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Cardioprotective PKG-independent NO signaling at reperfusion

Michael V Cohen1, Xi-Ming Yang, Yanping Liu

  • 1Department of Physiology, University of South Alabama College of Medicine, Mobile, Alabama 36688, USA. mcohen@usouthal.edu

American Journal of Physiology. Heart and Circulatory Physiology
|September 21, 2010
PubMed

Insights

Nitric oxide (NO) protects the heart during reperfusion independently of PKG, acting downstream of ERK and PI3-kinase. This NO signaling pathway is crucial for ischemic preconditioning (IPC) in intact hearts.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Ischemic Heart Disease

Background:

  • Ischemic preconditioning (IPC) offers cardiac protection during reperfusion, with nitric oxide (NO) implicated.
  • Previous cell models yielded conflicting results regarding NO's role via protein kinase G (PKG).
  • A more physiologically relevant intact heart model is needed to clarify NO's signaling pathway in IPC.

Purpose of the Study:

  • To investigate the role of nitric oxide (NO) and its signaling pathways in mediating protection during ischemic preconditioning (IPC) in an intact rabbit heart model.
  • To determine if NO acts independently of protein kinase G (PKG) and downstream of specific kinases like ERK and PI3-kinase.

Main Methods:

  • Isolated rabbit hearts subjected to 30-min coronary artery occlusion followed by 120-min reperfusion.
  • Administration of A(2b) adenosine receptor (A(2b)AR) agonist (BAY 60-6583), PKG activator (CPT-cGMP), and NO donor (SNAP) at reperfusion.
  • Use of pharmacological inhibitors: N(ω)-nitro-l-arginine methyl ester (l-NAME) for NO synthase, wortmannin for PI3-kinase, PD-98059 for ERK, and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) for soluble guanylyl cyclase.

Main Results:

  • Both A(2b)AR agonist and CPT-cGMP reduced infarct size, with protection abolished by l-NAME, indicating a PKG-independent NO synthase.
  • NO donor SNAP also protected against infarction, independent of PI3-kinase and ERK inhibitors, suggesting NO acts downstream of these kinases.
  • NO-mediated protection was independent of PKG, as shown by the lack of effect of ODQ, and involved a second signaling event dependent on NO generation.

Conclusions:

  • Nitric oxide (NO) plays a significant role in the protective mechanisms of ischemic preconditioning (IPC) in intact hearts.
  • NO signaling occurs downstream of ERK and PI3-kinase pathways and is independent of protein kinase G (PKG).
  • This study elucidates a novel NO-dependent, PKG-independent signaling cascade critical for cardiac protection during reperfusion.

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