AT1 blockade abolishes left ventricular hypertrophy in heterozygous cMyBP‐C null mice: role of FHL1. (18th April 2013)

• Record Type: Journal Article
• Authors: Vignier, Nicolas; Le Corvoisier, Philippe; Blard, Charlotte; Sambin, Lucien; Azibani, Feriel; Schlossarek, Saskia; Delcayre, Claude; Carrier, Lucie; Hittinger, Luc; Su, Jin Bo
• Is Part Of: Fundamental & clinical pharmacology. Volume 28:Number 3(2014)
• Page Start: 249
• Page End: 256
• Publication Date: 2013-04-18
• Subjects: Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/fcp.12031
• Languages: English
• ISSNs: 0767-3981

Abstract

<abstract abstract-type="main" id="fcp12031-abs-0001"> <title>Abstract</title> <p>This research investigated the impact of angiotensin AT1 receptor <italic>(Agtr1)</italic> blockade on left ventricular (LV) hypertrophy in a mouse model of human hypertrophic cardiomyopathy (HCM), which carries one functional allele of <italic>Mybpc3</italic> 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, <italic>P</italic> < 0.001), thicker interventricular septal wall (0.70 ± 0.02 vs. 0.65 ± 0.01 mm, <italic>P</italic> < 0.02), lower <italic>Mybpc3</italic> mRNA level (−43%, <italic>P</italic> < 0.02), higher four‐and‐a‐half LIM domains 1 (<italic>Fhl1, </italic> +110%, <italic>P</italic> < 0.01), and angiotensin‐converting enzyme 1 (<italic>Ace1</italic>, +67%, <italic>P</italic> < 0.05), but unchanged <italic>Agtr1</italic> mRNA levels in the septum. Treatment with irbesartan had no effect in wild‐type mice but abolished septum‐predominant LV hypertrophy and <italic>Fhl1</italic> upregulation without changes in <italic>Ace1</italic> but with an increased <italic>Agtr1</italic> (+42%) in Het‐KO mice. Thus, septum‐predominant LV hypertrophy in Het‐KO mice is combined with higher <italic>Fhl1</italic> expression, which can be abolished by AT1 receptor blockade, indicating a role of the renin‐angiotensin system and <italic>Fhl1</italic> in cMyBP‐C‐related HCM.</p> </abstract>