Downregulation of stanniocalcin 1 is responsible for sorafenib-induced cardiotoxicity
Miko Kawabata1, Noriko Umemoto1, Yasuhito Shimada2
1*Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan.
Abstract:
Sorafenib is associated with adverse cardiac effects, including left ventricular dysfunction. However, the precise mechanism remains unclear. Here, we aimed to establish the genes responsible for this cardiotoxicity using zebrafish and human cardiomyocytes. Fluorescent cardiac imaging using pigmentless zebrafish with green fluorescent protein hearts revealed that the ventricular dimensions of the longitudinal axis with sorafenib were significantly shorter than those of the control group. Transcriptome analysis of their hearts revealed that stanniocalcin 1 (stc1) was downregulated by sorafenib. stc1 knockdown in zebrafish revealed that reduction of stc1 decreased the longitudinal dimensions of zebrafish ventricles, similar to that which occurs during sorafenib treatment. STC1 downregulation and cytotoxicity were also seen in human cardiomyocytes exposed to sorafenib. To clarify the molecular function of stc1 in sorafenib-induced cardiotoxicity, we focused on oxidative stress in cardiomyocytes treated with sorafenib. Reactive oxygen species (ROS) production significantly increased in both species of human cardiomyocytes and zebrafish exposed to sorafenib and STC1 knockdown compared with the controls. Finally, we found that forced expression of stc1 normalized impairment, decreasing the longitudinal dimensions in zebrafish treated with sorafenib. Our study demonstrated that STC1 plays a protective role against ventricular dysfunction and ROS overproduction, which are induced by sorafenib treatment. We discovered for the first time that STC1 downregulation is responsible for sorafenib-induced cardiotoxicity through activated ROS generation.
Insights
Sorafenib causes heart dysfunction by downregulating stanniocalcin 1 (STC1). Reduced STC1 increases reactive oxygen species (ROS), leading to ventricular impairment. Restoring STC1 protects against this sorafenib-induced cardiotoxicity.
Area of Science:
- Cardiovascular toxicology
- Molecular biology
- Genetics
Background:
- Sorafenib treatment can lead to adverse cardiac effects, notably left ventricular dysfunction.
- The exact molecular mechanisms underlying sorafenib-induced cardiotoxicity are not fully understood.
Purpose of the Study:
- To identify the specific genes involved in sorafenib-induced cardiotoxicity.
- To elucidate the role of stanniocalcin 1 (STC1) in this process using zebrafish and human cardiomyocytes.
Main Methods:
- Utilized fluorescent cardiac imaging in pigmentless zebrafish with green fluorescent protein hearts to assess ventricular dimensions.
- Performed transcriptome analysis to identify gene expression changes in response to sorafenib.
- Investigated the effects of STC1 knockdown and forced expression on cardiac function and reactive oxygen species (ROS) production.
- Examined STC1 levels and cytotoxicity in human cardiomyocytes exposed to sorafenib.
Main Results:
- Sorafenib treatment significantly reduced longitudinal ventricular dimensions in zebrafish.
- Transcriptome analysis revealed sorafenib-induced downregulation of stanniocalcin 1 (STC1).
- STC1 knockdown mimicked sorafenib's effect on ventricular dimensions and increased ROS production in both zebrafish and human cardiomyocytes.
- Forced expression of STC1 ameliorated sorafenib-induced ventricular dysfunction and ROS overproduction.
Conclusions:
- STC1 plays a crucial protective role against sorafenib-induced cardiotoxicity.
- Downregulation of STC1 contributes to ventricular dysfunction and increased ROS generation.
- This study identifies STC1 downregulation as a key mechanism in sorafenib-induced cardiotoxicity.
More Related Videos
08:21A Modified Two Kidney One Clip Mouse Model of Renin Regulation in Renal Artery Stenosis
Published on: October 26, 2020
08:03Hybrid Cell Analysis System to Assess Structural and Contractile Changes of Human iPSC-Derived Cardiomyocytes for Preclinical Cardiac Risk Evaluation
Published on: October 20, 2022
Related Concept Videos
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
01:22Heart Failure Drugs: Diuretics