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

TY - JOUR

T1 - AT1 blockade abolishes left ventricular hypertrophy in heterozygous cMyBP-C null mice: role of FHL1

AU - Vignier, Nicolas

AU - Le Corvoisier, Philippe

AU - Blard, Charlotte

AU - Sambin, Lucien

AU - Azibani, Feriel

AU - Schlossarek, Saskia

AU - Delcayre, Claude

AU - Carrier, Lucie

AU - Hittinger, Luc

AU - Su, Jin Bo

N1 - © 2013 The Authors Fundamental and Clinical Pharmacology © 2013 Société Française de Pharmacologie et de Thérapeutique.

PY - 2014/6/1

Y1 - 2014/6/1

N2 - 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.

AB - 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.

U2 - 10.1111/fcp.12031

DO - 10.1111/fcp.12031

M3 - SCORING: Journal article

C2 - 23600722

VL - 28

SP - 249

EP - 256

JO - FUND CLIN PHARMACOL

JF - FUND CLIN PHARMACOL

SN - 0767-3981

IS - 3

ER -