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Published on: May 26, 2010
Effects of different small HSPB members on contractile dysfunction and structural changes in a Drosophila
Deli Zhang1, Lei Ke, Katarina Mackovicova
1Department of Clinical Pharmacology, University Institute for Drug Exploration, University of Groningen, University Medical Center Groningen, The Netherlands.
Insights
Fruit flies can model atrial fibrillation (AF) remodeling. Heat shock proteins (HSPs), particularly DmHSP23, protect against this remodeling, offering a new screening tool for AF therapies.
Area of Science:
- Cardiovascular Biology
- Model Organisms
- Molecular Cardiology
Background:
- Atrial Fibrillation (AF) is a progressive tachycardia causing cardiomyocyte remodeling and heart dysfunction.
- Heat shock proteins (HSPs) show protective effects against tachycardia remodeling in experimental models.
- A lack of suitable in vivo models hinders the study of tachycardia remodeling and drug screening.
Purpose of the Study:
- To investigate the utility of Drosophila melanogaster as an in vivo model for studying tachycardia-induced cardiomyocyte remodeling.
- To assess the protective effects of heat shock proteins (HSPs) against tachycardia remodeling in Drosophila.
- To identify specific small HSPs that confer protection against tachycardia remodeling.
Main Methods:
- Tachypacing of Drosophila pupae to induce cardiomyocyte remodeling.
- Treatment with heat shock or HSP-inducers (GGA, BGP-15) to modulate endogenous HSP levels.
- Genetic manipulation of Drosophila to overexpress specific small HSPs (DmHSP23, DmHSP27, etc.).
- Assessment of cardiac function (contraction rate, shortening) and ultrastructure (sarcomeres, mitochondria).
- Measurement of calpain activity.
Main Results:
- Tachypacing Drosophila induced significant cardiomyocyte remodeling, characterized by reduced contraction rate and heart wall shortening.
- Heat shock or HSP-inducer treatment protected against tachycardia remodeling by increasing endogenous HSPs.
- Overexpression of DmHSP23, but not other small HSPs, protected Drosophila against tachycardia remodeling.
- DmHSP23 overexpression prevented sarcomere loss, mitochondrial damage, and increased calpain activity induced by tachypacing.
Conclusions:
- Tachypaced Drosophila serve as a viable in vivo model for studying cardiomyocyte remodeling associated with tachycardia.
- DmHSP23 confers significant protection against tachycardia-induced cardiac remodeling.
- This Drosophila model facilitates rapid screening of novel therapeutic targets for AF-related cardiomyocyte remodeling.
Abstract:
The most common clinical tachycardia, Atrial Fibrillation (AF), is a progressive disease, caused by cardiomyocyte remodeling, which finally results in contractile dysfunction and AF persistence. Recently, we identified a protective role of heat shock proteins (HSPs), especially the small HSPB1 member, against tachycardia remodeling in experimental AF models. Our understanding of tachycardia remodeling and anti-remodeling drugs is currently hampered by the lack of suitable (genetic) manipulatable in vivo models for rapid screening of key targets in remodeling. We hypothesized that Drosophila melanogaster can be exploited to study tachycardia remodeling and protective effects of HSPs by drug treatments or by utilizing genetically manipulated small HSP-overexpressing strains. Tachypacing of Drosophila pupae resulted in gradual and significant cardiomyocyte remodeling, demonstrated by reduced contraction rate, increase in arrhythmic episodes and reduction in heart wall shortening, compared to normal paced pupae. Heat shock, or pre-treatment with HSP-inducers GGA and BGP-15, resulted in endogenous HSP overexpression and protection against tachycardia remodeling. DmHSP23 overexpressing Drosophilas were protected against tachycardia remodeling, in contrast to overexpression of other small HSPs (DmHSP27, DmHSP67Bc, DmCG4461, DmCG7409, and DmCG14207). (Ultra)structural evaluation of the tachypaced heart wall revealed loss of sarcomeres and mitochondrial damage which were absent in tachypaced DmHSP23 overexpressing Drosophila. In addition, tachypacing induced a significant increase in calpain activity, which was prevented in tachypaced Drosophila overexpressing DmHSP23. Tachypacing of Drosophila resulted in cardiomyocyte remodeling, which was prevented by general HSP-inducing treatments and overexpression of a single small HSP, DmHSP23. Thus, tachypaced D. melanogaster can be used as an in vivo model system for rapid identification of novel targets to combat AF associated cardiomyocyte remodeling.
