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A Murine Model of Myocardial Ischemia-reperfusion Injury through Ligation of the Left Anterior Descending Artery
Published on: April 10, 2014
Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury
Youn Wook Chung1, Claudia Lagranha2, Yong Chen3
1Cardiovascular and Pulmonary Branch, Yonsei Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 120-752, Korea; chungyw@yuhs.ac manganiv@nhlbi.nih.gov.
Insights
Targeted disruption of phosphodiesterase type 3B (PDE3B) protects the heart from ischemia/reperfusion injury by enhancing protective protein accumulation. This suggests PDE3B as a potential target for cardiovascular therapies.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Mitochondrial Function
Background:
- Cyclic nucleotide phosphodiesterase type 3 (PDE3) inhibition shows cardioprotection in rodents against ischemia/reperfusion (I/R) injury.
- The specific PDE3 isoform and mechanisms involved in this protection remain unidentified.
Purpose of the Study:
- To identify the specific PDE3 isoform responsible for cardioprotection against I/R injury.
- To elucidate the underlying molecular mechanisms of PDE3-mediated cardioprotection.
Main Methods:
- Targeted gene disruption of PDE3 subfamily B (PDE3B) and PDE3 subfamily A (PDE3A) in mice.
- In vivo and in vitro assessment of cardiac function and infarct size following I/R.
- Pharmacological inhibition of cAMP-dependent protein kinase A (PKA) and mitochondrial calcium-activated K channels.
- Mitochondrial isolation and analysis of reactive oxygen species production, Bcl-2 content, and interaction with transverse tubules.
- Proteomics analysis of ischemia-induced caveolin-3-enriched fractions (ICEFs).
Main Results:
- PDE3B knockout (PDE3B(-/-)) mice exhibited significantly reduced infarct size and improved cardiac function after I/R injury compared to wild-type (WT) mice.
- The cardioprotective effect in PDE3B(-/-) hearts was abolished by PKA inhibition or paxilline treatment.
- PDE3B(-/-) mitochondria showed increased antiapoptotic Bcl-2, reduced reactive oxygen species production, and enhanced resistance to mitochondrial permeability transition pore opening.
- Proteomics revealed enrichment of cardioprotective proteins within ICEFs in PDE3B(-/-) hearts, an accumulation dependent on PKA signaling.
Conclusions:
- PDE3B deletion confers cardioprotection against I/R injury through a mechanism involving cAMP/PKA-dependent preconditioning.
- This preconditioning is associated with the accumulation of cardioprotective proteins in ICEFs.
- PDE3B is identified as a key player in cardiac I/R injury, making it a potential therapeutic target for cardiovascular diseases.
Abstract:
Although inhibition of cyclic nucleotide phosphodiesterase type 3 (PDE3) has been reported to protect rodent heart against ischemia/reperfusion (I/R) injury, neither the specific PDE3 isoform involved nor the underlying mechanisms have been identified. Targeted disruption of PDE3 subfamily B (PDE3B), but not of PDE3 subfamily A (PDE3A), protected mouse heart from I/R injury in vivo and in vitro, with reduced infarct size and improved cardiac function. The cardioprotective effect in PDE3B(-/-) heart was reversed by blocking cAMP-dependent PKA and by paxilline, an inhibitor of mitochondrial calcium-activated K channels, the opening of which is potentiated by cAMP/PKA signaling. Compared with WT mitochondria, PDE3B(-/-) mitochondria were enriched in antiapoptotic Bcl-2, produced less reactive oxygen species, and more frequently contacted transverse tubules where PDE3B was localized with caveolin-3. Moreover, a PDE3B(-/-) mitochondrial fraction containing connexin-43 and caveolin-3 was more resistant to Ca(2+)-induced opening of the mitochondrial permeability transition pore. Proteomics analyses indicated that PDE3B(-/-) heart mitochondria fractions were enriched in buoyant ischemia-induced caveolin-3-enriched fractions (ICEFs) containing cardioprotective proteins. Accumulation of proteins into ICEFs was PKA dependent and was achieved by ischemic preconditioning or treatment of WT heart with the PDE3 inhibitor cilostamide. Taken together, these findings indicate that PDE3B deletion confers cardioprotective effects because of cAMP/PKA-induced preconditioning, which is associated with the accumulation of proteins with cardioprotective function in ICEFs. To our knowledge, our study is the first to define a role for PDE3B in cardioprotection against I/R injury and suggests PDE3B as a target for cardiovascular therapies.
