title: AT1 blockade abolishes left ventricular hypertrophy in heterozygous cMyBP-C null mice: role of FHL1.
abstract: 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.
authors.affiliation: 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.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vignier
authors.forename: Philippe
authors.initials: P
authors.lastname: Le Corvoisier
authors.forename: Charlotte
authors.initials: C
authors.lastname: Blard
authors.forename: Lucien
authors.initials: L
authors.lastname: Sambin
authors.forename: Feriel
authors.initials: F
authors.lastname: Azibani
authors.forename: Saskia
authors.initials: S
authors.lastname: Schlossarek
authors.forename: Claude
authors.initials: C
authors.lastname: Delcayre
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
authors.forename: Luc
authors.initials: L
authors.lastname: Hittinger
authors.forename: Jin Bo
authors.initials: JB
authors.lastname: Su
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D004452:Echocardiography; D006579:Heterozygote; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000077405:Irbesartan; D060588:LIM Domain Proteins / Q000378:metabolism*; D016014:Linear Models; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009929:Organ Size / Q000187:drug effects; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016277:Ventricular Function, Left; D000099163:Myosin Binding Protein C
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000077405:Irbesartan; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D013777:Tetrazoles; D000099163:Myosin Binding Protein C; C486306:Fhl1 protein, mouse
keywords: AT1 receptor blockade; four-and-a-half LIM domains 1 protein; gene expression; hypertrophic cardiomyopathy; myosin-binding protein C; the renin-angiotensin system