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ZYZ-772 Prevents Cardiomyocyte Injury by Suppressing Nox4-Derived ROS Production and Apoptosis
Ying Wang1, Liangjie Zhong2, Xinhua Liu3
1Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China. tiantianwangying@126.com.
Abstract:
Nox-dependent signaling plays critical roles in the development of heart failure, cardiac hypertrophy, and myocardial infarction. NADPH oxidase 4 (Nox4) as a major source of oxidative stress in the heart offers a new therapeutic target in cardiovascular disease. In the present work, a novel flavonoid was isolated from Zanthoxylum bungeanum. Its structure was elucidated as Quercetin-3-O-(6''-O-α-l-rhamnopyransoyl)-β-d-glucopyranoside-7-O-β-d-glucopyranoside (ZYZ-772) for the first time. ZYZ-772 exhibited significant cardio-protective property against CoCl₂ induced H9c2 cardiomyocyte cells injury. In CoCl₂ stimulated cardiomyocyte injury, ZYZ-772 inhibited expression of Nox4, and alleviated ROS overproduction. Importantly, ROS triggered MAPKs phosphorylation and P53 signaling mediated apoptosis were restored by ZYZ-772. Our findings present the first piece of evidence for the therapeutic properties of ZYZ-772 in preventing cardiomyocyte injury, which could be attributed to the suppression of Nox4/MAPKs/P53 axis. This will offer a novel therapeutic strategy for the treatment of cardiac ischemia disease.
Insights
A novel flavonoid, ZYZ-772, protects heart cells from injury by inhibiting NADPH oxidase 4 (Nox4) and reducing oxidative stress. This discovery offers a new therapeutic strategy for treating cardiac ischemia disease.
Area of Science:
- Cardiovascular Science
- Pharmacology
- Biochemistry
Background:
- Nox-dependent signaling is crucial in heart failure, cardiac hypertrophy, and myocardial infarction.
- NADPH oxidase 4 (Nox4) is a key contributor to cardiac oxidative stress and a potential therapeutic target.
- Oxidative stress and Nox4 signaling are implicated in cardiomyocyte injury.
Purpose of the Study:
- To isolate and identify a novel flavonoid from Zanthoxylum bungeanum with potential cardioprotective properties.
- To investigate the therapeutic effects of the novel flavonoid ZYZ-772 against cardiomyocyte injury.
- To elucidate the molecular mechanisms underlying the cardioprotective effects of ZYZ-772, focusing on the Nox4/MAPKs/P53 axis.
Main Methods:
- Isolation and structural elucidation of a novel flavonoid (ZYZ-772) from Zanthoxylum bungeanum.
- Assessment of ZYZ-772's protective effects against CoCl₂-induced H9c2 cardiomyocyte injury.
- Evaluation of Nox4 expression, reactive oxygen species (ROS) production, MAPKs phosphorylation, and P53 signaling in injured cardiomyocytes treated with ZYZ-772.
Main Results:
- A novel flavonoid, Quercetin-3-O-(6''-O-α-l-rhamnopyransoyl)-β-d-glucopyranoside-7-O-β-d-glucopyranoside (ZYZ-772), was successfully isolated and identified.
- ZYZ-772 demonstrated significant protection against CoCl₂-induced cardiomyocyte injury.
- ZYZ-772 inhibited Nox4 expression, reduced ROS overproduction, and restored MAPKs phosphorylation and P53 signaling, thereby alleviating apoptosis.
Conclusions:
- ZYZ-772 exhibits significant therapeutic potential for preventing cardiomyocyte injury.
- The cardioprotective mechanism of ZYZ-772 involves the suppression of the Nox4/MAPKs/P53 signaling pathway.
- ZYZ-772 represents a promising novel therapeutic strategy for cardiac ischemia diseases.
