Institut de Myologie, Inserm, U974, F-75013, Paris, France; Institut de Myologie, IFR14, Université Pierre et Marie Curie, UMR-S974, UM76, CNRS, UMR7215, F-75013, Paris, France.
Fundam Clin Pharmacol. 2014 Jun;28(3):249-56. doi: 10.1111/fcp.12031. Epub 2013 Apr 18.
This research investigated the impact of angiotensin AT1 receptor (Agtr1) blockade on left ventricular (LV) hypertrophy in a mouse model of human hypertrophic cardiomyopathy (HCM), which carries one functional allele of Mybpc3 gene coding cardiac myosin-binding protein C (cMyBP-C). Five-month-old heterozygous cMyBP-C knockout (Het-KO) and wild-type mice were treated with irbesartan (50 mg/kg/day) or vehicle for 8 weeks. Arterial blood pressure was measured by tail cuff plethysmography. LV dimension and function were accessed by echocardiography. Myocardial gene expression was evaluated using RT-qPCR. Compared with wild-type littermates, Het-KO mice had greater LV/body weight ratio (4.0 ± 0.1 vs. 3.3 ± 0.1 mg/g, P < 0.001), thicker interventricular septal wall (0.70 ± 0.02 vs. 0.65 ± 0.01 mm, P < 0.02), lower Mybpc3 mRNA level (-43%, P < 0.02), higher four-and-a-half LIM domains 1 (Fhl1, +110%, P < 0.01), and angiotensin-converting enzyme 1 (Ace1, +67%, P < 0.05), but unchanged Agtr1 mRNA levels in the septum. Treatment with irbesartan had no effect in wild-type mice but abolished septum-predominant LV hypertrophy and Fhl1 upregulation without changes in Ace1 but with an increased Agtr1 (+42%) in Het-KO mice. Thus, septum-predominant LV hypertrophy in Het-KO mice is combined with higher Fhl1 expression, which can be abolished by AT1 receptor blockade, indicating a role of the renin-angiotensin system and Fhl1 in cMyBP-C-related HCM.
本研究旨在探讨血管紧张素 AT1 受体（Agtr1）阻断对携带心肌肌球蛋白结合蛋白 C（cMyBP-C）功能等位基因的人类肥厚型心肌病（HCM）小鼠模型左心室（LV）肥厚的影响。将 5 月龄杂合型 cMyBP-C 敲除（Het-KO）和野生型小鼠分别用厄贝沙坦（50mg/kg/天）或载体处理 8 周。采用尾套测压法测量动脉血压。通过超声心动图评估 LV 大小和功能。采用 RT-qPCR 评估心肌基因表达。与野生型同窝仔鼠相比，Het-KO 小鼠的 LV/体重比（4.0±0.1 比 3.3±0.1mg/g，P<0.001）更大，室间隔壁更厚（0.70±0.02 比 0.65±0.01mm，P<0.02），Mybpc3 mRNA 水平更低（-43%，P<0.02），四个半 LIM 结构域 1（Fhl1，+110%，P<0.01）和血管紧张素转换酶 1（Ace1，+67%，P<0.05）更高，但室间隔的 Agtr1 mRNA 水平没有变化。厄贝沙坦处理对野生型小鼠没有影响，但消除了 Het-KO 小鼠以室间隔为主的 LV 肥厚和 Fhl1 的上调，而 Ace1 没有变化，但 Agtr1 增加（+42%）。因此，Het-KO 小鼠以室间隔为主的 LV 肥厚与更高的 Fhl1 表达有关，而 AT1 受体阻断可消除这种表达，提示肾素-血管紧张素系统和 Fhl1 在 cMyBP-C 相关 HCM 中的作用。
