Department of Pathology, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
PLoS One. 2013 Nov 29;8(11):e82026. doi: 10.1371/journal.pone.0082026. eCollection 2013.
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.
马凡综合征患者常合并瓣膜病，并可导致心肌病。然而，一些患者在不存在血流动力学显著瓣膜功能障碍的情况下发生心肌病，提示存在疾病进展的其他机制。已有研究表明，血管平滑肌细胞中 LDL 受体相关蛋白-1（Lrp1）的缺失可导致类似于马凡综合征的血管病变，包括平滑肌细胞激活、血管功能障碍和主动脉瘤。本研究使用超声心动图和血压监测，在小鼠模型中确定血管平滑肌中 Lrp1 的失活是否导致心肌病，如果是，其机制是否是瓣膜病的结果。还评估了卡托普利治疗期间的血液动力学变化。在年轻的 Lrp1 敲除小鼠中观察到主动脉根部扩张，且随着年龄的增长而进展，而在野生型同窝仔鼠中未检测到明显的主动脉扩张。Lrp1 敲除小鼠的舒张压较低，脉搏压较高，用卡托普利治疗后可恢复正常。主动脉扩张后发生主动脉瓣关闭不全，随后因瓣膜病导致扩张型心肌病。因此，平滑肌细胞 Lrp1 缺失导致主动脉扩张和关闭不全，继而引起继发性心肌病，卡托普利可改善这种心肌病。这些发现为与血管激活相关的心肌病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。
