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Celastrol, an oral heat shock activator, ameliorates multiple animal disease models of cell death
Sudhish Sharma1, Rachana Mishra, Brandon L Walker
1Division of Cardiac Surgery, University of Maryland Medical Center, 110 S. Paca Street, 7th Floor, Baltimore, MD, 21201, USA.
Abstract:
Protein homeostatic regulators have been shown to ameliorate single, loss-of-function protein diseases but not to treat broader animal disease models that may involve cell death. Diseases often trigger protein homeostatic instability that disrupts the delicate balance of normal cellular viability. Furthermore, protein homeostatic regulators have been delivered invasively and not with simple oral administration. Here, we report the potent homeostatic abilities of celastrol to promote cell survival, decrease inflammation, and maintain cellular homeostasis in three different disease models of apoptosis and inflammation involving hepatocytes and cardiomyocytes. We show that celastrol significantly recovers the left ventricular function and myocardial remodeling following models of acute myocardial infarction and doxorubicin-induced cardiomyopathy by diminishing infarct size, apoptosis, and inflammation. Celastrol prevents acute liver dysfunction and promotes hepatocyte survival after toxic doses of thioacetamide. Finally, we show that heat shock response (HSR) is necessary and sufficient for the recovery abilities of celastrol. Our observations may have dramatic clinical implications to ameliorate entire disease processes even after cellular injury initiation by using an orally delivered HSR activator.
Insights
Celastrol, an orally administered compound, promotes cell survival and reduces inflammation in various disease models. Its recovery abilities are dependent on activating the heat shock response (HSR).
Area of Science:
- Cellular homeostasis and disease pathology
- Protein homeostasis and therapeutic interventions
- Heat shock response (HSR) activation
Background:
- Protein homeostasis regulators typically treat single-function protein diseases, not complex conditions involving cell death.
- Disease states often disrupt cellular viability by destabilizing protein homeostasis.
- Existing protein homeostatic regulators require invasive delivery, limiting their clinical application.
Purpose of the Study:
- To investigate celastrol's homeostatic and cell-protective effects in disease models.
- To evaluate celastrol's efficacy in models of apoptosis and inflammation.
- To determine the role of the heat shock response (HSR) in celastrol's therapeutic actions.
Main Methods:
- Utilized three distinct disease models involving hepatocytes and cardiomyocytes, focusing on apoptosis and inflammation.
- Assessed celastrol's impact on left ventricular function, myocardial remodeling, infarct size, and apoptosis in cardiac disease models.
- Investigated celastrol's effects on liver dysfunction and hepatocyte survival in a toxic liver injury model.
- Determined the necessity and sufficiency of the heat shock response (HSR) for celastrol's recovery effects.
Main Results:
- Celastrol demonstrated potent cell survival, anti-inflammatory, and homeostatic maintenance capabilities across all tested disease models.
- In cardiac models, celastrol significantly improved left ventricular function and myocardial remodeling by reducing infarct size and apoptosis.
- Celastrol effectively prevented acute liver dysfunction and enhanced hepatocyte survival following toxic insult.
- The heat shock response (HSR) was identified as both necessary and sufficient for celastrol's observed recovery effects.
Conclusions:
- Celastrol exhibits significant therapeutic potential for a range of diseases involving apoptosis and inflammation.
- Oral administration of celastrol, an activator of the heat shock response (HSR), offers a promising therapeutic strategy.
- These findings suggest celastrol can ameliorate disease processes even after cellular injury initiation, with broad clinical implications.
