Adiponectin inhibits oxidative/nitrative stress during myocardial ischemia and reperfusion via PKA signaling.

Abstract

The cardioprotective effects of adiponectin (APN) against myocardial ischemia/reperfusion (MI/R) injury are well known. However, comprehension of the mechanisms mediating intracellular APN signaling remains incomplete. We recently demonstrate the antioxidant/antinitrative effects of APN are not dependent on AMPK. Protein kinase A (PKA) has been previously shown to be activated by APN, with uncertain relevance to APN cardiac protection. The current study determined whether the antioxidative/antinitrative effect of APN is mediated by PKA. Administration of APN (2 μg/g) 10 min before reperfusion significantly enhanced cardiac PKA activity, reduced oxidative stress, and decreased infarct size. Knockdown of cardiac PKA expression (PKA-KD) by intramyocardial injection of PKA-siRNAs (>70% suppression) significantly inhibited APN cardioprotection determined by cardiac apoptosis, infarct size, and cardiac function. Moreover, PKA-KD virtually abolished the suppressive effect of APN on MI/R-induced NADPH oxidase overexpression and superoxide overproduction and partially inhibited the effect of APN on nitrative protein modification in MI/R heart. Mechanistically, APN significantly inhibited MI/R-induced IKK/IκB phosphorylation and NF-κB activation, which were blocked in PKA-KD heart. Finally, the PKA-mediated antioxidant/antinitrative and cardioprotective effects of APN are intact in AMPK-deficient mice, suggesting that there is no cross talk between AMPK and PKA signaling in APN cardioprotection. Collectively, we demonstrate for the first time that APN inhibits oxidative/nitrative stress during MI/R via PKA-dependent NF-κB inhibition.

• Authors: Yanqing Zhang, Xiao-Liang Wang, Jianli Zhao, Ya-Jing Wang, Wayne Bond Lau, Yue-Xing Yuan, Er-He Gao, Walter J Koch, Xin-Liang Ma
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 305 Issue 12 Pg. E1436-43 (Dec 2013) ISSN: 1522-1555 [Electronic] United States
• PMID: 24129398 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adiponectin
• RNA, Small Interfering
• Reactive Nitrogen Species
• Reactive Oxygen Species
• Cyclic AMP-Dependent Protein Kinases

Topics

• Adiponectin (administration & dosage)
• Animals
• Cyclic AMP-Dependent Protein Kinases (genetics, metabolism)
• Down-Regulation (drug effects)
• Male
• Mice
• Mice, Transgenic
• Myocardial Ischemia (enzymology, genetics)
• Myocardial Reperfusion
• Myocardial Reperfusion Injury (enzymology)
• Oxidative Stress (drug effects, genetics)
• RNA, Small Interfering (genetics)
• Reactive Nitrogen Species (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects, physiology)