Losartan promotes myocardial apoptosis after acute myocardial infarction in rats through inhibiting Ang II-induced JAK/STAT pathway.

Abstract

To study the pro-apoptotic effect of Losartan on myocardial cells after acute myocardial infarction (AMI) in rats. Before intervention, a total of 48 male Wistar rats were randomly divided into the Sham group (n=12), AMI group (n=12), 5 mg/kg Losartan group (n=12) and 1 mg/kg AG-490 group (n=12). The rats in the Sham group and AMI group received gavage with normal saline, those in the Losartan group received gavage with Losartan for 7 d and those in the AG-490 group were intravenously injected with AG-490 at 30 min before the operation. At 4 d after drug administration, the anterior descending coronary artery was ligated to establish the AMI model in the AMI group and Losartan group, while the same operation was performed, and the anterior descending coronary artery was only threaded in the Sham group. The rats were sacrificed at 24 h after operation. Then, the myocardial apoptosis was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and the protein expressions of Janus kinase 2 (JAK2), the signal transducer and activator of transcription 3 (STAT3), the B-cell lymphoma-2 (Bcl-2) and the Bcl-2 associated X protein (Bax) were detected via immunohistochemistry and Western blotting. Moreover, the myocardial cells of rats were incubated with angiotensin II (Ang II) at the same concentration at different time points and blocked with Losartan. Finally, the changes in protein expressions of p-JAK2, p-STAT3, Bax, and Bcl-2 were detected via Western blotting. Losartan treatment could increase the number of apoptotic myocardial cells after AMI in rats. In Losartan group, the protein expressions of JAK2, STAT3, and Bcl-2 declined, while the protein expression of Bax was increased, and the Bax/Bcl-2 ratio was also increased, which are consistent with the conditions under the treatment with the JAK-STAT pathway inhibitor AG-490. With the prolonged time of stimulation (5 min, 30 min, 2 h, and 24 h) in myocardial cells using 1.0×10-6 mol/L Ang II, the protein expressions of p-JAK2 and p-STAT3 were increased and reached the peak at 24 h. After the application of Losartan, the increased protein expressions of p-JAK2 and p-STAT3 returned to normal levels, and the protein expression of Bax was increased, while that of Bcl-2 was decreased. Losartan promotes myocardial apoptosis after AMI in the rats through inhibiting the Ang II-induced JAK/STAT pathway.