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A thrombospondin-dependent pathway for a protective ER stress response
Jeffrey M Lynch1, Marjorie Maillet, Davy Vanhoutte
1Department of Pediatrics, Cincinnati Children's Hospital, University of Cincinnati, OH 45247, USA.
Cell
|June 12, 2012
Summary
Thrombospondins (Thbs) proteins protect against cardiac injury by enhancing the endoplasmic reticulum (ER) stress response. Thbs4 specifically promotes adaptive ER stress, augmenting ER function and protecting the heart during disease.
Area of Science:
- Cardiovascular Biology
- Cellular Stress Response
- Molecular Medicine
Background:
- Thrombospondins (Thbs) are proteins upregulated at sites of tissue damage and remodeling.
- Endoplasmic reticulum (ER) stress response is activated during disease, regulating protein homeostasis.
- A potential link between Thbs and ER stress in disease adaptation is unexplored.
Purpose of the Study:
- To investigate the role of Thrombospondins (Thbs) as effectors of the adaptive ER stress response.
- To determine the function of Thbs4 in cardiac injury and maladaptation.
- To elucidate the mechanism by which Thbs influences ER function and cellular protection.
Main Methods:
- Utilized cardiac-specific Thbs4 transgenic and Thbs4 knockout mouse models.
- Analyzed adaptive ER stress response factors and ER morphology.
- Investigated the interaction between Thbs and activating transcription factor 6α (Atf6α) in vivo and in vitro.
- Assessed cardiac injury and maladaptation phenotypes.
Main Results:
- Thbs4 transgenic mice showed protection from myocardial injury, while Thbs4(-/-) mice were sensitized.
- Thbs induction led to adaptive ER stress factor profiles and ER expansion.
- Thbs bind to the ER lumenal domain of Atf6α, promoting its nuclear translocation.
- Thbs4(-/-) mice exhibited blunted Atf6α activation, and Thbs4-mediated protection was dependent on Atf6α.
Conclusions:
- Thrombospondins (Thbs) function intracellularly as ER-resident effectors of an adaptive ER stress response.
- Thbs4 plays a protective role in cardiac remodeling by augmenting ER function via Atf6α regulation.
- This mechanism highlights Thbs as a potential therapeutic target for cardiovascular diseases involving ER stress.
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