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A6319 Diminazine Aceturate Attenuates Cardiac Remodeling by Targeting MicroRNA-21/29 Expression

Objectives: To assess the effect of diminazine aceturate (DIZE), which has been described as an ACE2 activator, on ACE2-Ang-(1-7)-Mas axis and miR-21/29b in DOCA-salt rats. Methods: Male SD rats were uninephrectomized and received either DOCA-salt (50 mg/kg SC and 1% NaCl+0.2% KCl in drinking water) or control (tap water) for 8 weeks. A subset of DOCA-salt rats were treateed with DIZE (15 mg/kg/day, s.c.) throughout the study-period. Systolic blood pressure (SBP) was measured by the tail-cuff method. The protein level of ACE2/Ang-(1-7)/Mas axis in left ventricular were detected by Western blot or Elisa. RT-PCR of the miRs was performed using TaqMan MicroRNA assay kits for rno-miR-21, rno-miR-29b and U6. Results: This was demonstrated by the findings that DIZE were protected against a fall in SBP and cardiomyocyte diameter/cross-sectional area, an increase in left ventricular mass, and the development of cardiac fibrosis, including upregulation of transforming growth factor-1, collagen I/III. The expression of ACE2/Ang-(1-7)/Mas in DOCA-salt rats were decreased compare to control. Treatment with DIZE resulted in a upregulation of ACE2 expression in left ventricular, suggesting that activation of intrinsic ACE2 would be protective against cardiac remodeling. RT-PCR analyse showed a significant increase in the expression level of miR-21, but a reduce in miR-29b of left ventricular compared with control. At the same time, this induction was attenuated by treatment with DIZE. Conclusion: These findings strongly indicate that cardiac remodeling is associatedwith positive regulation of miR-21 and negative regulation of miR-29 that is mediated by ACE2 signaling mechanism in DOCA-salt rats. Therefore, targeting miR-21/29 may be a better alternative ACE2-mediated remodeling in heart.