Protective actions of angiotensin II type 2 receptors in male mice with muscular dystrophy

Rasna Sabharwal; Liping Yang; Kathy Zimmerman; Robert Weiss

doi:10.1096/fasebj.2019.33.1_supplement.746.1

Muscular dystrophies are inherited group of heterogeneous genetic disorders that cause progressive muscle atrophy and dilated cardiomyopathy (DCM). We have identified that the renin‐angiotensin system plays a crucial role in pathogenesis of muscular dystrophy. In particular, we have demonstrated that angiotensin II (Ang II) via type 1 receptors (AT1R) mediate autonomic and skeletal muscle dysfunction at young age (<10 weeks) and predicts onset of DCM at older ages (>45 weeks) in the sarcoglycan delta deficient (Sgcd−/−) mice, an established model of muscular dystrophy [Exp Physiol 2013, 2015]. It is becoming evident that AngII/AT2R can offset the deleterious actions of AngII/AT1R [Curr Opin Nephrol Hypertens 2017; Pharmacol Res 2017]. Therefore, we hypothesized that agonism of AT2R by a non‐peptide small molecule compound 21 (C21; Vicore Pharma) will ameliorate AngII‐induced autonomic and skeletal muscle dysfunction and delay development of DCM in Sgcd−/− mice. Control C57BL6 (n=5–8) and Sgcd−/− (n=6–10) male mice were infused with either vehicle (saline) or C21 (0.03 mg/kg/min, minpump) for eight‐ten weeks, beginning at 3 weeks of age for group 1 (younger‐aged), and at 45 weeks of age for group 2 (older‐aged) experiments. Mean blood pressure (BP), heart rate (HR) and locomotor activity were recorded by telemetry, while cardiac function was assessed by echocardiography. Autonomic indices including baroreflex sensitivity (BRS, sequence technique) and resting cardiac vagal and sympathetic tone (HR responses to atropine and propranolol) were calculated. Group 1: As expected, Sgcd−/− mice exhibit lower BP (105±5 mmHg) and activity (3±1 counts/min), reduced BRS and vagal tone, and increased sympathetic tone (P<0.05 vs. control). C21 improved BRS and restored sympathovagal balance in Sgcd−/− mice; albeit it did not influence these variables in control mice (P<0.05 vs. vehicle). Importantly, C21 normalized locomotor activity and decreased AT1R expression in skeletal muscle of Sgcd−/− mice (P<0.05 vs. vehicle). Group 2: Compared to older‐aged control mice, Sgcd−/− mice exhibit increased left ventricular end‐diastolic and end‐systolic volumes, and reduced ejection fraction (P<0.05). Chronic C21 infusion remarkably improved cardiac function in Sgcd−/− mice (P<0.05 vs. vehicle; NS vs. control). Furthermore, the protective effects of C21 persisted for an additional two weeks after the treatment was discontinued in Sgcd−/− mice. Thus, we conclude that activation of AT2R is a potential novel treatment strategy that alleviates muscular dystrophy phenotype and delays the onset/severity of dilated cardiomyopathy. This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.

Protective actions of angiotensin II type 2 receptors in male mice with muscular dystrophy

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