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Transient Expression of Foreign Genes in Insect Cells (sf9) for Protein Functional Assay
Published on: February 22, 2018
Cardioprotective effect afforded by transient exposure to phosphodiesterase III inhibitors: the role of protein
S Sanada1, M Kitakaze, P J Papst
1Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan.
Circulation
|August 8, 2001
Summary
Phosphodiesterase III inhibitors (PDEIII-Is) offer cardioprotection by reducing infarct size in canine hearts. This effect is mediated through cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), and p38 mitogen-activated protein kinase (MAPK) pathways.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Phosphodiesterase III inhibitors (PDEIII-Is) are known to improve cardiac function through increased intracellular cyclic adenosine monophosphate (cAMP) levels.
- The direct cardioprotective effects of PDEIII-Is and their underlying molecular mechanisms remain largely unidentified.
- This study investigated the infarct size-limiting potential of PDEIII-Is and the involvement of cAMP, protein kinase A (PKA), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) signaling pathways.
Purpose of the Study:
- To determine if PDEIII inhibitors possess direct cardioprotective effects.
- To elucidate the specific intracellular signaling pathways (cAMP, PKA, PKC, MAPK) involved in PDEIII inhibitor-induced cardioprotection.
- To evaluate the role of these pathways in limiting myocardial infarct size.
Main Methods:
- Open-chest dogs were pretreated with PDEIII inhibitors (milrinone, olprinone) or dibutyryl-cAMP (db-cAMP) before inducing 90 minutes of ischemia and 6 hours of reperfusion.
- Specific inhibitors for PKA (H89), PKC (GF109203X), MEK (PD98059), and p38 MAPK (SB203580) were used in conjunction with olprinone.
- Myocardial p38 MAPK activity and infarct size were assessed.
Main Results:
- PDEIII-Is and db-cAMP induced significant hemodynamic changes that normalized within 30 minutes.
- Both PDEIII-Is and db-cAMP increased myocardial p38 MAPK activity during the preischemic period, an effect blocked by H89.
- PDEIII-Is and db-cAMP significantly reduced infarct size compared to controls. Olprinone's protective effect was diminished by H89 (PKA inhibitor) and SB203580 (p38 MAPK inhibitor), but not by GF109203X or PD98059.
Conclusions:
- Pretreatment with PDEIII inhibitors demonstrates significant cardioprotective effects, reducing myocardial infarct size.
- The cardioprotection mediated by PDEIII inhibitors is dependent on the cAMP-PKA and p38 MAPK signaling pathways.
- These protective mechanisms are independent of protein kinase C (PKC) activation.
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