Angiotensin-(1-9) attenuates adriamycin-induced cardiomyopathy in rats via the angiotensin type 2 receptor

Adriamycin (ADR) causes irreversible damage to the heart, leading to ADR-induced cardiomyopathy (ACM). Angiotensin-(1-9) [Ang-(1-9)] is a peptide from the counter-regulatory renin-angiotensin system, but the effects on ACM is unclear. Our study was aimed to explore the effects and underlying molecular mechanisms of Ang-(1-9) against ACM in Wistar rats. Rats were injected intraperitoneally with ADR via six equal doses (each containing 2.5 mg/kg) within a period of 2 weeks to induce ACM. After 2 weeks of ADR treatment, the rats were treated with Ang-(1-9) (200 ng/kg/min) or angiotensin type 2 receptor (AT2R) antagonist PD123319 (100 ng/kg/min) for 4 weeks. Although Ang-(1-9) treatment did not influence blood pressure, it significantly improved left ventricular function and remodeling in ADR-treated rats, by inhibiting collagen deposition, the expression of TGF-beta 1, inflammatory response, cardiomyocyte apoptosis and oxidative stress. Moreover, Ang-(1-9) reduced ERK1/2 and P38 MAPK phosphorylation. The therapeutic effects of Ang-(1-9) were blocked by the AT2R antagonist PD123319, which also offset the down-regulation protein expression of pERK1/2 and pP38 MAPK induced by Ang-(1-9). These data suggest that Ang-(1-9) improved left ventricular function and remodeling in ADR-treated rats by an AT2R/ ERK1/2 and P38 MAPK-dependent mechanism. Thus, the Ang-(1-9)/AT2R axis may provide a novel and promising target to the prevention and treatment of ACM.