Apelin-13 protects the heart against ischemia-reperfusion injury through inhibition of ER-dependent apoptotic pathways in a time-dependent fashion.

Abstract

Endoplasmic reticulum (ER) stress is activated during and contributes to ischemia-reperfusion (I/R) injury. Attenuation of ER stress-induced apoptosis protects the heart against I/R injury. Using apelin, a ligand used to activate the apelin APJ receptor, which is known to be cardioprotective, this study was designed to investigate 1) the time course of changes in I/R injury after ER stress; 2) whether apelin infusion protects the heart against I/R injury via modulation of ER stress-dependent apoptosis signaling pathways; and 3) how phosphatidylinositol 3-kinase (PI3K)/Akt, endothelial nitric oxide synthase (eNOS), AMP-activated protein kinase (AMPK), and ERK activation are involved in the protection offered by apelin treatment. The results showed that, using an in vivo rat I/R model induced by 30 min of ischemia followed by reperfusion, infarct size (IS) increased from 2 h of reperfusion (34.85 ± 2.14%) to 12 h of reperfusion (48.98 ± 3.35, P < 0.05), which was associated with an abrupt increase in ER stress-dependent apoptosis activation, as evidenced by increased CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, and JNK activation (CHOP: 2.49-fold increase, caspase-12: 2.09-fold increase, and JNK: 3.38-fold increase, P < 0.05, respectively). Administration of apelin at 1 μg/kg not only completely abolished the activation of ER stress-induced apoptosis signaling pathways at 2 h of reperfusion but also significantly attenuated time-related changes at 24 h of reperfusion. Using pharmacological inhibition, we also demonstrated that PI3K/Akt, AMPK, and ERK activation were involved in the protection against I/R injury via inhibition of ER stress-dependent apoptosis activation. In contrast, although eNOS activation played a role in decreasing IS at 2 h of reperfusion, it failed to modify either IS or ER stress-induced apoptosis signaling pathways at 24 h after reperfusion.

• Authors: Jianping Tao, Wei Zhu, Yapeng Li, Ping Xin, Jing Li, Mingya Liu, Jingbo Li, Andrew N Redington, Meng Wei
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 301 Issue 4 Pg. H1471-86 (Oct 2011) ISSN: 1522-1539 [Electronic] United States
• PMID: 21803944 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Intercellular Signaling Peptides and Proteins
• apelin-13 peptide
• Nitric Oxide Synthase Type III
• Phosphatidylinositol 3-Kinases
• Oncogene Protein v-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Apoptosis (drug effects)
• Blood Pressure (drug effects)
• Blotting, Western
• Cardiotonic Agents
• Endoplasmic Reticulum (drug effects)
• Extracellular Signal-Regulated MAP Kinases (physiology)
• Intercellular Signaling Peptides and Proteins (pharmacology)
• Microscopy, Confocal
• Myocardial Infarction (pathology)
• Myocardial Reperfusion Injury (mortality, prevention & control)
• Nitric Oxide Synthase Type III (physiology)
• Oncogene Protein v-akt (physiology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Rats
• Rats, Sprague-Dawley
• Risk Assessment
• Signal Transduction (drug effects)
• Time Factors