Angiotensin-(3–7) alleviates isoprenaline-induced cardiac remodeling via attenuating cAMP-PKA and PI3K/Akt signaling pathways

The renin–angiotensin system is involved in the regulation of various heart diseases. The present study aimed to determine the effects of angiotensin (Ang)-(3–7) on cardiac remodeling and its downstream signaling pathways in neonatal rat cardiomyocytes (NRCMs) and neonatal rat cardiac fibroblasts (NRCFs). The administration of Ang-(3–7) alleviated isoprenaline (ISO)-induced cardiac hypertrophy and fibrosis of mice. ISO treatment increased the levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and beta-myosin heavy chain (β-MHC) in NRCMs, and reduced the levels of collagen I, collagen III, fibronectin, and alpha-smooth muscle actin (α-SMA) in NRCFs. These changes were inhibited by Ang-(3–7) administration. The levels of protein kinase A (PKA), phosphorylated phosphatidylinositol-3-kinase (p-PI3K), and phosphorylated protein kinase B (p-Akt) were increased in NRCMs and NRCFs treated with ISO. The increase of PKA, but not p-PI3K or p-Akt was attenuated by Ang-(3–7) treatment in NRCMs. The increases of p-PI3K and p-Akt, but not PKA were reversed by Ang-(3–7) treatment in NRCFs. Treatment with cAMP or PKA overexpression reversed the attenuating effects of Ang-(3–7) on ISO-induced hypertrophy of NRCMs. The administration of PI3K inhibitor or Akt inhibitor alleviated ISO-induced fibrosis of NRCFs. These results indicated that Ang-(3–7) could alleviate cardiac remodeling. The administration of Ang-(3–7) attenuated hypertrophy of NRCMs via inhibiting the cAMP/PKA signaling pathway, and alleviated fibrosis of NRCFs via inhibiting PI3K/Akt signaling pathway.