AT1 blockade abolishes left ventricular hypertrophy in heterozygous c My BP- C null mice: role of FHL1.

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 (c My BP- C). Five-month-old heterozygous c My BP- 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-q PCR. 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 m RNA 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 m RNA 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 c My BP- C-related HCM. [ABSTRACT FROM AUTHOR]