Apelin-13 Reverses Bupivacaine-Induced Cardiotoxicity via the Adenosine Monophosphate-Activated Protein Kinase Pathway.

Abstract

BACKGROUND:

Cardiotoxicity can be induced by the commonly used amide local anesthetic, bupivacaine. Bupivacaine can inhibit protein kinase B (AKT) phosphorylation and activated adenosine monophosphate-activated protein kinase alpha (AMPKα). It can decouple mitochondrial oxidative phosphorylation and enhance reactive oxygen species (ROS) production. Apelin enhances the phosphatidylinositol 3-kinase (PI3K)/AKT and AMPK/acetyl-CoA carboxylase (ACC) pathways, promotes the complete fatty acid oxidation in the heart, and reduces the release of ROS. In this study, we examined whether exogenous (Pyr1) apelin-13 could reverse bupivacaine-induced cardiotoxicity.

METHODS:

We used the bupivacaine-induced inhibition model in adult male Sprague Dawley (SD) rats (n = 48) and H9c2 cardiomyocyte cell cultures to explore the role of apelin-13 in the reversal of bupivacaine cardiotoxicity, and its possible mechanism of action. AMPKα, ACC, carnitine palmitoyl transferase (CPT), PI3K, AKT, superoxide dismutase 1 (SOD1), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p47-phox) were quantified. Changes in mitochondrial ultrastructure were examined, and mitochondrial DNA, cell viability, ROS release, oxygen consumption rate (OCR) were determined.

RESULTS:

Apelin-13 reduced bupivacaine-induced mitochondrial DNA lesions in SD rats (P < .001), while increasing the expression of AMPKα (P = .007) and PI3K (P = .002). Furthermore, apelin-13 blocked bupivacaine-induced depolarization of the mitochondrial membrane potential (P = .019) and the bupivacaine-induced increases in ROS (P = .001). Also, the AMPK pathway was activated by bupivacaine as well as apelin-13 (P = .002) in H9c2 cardiomyocytes. Additionally, the reduction in the PI3K expression by bupivacaine was mitigated by apelin-13 in H9c2 cardiomyocytes (P = .001). While the aforementioned changes induced by bupivacaine were not abated by apelin-13 after pretreatment with AMPK inhibitor compound C; the bupivacaine-induced changes were still mitigated by apelin-13, even when pretreated with PI3K inhibitor-LY294002.

CONCLUSIONS:

Apelin-13 treatment reduced bupivacaine-induced oxidative stress, attenuated mitochondrial morphological changes and mitochondrial DNA damage, enhanced mitochondrial energy metabolism, and ultimately reversed bupivacaine-induced cardiotoxicity. Our results suggest a role for the AMPK in apelin-13 reversal of bupivacaine-induced cardiotoxicity.

• Authors: Yingchao Ye, Yaoyao Cai, Erjie Xia, Kejian Shi, Zhousheng Jin, Hongfei Chen, Fangfang Xia, Yun Xia, Thomas J Papadimos, Xuzhong Xu, Le Liu, Quanguang Wang
• Journal: Anesthesia and analgesia (Anesth Analg) Vol. 133 Issue 4 Pg. 1048-1059 (10 01 2021) ISSN: 1526-7598 [Electronic] United States
• PMID: 34524989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 International Anesthesia Research Society.

Chemical References

• Intercellular Signaling Peptides and Proteins
• apelin-13 peptide
• Phosphatidylinositol 3-Kinase
• AMP-Activated Protein Kinases
• Bupivacaine

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Bupivacaine
• Cardiotoxicity
• Cell Line
• DNA Damage
• Disease Models, Animal
• Heart Diseases (chemically induced, enzymology, pathology, prevention & control)
• Intercellular Signaling Peptides and Proteins (pharmacology)
• Male
• Mitochondria, Heart (drug effects, enzymology, pathology)
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Oxidative Stress
• Phosphatidylinositol 3-Kinase (metabolism)
• Rats, Sprague-Dawley
• Signal Transduction