Paraoxonase 2 (PON2) appears to play a cardioprotective role in both human and experimental heart failure: Cardiologist Wai Hong Wilson Tang, MD, Director of Cleveland Clinic Lerner Research Institute’s Center for Clinical Genomics.
Reporter: Aviva Lev-Ari, PhD, RN
Enzyme Protects Heart Against Stress and Could Potentially Lead to New Heart Failure Treatments
Free Radic Biol Med. 2018 Jun;121:117-126. doi: 10.1016/j.freeradbiomed.2018.04.583. Epub 2018 May 2.Paraoxonase 2 prevents the development of heart failure.
Li W1, Kennedy D2, Shao Z3, Wang X4, Kamdar AK5, Weber M3, Mislick K3, Kiefer K3, Morales R3, Agatisa-Boyle B3, Shih DM6, Reddy ST6, Moravec CS7, Tang WHW8.Abstract
BACKGROUND:
Mitochondrial oxidation is a major source of reactive oxygen species (ROS) and mitochondrial dysfunction plays a central role in development of heart failure (HF). Paraoxonase 2 deficient (PON2-def) mitochondria are impaired in function. In this study, we tested whether PON2-def aggravates HF progression.
METHODS AND RESULTS:
Using qPCR, immunoblotting and lactonase activity assay, we demonstrate that PON2 activity was significantly decreased in failing hearts despite increased PON2 expression. To determine the cardiac-specific function of PON2, we performed heart transplantations in which PON2-def and wild type (WT) donor hearts were implanted into WT recipient mice. Beating scores of the donor hearts, assessed at 4 weeks post-transplantation, were significantly decreased in PON2-def hearts when compared to WT donor hearts. By using a transverse aortic constriction (TAC) model, we found PON2 deficiency significantly exacerbated left ventricular remodeling and cardiac fibrosis post-TAC. We further demonstrated PON2 deficiency significantly enhanced ROS generation in heart tissues post-TAC. ROS generation was measured through dihydroethidium (DHE) using high-pressure liquid chromatography (HPLC) with a fluorescent detector. By using neonatal cardiomyocytes treated with CoCl2 to mimic hypoxia, we found PON2 deficiency dramatically increased ROS generation in the cardiomyocytes upon CoCl2 treatment. In response to a short CoCl2 exposure, cell viability and succinate dehydrogenase (SDH) activity assessed by MTT assay were significantly diminished in PON2-def cardiomyocytes compared to those in WT cardiomyocytes. PON2-def cardiomyocytes also had lower baseline SDH activity. By using adult mouse cardiomyocytes and mitochondrial ToxGlo assay, we found impaired cellular ATP generation in PON2-def cells compared to that in WT cells, suggesting that PON2 is necessary for proper mitochondrial function.
CONCLUSION:
Our study suggests a cardioprotective role for PON2 in both experimental and human heart failure, which may be associated with the ability of PON2 to improve mitochondrial function and diminish ROS generation.
Copyright © 2018 Elsevier Inc. All rights reserved.
KEYWORDS:
Cardiomyopathy; Heart failure; Paraoxonase 2
- PMID:
- 29729330
- PMCID:
- PMC5971153
- [Available on 2019-06-01]
- DOI:
- 10.1016/j.freeradbiomed.2018.04.583
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