3-Bromo-4,5-Dihydroxybenzaldehyde Protects Against Myocardial Ischemia and Reperfusion Injury Through the Akt-PGC1α-Sirt3 Pathway.

Shu-Guang Qin,Hong-Yan Tian,Zhen-Hua Han,Ming-Juan Zhang,Long-Fei Pan,Xin Liu,Guang-Hua Hao,Jin Wei

doi:10.3389/fphar.2018.00722

Abstract

Natural marine products are useful candidates for the treatment of oxidative and inflammatory diseases, including myocardial ischemia. 3-bromo-4,5 - dihydroxybenzaldehyde (BDB), a natural bromophenol isolated from marine red algae, has been shown to display anti-microbial, anti-oxidative, anti-cancer, anti-inflammatory, and free radical scavenging activities. In this study, the potential protective effects of BDB against myocardial ischemia and reperfusion (IR) injury was investigated in an in vitro model mimicked by oxygen and glucose deprivation (OGD) in cardiomyocytes and in an in vivo model induced by coronary artery ligation in rats. The results showed that BDB attenuated the OGD-induced cytotoxicity in a dose-dependent manner, with no toxic effect when treated alone. BDB significantly decreased apoptosis and the cleavage of caspase-3 after OGD. We found that OGD-induced oxidative stress, as evidenced by increases of reactive oxygen species (ROS) and lipid peroxidation, as well as mitochondrial dysfunction, as measured by mitochondrial reporter gene, cytochrome c release and ATP synthesis, were markedly attenuated by BDB treatment. In addition, BDB increased the enzymatic activities of mitochondrial antioxidant enzymes, including IDH2, GSH-Px and SOD2. Western blot analysis showed that BDB increased Akt phosphorylation and upregulated the expression of Sirt3 and PGC1α after OGD. Furthermore, BDB-induced protection in cardiomyocytes was partially reversed by the Akt inhibitor and downregulation of PGC1α. BDB also attenuated myocardial contractile dysfunction and activated the Akt-PGC1α-Sirt3 pathway in vivo. All these data suggest that BDB protects against myocardial IR injury through activating the Akt-PGC1α-Sirt3 pathway.

Highlights

With the rising incidence of obesity and diabetes in recent years, cardiovascular disease is becoming the major cause of death worldwide
We performed western blot using the MDA and 4-HNE antibodies to detect lipid peroxidation, and the results showed that increased expression of release assay shows that BDB reduced the increase in lactate dehydrogenase (LDH) release induced by oxygen glucose deprivation (OGD). (C,D) Flow cytometry (C) and quantification (D) show that BDB inhibited apoptosis induced by OGD. (E) Western blot shows that BDB inhibited caspase-3 activation induced by OGD
Our present results provide evidence that BDB, a natural bromophenol compound isolated from red algae, protects against myocardial ischemia and reperfusion (IR) in vitro and in vivo

Summary

Introduction

With the rising incidence of obesity and diabetes in recent years, cardiovascular disease is becoming the major cause of death worldwide. Myocardial infarction induced by coronary artery occlusion is the leading cause of morbidity and mortality for both men and women (Benjamin et al, 2018). Natural marine products are useful candidates for the identification of bioactive compounds for the treatment of oxidative and inflammatory disorders, including myocardial ischemia and reperfusion (IR) injury. BDB was found to activate NF-E2-related factor 2 (Nrf2) and promote its localization into the nucleus, thereby enhance the level of reduced glutathione to induce anti-oxidative effects (Kim et al, 2017). We investigated the effects of BDB on myocardial IR injury mimicked by oxygen glucose deprivation (OGD) in vitro or by coronary artery ligation in vivo, and elucidated the potential underlying molecular mechanisms with focus on the Akt-PGC1α-Sirt pathway

Methods

Results

Conclusion