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A Flow Cytometry-based Assay for Measuring Mitochondrial Membrane Potential in Cardiac Myocytes After Hypoxia/Reoxygenation
Published on: July 13, 2018
Exploration of novel 20S proteasome activators featuring anthraquinone structures and their application in hypoxic
Qian Yu1, Lixin Gao2, Linhao Xu3
1Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, Zhejiang Province, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang Province, China.
Abstract:
Under hypoxic conditions, the accumulation of misfolded proteins primarily relies on the autonomous activity of 20S proteasome for degradation. The buildup of toxic proteins in cardiomyocyte contribute to various cardiovascular diseases. Therefore, enhancing the 20S proteasome degradation capacity and restoring protein homeostasis in myocardial cells with small molecule activators represent a promising therapeutic strategy for the treatment of ischemic cardiomyopathy. In this study, the lead compound 8016-8398 was identified through virtual screening, and subsequent structure optimization resulted in a series of highly potent 20S proteasome activators. Intracellular protein degradation assessment revealed that these compounds possessed abilities to alleviate endoplasmic reticulum stress, as demonstrated by the luciferase reporter system. Additionally, selected compound B-03 significantly enhanced the survival rate of hypoxic-damaged cardiomyocytes. Mechanistic investigations verified B-03 rescued hypoxic damaged cardiomyocyte through apoptosis inhibition and proliferation promotion.
Insights
Researchers developed novel small molecule activators targeting the 20S proteasome to combat toxic protein buildup in heart cells. These compounds show promise for treating ischemic cardiomyopathy by restoring protein homeostasis and protecting against hypoxia.
Area of Science:
- Biochemistry
- Cardiovascular Biology
- Pharmacology
Background:
- Misfolded protein accumulation under hypoxia contributes to cardiovascular diseases.
- The 20S proteasome is crucial for degrading misfolded proteins in cardiomyocytes.
- Restoring protein homeostasis via 20S proteasome activation is a potential therapeutic strategy for ischemic cardiomyopathy.
Purpose of the Study:
- To identify and optimize small molecule activators of the 20S proteasome.
- To evaluate the efficacy of these activators in degrading misfolded proteins and alleviating endoplasmic reticulum stress.
- To assess the therapeutic potential of these compounds in protecting cardiomyocytes against hypoxic damage.
Main Methods:
- Virtual screening to identify lead compounds.
- Structure-based optimization to develop potent 20S proteasome activators.
- Luciferase reporter assay to assess endoplasmic reticulum stress.
- In vitro assessment of cardiomyocyte survival and mechanistic studies.
Main Results:
- A series of potent 20S proteasome activators were synthesized, starting from lead compound 8016-8398.
- Compounds demonstrated the ability to alleviate endoplasmic reticulum stress by enhancing intracellular protein degradation.
- Compound B-03 significantly improved the survival rate of hypoxic cardiomyocytes.
- B-03 was shown to inhibit apoptosis and promote proliferation in damaged cardiomyocytes.
Conclusions:
- Small molecule 20S proteasome activators represent a promising therapeutic avenue for ischemic cardiomyopathy.
- Compound B-03 effectively protects cardiomyocytes from hypoxic injury by modulating apoptotic and proliferative pathways.
- Targeting the 20S proteasome offers a novel strategy for restoring protein homeostasis in cardiovascular diseases.
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