Abstract 9615: PP1-12, a Novel Protein Phosphatase-1 Inhibitor, Ameliorates Ventricular Function After Myocardial Infarction in Rats
Objectives: Myocardial apoptosis has been known to induce heart function damage after myocardial infarction(MI).PP1-12 was designed to inhibit endoplasmic reticulum stress (ERS)-related apoptosis. In this study, we tested the effect of PP1-12 on cardiomyocyte apoptosis as well as on heart function after MI in rats.
Methods: In vitro, neonatal rat cardiomyocytes were cultured and exposed to different concentrations of PP1-12 (0.3, 1, and 3 μg/mL) for 30 min followed by tunicamycin, which can induce ERS, for 36h. Apoptosis was measured using multiparameter high content screening. Phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (eIF2α) and C/EBP homologous protein (CHOP) were determined by western blotting. In vivo, rats that survived MI were divided into six groups: Normal; Vehicle; Perindopril (2mg/kg/d) and PP1-12 (1,3 and10 mg/kg/d). After 4 weeks, transthoracic echocardiographic and hemodynamic parameters were evaluated. The cardiac tissue sections were subjected to TUNEL to assess the level of apoptosis.
Results: In vitro, compared with the vehicle group, PP1-12 suppressed cell apoptosis with maximum protection at a concentration of 3μg/mL. Western blotting showed that PP1-12 protected cardiomyocytes against apoptosis by inducing eIF2α phosphorylation and down-regulating CHOP. In vivo, the LVEDD and LVESD were significantly decreased while the EF and FS were greatest increased by PP1-12 at 10mg/kg/d. The hemodynamic parameters including LVEDP, +dp/dtmax and -dp/dtmax were ameliorated by PP1-12. By calculating the apoptotic index, we found that PP1-12 at 10 mg/kg/d had a great anti-apoptotic effect.
Conclusions: PP1-12 can efficiently inhibit apoptosis and improve heart function. The mechanism was proved to be associated with its ability to depress myocardial apoptosis induced by ERS.
Molecular structure of PP1-12:
- © 2013 by American Heart Association, Inc.