ORIGINAL ARTICLE AT1 blockade abolishes left ventricular hypertrophy in heterozygous cMyBP-C null mice: role of FHL1 Nicolas Vignier a,b# , Philippe Le Corvoisier c,d# , Charlotte Blard a , Lucien Sambin c,d , Feriel Azibani e , Saskia Schlossarek f , Claude Delcayre e , Lucie Carrier a,b,f , Luc Hittinger c,d , Jin Bo Su c * a Institut de Myologie, Inserm, U974, F-75013 Paris, France b Institut de Myologie, IFR14, Universit  e Pierre et Marie Curie, UMR-S974, UM76, CNRS, UMR7215, F-75013 Paris, France c Inserm, U955, F-94010 Cr eteil, France d Facult  e de M edecine, Universit  e Paris-Est, F-94010 Cr  eteil, France e Inserm, U942, H^ opital Lariboisi  ere, Universit  e Paris-Diderot, F-75475 Paris, France f Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany Keywords AT1 receptor blockade, four-and-a-half LIM domains 1 protein, gene expression, hypertrophic cardiomyopathy, myosin-binding protein C, the renin-angiotensin system Received 17 July 2012; revised 27 February 2013; accepted 22 March 2013 *Correspondence and reprints: jin-bo.su@inserm.fr # These authors contributed equally to this study. ABSTRACT This research investigated the impact of angiotensin AT1 receptor (Agtr1) blockade on left ventricular (LV) hypertrophy in a mouse model of human hypertrophic car- diomyopathy (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 Æ 0.1 vs. 3.3 Æ 0.1 mg/g, P < 0.001), thicker interventricular septal wall (0.70 Æ 0.02 vs. 0.65 Æ 0.01 mm, P < 0.02), lower Mybpc3 mRNA level (À43%, P < 0.02), higher four-and-a-half LIM domains 1 (Fhl1, +110%, P < 0.01), and angiotensin-convert- ing 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-predomi- nant 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. INTRODUCTION Hypertrophic cardiomyopathy (HCM) is an autosomal- dominant disease and an important cause of morbidity and sudden cardiac death in young people [1–3]. HCM is characterized by left ventricular hypertrophy (LVH), predominantly involving the interventricular septum, and associated with myocardial disarray and interstitial fibrosis [1,2]. A majority of human HCM cases is famil- ial and mainly caused by mutations in genes encoding sarcomeric proteins. Mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C) represent 20–45% of familial HCM [4,5]. Truncated proteins resulting from different MYBPC3 mutations are unsta- ble in myocardial tissue of patients [6–8] and are degraded at least by the ubiquitin–proteasome system ª 2013 The Authors Fundamental and Clinical Pharmacology © 2013 Soci et e Franc ßaise de Pharmacologie et de Th erapeutique Fundamental & Clinical Pharmacology 28 (2014) 249–256 249 doi: 10.1111/fcp.12031 Fundamental & Clinical Pharmacology