AT1 blockade abolishes left ventricular hypertrophy in heterozygous cMyBP-C null mice: role of FHL1

作者：Vignier Nicolas; Le Corvoisier Philippe; Blard Charlotte; Sambin Lucien; Azibani Feriel; Schlossarek Saskia; Delcayre Claude; Carrier Lucie; Hittinger Luc; Su Jin Bo^*

来源：Fundamental & Clinical Pharmacology, 2014, 28(3): 249-256.

DOI：10.1111/fcp.12031

• the renin-angiotensin system
• four-and-a-half LIM domains 1 protein
• AT1 receptor blockade
• gene expression
• hypertrophic cardiomyopathy
• myosin-binding protein C

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 8weeks. 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 +/- 0.1mg/g, P<0.001), thicker interventricular septal wall (0.70 +/- 0.02 vs. 0.65 +/- 0.01mm, 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.

• 出版日期2014-6