooth muscle cell Lrp1 deficiency results in aortic dilation and insufficiency that causes secondary cardiomyopathy that can be improved by captopril. These findings provide novel insights into mechanisms of cardiomyopathy associated with vascular activation and offer a new model of valvular cardiomyopathy.
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影响因子：
37.8
作者：
Mitchell GF;Hwang SJ;Vasan RS;Larson MG;Pencina MJ;Hamburg NM;Vita JA;Levy D;Benjamin EJ
通讯作者：
Benjamin EJ
DOI：
10.1126/science.1192149
发表时间：
2011-04-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Holm TM;Habashi JP;Doyle JJ;Bedja D;Chen Y;van Erp C;Lindsay ME;Kim D;Schoenhoff F;Cohn RD;Loeys BL;Thomas CJ;Patnaik S;Marugan JJ;Judge DP;Dietz HC
通讯作者：
Dietz HC
影响因子：
3.7
作者：
Boucher, Philippe;Li, Wei-Ping;Matz, Rachel L.;Takayama, Yoshiharu;Auwerx, Johan;Anderson, Richard G. W.;Herz, Joachim
通讯作者：
Herz, Joachim
影响因子：
9.8
作者：
Bown, Matthew J.;Jones, Gregory T.;Samani, Nilesh J.
通讯作者：
Samani, Nilesh J.
影响因子：
2.8
作者：
Meijboom, LJ;Timmermans, J;Mulder, BJM
通讯作者：
Mulder, BJM