Specific Inhibition of CYP4A Alleviates Myocardial Oxidative Stress and Apoptosis Induced by Advanced Glycation End-Products

Rui Wang,Xiaojing Yang,Jinyong Peng,Jinsong Yan,Jianling Du,Li Wang,Jinlong He,Shanshan Li,Hua Li,Yuhui Yuan,Pengyuan Sun

doi:10.3389/fphar.2019.00876

Abstract

High exposure to advanced glycation end-products (AGEs) may induce cardiotoxicity. However, the effects and mechanisms remain to be further clarified. CYP4A plays an important role in the pathophysiological process of myocardial abnormalities by modulating oxidative stress and apoptosis (OS/Apop) signaling pathway. The present work aimed to investigate whether CYP4A mediates AGEs-induced myocardial injury. AGEs solution was administered intragastrically to C57BL/6 mice for 60 days, while the specific inhibitor of CYP4A, HET0016, was given from the 47th day via intraperitoneal injection for 2 weeks. Levels of OS/Apop in heart tissue were measured. The effects on the cell viability and apoptosis were detected in primary rat cardiomyocytes. To further investigate the mechanism, H9c2 cells were treated with HET0016 or small interfering RNAs (siRNAs) against CYP4a mRNA before incubation with AGEs. Exposure to AGEs led to significantly increased expression of CYP4A and levels of OS/Apop in heart and H9c2 cells both in vivo and in vitro. The OS/Apop pathway was activated with increased expression of NOX2, p-JNK, and cleaved caspase-3 (c-caspase-3) and decreased expression of p-Akt and Bcl-xL both in vivo and in vitro. Specific CYP4A suppression by HET0016 or siRNA exerted significant protective effects by attenuating AGEs-induced OS/Apop pathways in vitro. Our results demonstrate that specific inhibition of CYP4A might be a potential therapeutic option for myocardial injury induced by AGEs.

Highlights

Advanced glycation end-products (AGEs) are heterogeneous compounds formed by nonenzymatic glycation and the oxidation of proteins and lipids via Maillard reactions (Delgado-Andrade et al, 2007)
To investigate whether AGEs is involved in the development of cardiac dysfunction, we detected the cardiac function by ultrasonic cardiogram (Supplementary Table 1)
In AGEs group mice, serum AGEs levels and lactate dehydrogenase (LDH) activity, cardiac H2O2 and MDA content, and NOX2 expression were higher compared to the control group, and the cardiac superoxide diamutase (SOD) activity was lower compared to the control group

Summary

Introduction

Advanced glycation end-products (AGEs) are heterogeneous compounds formed by nonenzymatic glycation and the oxidation of proteins and lipids via Maillard reactions (Delgado-Andrade et al, 2007). Most in vivo studies are performed in diabetic subjects, and there are many other factors, such as impaired cardiac insulin signaling, cardiac metabolic abnormalities, and endogenous AGEs that are involved in the progression of diabetic cardiomyopathy (Zhang et al, 2018). These factors and their interactions with AGEs need to be considered when the roles of AGEs are interpreted in these investigations. Several studies indicated that long-term intake of excessive dietary AGEs leads to myocardial injury and cardiac dysfunction prior to the occurrence of diabetes, strongly suggesting that AGEs alone may induce cardiotoxicity (Cai et al, 2014; Clarke et al, 2016; Deluyker et al, 2016). The effects and mechanisms of AGEs on the myocardium remain far from clear and require further research efforts

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