Fisetin protects against cardiac cell death through reduction of ROS production and caspases activity

Sophie Rodius,Héctor Sánchez-Iranzo,Isaac Crespo,Mark Ibberson,Ioannis Xenarios,Niek De Klein,Nadia Mercader,Francisco Azuaje,Simone P Niclou,Gunnar Dittmar,Céline Jeanty

doi:10.1038/s41598-020-59894-4

Abstract

Myocardial infarction (MI) is a leading cause of death worldwide. Reperfusion is considered as an optimal therapy following cardiac ischemia. However, the promotion of a rapid elevation of O2 levels in ischemic cells produces high amounts of reactive oxygen species (ROS) leading to myocardial tissue injury. This phenomenon is called ischemia reperfusion injury (IRI). We aimed at identifying new and effective compounds to treat MI and minimize IRI. We previously studied heart regeneration following myocardial injury in zebrafish and described each step of the regeneration process, from the day of injury until complete recovery, in terms of transcriptional responses. Here, we mined the data and performed a deep in silico analysis to identify drugs highly likely to induce cardiac regeneration. Fisetin was identified as the top candidate. We validated its effects in an in vitro model of MI/IRI in mammalian cardiac cells. Fisetin enhances viability of rat cardiomyocytes following hypoxia/starvation – reoxygenation. It inhibits apoptosis, decreases ROS generation and caspase activation and protects from DNA damage. Interestingly, fisetin also activates genes involved in cell proliferation. Fisetin is thus a highly promising candidate drug with clinical potential to protect from ischemic damage following MI and to overcome IRI.

Highlights

During Myocardial infarction (MI), myocardial cells are deprived from oxygen and nutrients, leading to cell death
Our hypothesis was that a drug predicted to induce, in vitro, expression signatures observed at different key stages of heart regeneration in the zebrafish could represent a promising compound for cardiac damage healing and ischemia reperfusion injury (IRI) reduction
Based on a combination of computational processing and human expert analysis, we selected different sets of most relevant dynamic signatures for different post-injury time points. The size of these signatures ranged from a few dozen to hundreds of genes, and they were significantly enriched in diverse biological processes relevant to cardiac regeneration

Summary

Introduction

During MI, myocardial cells are deprived from oxygen (hypoxia) and nutrients (starvation), leading to cell death. Reoxygenation is crucial for patient survival, reperfusion promotes a rapid elevation in O2 levels in ischemic cells, which induces a high production of ROS in mitochondria resulting in cardiomyocytes injury This phenomenon, called ischemia reperfusion injury (IRI), can lead to cardiac remodeling and heart failure[16,17]. Results indicate that fisetin is able to enhance cell viability of rat cardiomyocytes following hypoxia/starvation – reoxygenation, to protect from apoptotic cell death, by decreasing ROS generation as well as caspases activation, and to reduce DNA damage.

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