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

• Published in: Molecular and cellular biochemistry 2024, Vol.479 (1), p.73-83
• Main Authors: Ma, Hui, Mao, Chenggang, Hu, Yang, Wang, Liqin, Guo, Xingqing, Li, Lei, Wang, Fang, Guan, Renzheng
• Format: Article
• Language: English
• Subjects: Angiotensin AT2 receptors; Angiotensin II - pharmacology; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Blood pressure; Cancer Research; Cardiology; Cardiomyocytes; Cardiomyopathies - chemically induced; Cardiomyopathies - drug therapy; Cardiomyopathies - prevention & control; Cardiomyopathy; Down-regulation; Doxorubicin - adverse effects; Extracellular signal-regulated kinase; Heart; Inflammation; Inflammatory response; Life Sciences; MAP kinase; Medical Biochemistry; Molecular modelling; Oxidative stress; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2 - metabolism; Receptors; Renin; Transforming growth factor-b1; Ventricle
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-023-04718-y

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-β1, 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.