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Hsp20-Mediated Activation of Exosome Biogenesis in Cardiomyocytes Improves Cardiac Function and Angiogenesis in
Xiaohong Wang1, Haitao Gu1, Wei Huang2
1Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH.
Abstract:
Decreased heat shock protein (Hsp) expression in type 1 and type 2 diabetes has been implicated as a primary factor contributing to diabetes-induced organ damage. We recently showed that diabetic cardiomyocytes could release detrimental exosomes, which contain lower levels of Hsp20 than normal ones. To investigate whether such detrimental exosomes could be modified in cardiomyocytes by raising Hsp20 levels to become protective, we used a transgenic (TG) mouse model with cardiac-specific overexpression of Hsp20. TG and control wild-type (WT) mice were injected with streptozotocin (STZ) to induce diabetes. We observed that overexpression of Hsp20 significantly attenuated STZ-caused cardiac dysfunction, hypertrophy, apoptosis, fibrosis, and microvascular rarefaction. Moreover, Hsp20-TG cardiomyocytes exhibited an increased generation/secretion of exosomes by direct interaction of Hsp20 with Tsg101. Of importance, exosomes derived from TG cardiomyocytes encased higher levels of Hsp20, p-Akt, survivin, and SOD1 than WT exosomes and protected against in vitro hyperglycemia-triggered cell death, as well as in vivo STZ-induced cardiac adverse remodeling. Last, blockade of exosome generation by GW4869 remarkably offset Hsp20-mediated cardioprotection in diabetic mice. Our results indicate that elevation of Hsp20 in cardiomyocytes can offer protection in diabetic hearts through the release of instrumental exosomes. Thus, Hsp20-engineered exosomes might be a novel therapeutic agent for diabetic cardiomyopathy.
Insights
Elevating heat shock protein 20 (Hsp20) in heart cells protects against diabetes-induced damage by enhancing protective exosomes. This suggests Hsp20-engineered exosomes could treat diabetic cardiomyopathy.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cell Biology
Background:
- Decreased heat shock protein (Hsp) expression contributes to diabetes-induced organ damage.
- Diabetic cardiomyocytes release exosomes with lower Hsp20 levels, exacerbating damage.
- Hsp20 plays a crucial role in cellular protection and stress response.
Purpose of the Study:
- To investigate if increasing Hsp20 levels in cardiomyocytes can create protective exosomes.
- To determine the therapeutic potential of Hsp20-overexpressing exosomes in diabetic cardiomyopathy.
- To elucidate the mechanism by which Hsp20 influences exosome function in diabetes.
Main Methods:
- Utilized a transgenic mouse model with cardiac-specific Hsp20 overexpression.
- Induced diabetes using streptozotocin (STZ) in transgenic (TG) and wild-type (WT) mice.
- Analyzed cardiac function, histology, apoptosis, fibrosis, and microvascular density.
- Investigated exosome generation and cargo via Hsp20-Tsg101 interaction.
- Assessed the protective effects of exosomes in vitro (hyperglycemia) and in vivo (STZ-induced diabetes).
Main Results:
- Hsp20 overexpression significantly attenuated STZ-induced cardiac dysfunction, hypertrophy, apoptosis, fibrosis, and microvascular rarefaction.
- Hsp20-TG cardiomyocytes showed increased exosome generation, with exosomes containing higher Hsp20, p-Akt, survivin, and SOD1.
- Exosomes derived from TG cardiomyocytes protected against hyperglycemia-induced cell death and STZ-induced cardiac remodeling.
- Blocking exosome generation with GW4869 diminished Hsp20-mediated cardioprotection.
Conclusions:
- Elevating cardiomyocyte Hsp20 levels protects the diabetic heart via enhanced release of functional exosomes.
- Hsp20 directly interacts with Tsg101 to promote exosome generation and loading of protective cargo.
- Hsp20-engineered exosomes represent a promising novel therapeutic strategy for diabetic cardiomyopathy.
