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CD36 attenuates pressure overload-induced myocardial insulin resistance via HSF1-dependent HSP90α suppression and
Hongyang Shu1,2, Na Li3, Qinqing Zhao4,5
1Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China. shy@tjh.tjmu.edu.cn.
Insights
CD36 combats heart failure by improving insulin sensitivity. It reduces insulin resistance through two key actions, enhancing metabolic function and offering a potential therapeutic target for heart conditions.
Area of Science:
- Cardiology
- Metabolic Disorders
- Molecular Biology
Background:
- Insulin resistance (IR) is an early indicator of myocardial injury and heart failure due to pressure overload.
- The role of CD36, a fatty acid transporter, in myocardial IR under pressure overload is not well understood.
- This study investigates CD36's protective mechanisms against pressure overload-induced cardiac insulin resistance.
Purpose of the Study:
- To elucidate the cardioprotective mechanisms of CD36 in pressure overload-induced heart failure.
- To determine how CD36 influences insulin sensitivity and signaling in the heart.
- To identify key molecular interactions and pathways regulated by CD36 in cardiac hypertrophy.
Main Methods:
- Analysis of myocardial tissues from heart failure patients and pressure-overloaded mice.
- Investigating CD36 effects via genetic manipulation (rAAV9-tnt-CD36) and pharmacological agents.
- Utilizing mass spectrometry to identify CD36-interacting proteins, specifically HSP90α.
- Assessing glucose uptake, insulin receptor (InsR)/Akt phosphorylation, and subcellular localization of InsR.
Main Results:
- Reduced CD36 levels and insulin sensitivity were observed in pathological cardiac conditions.
- CD36 overexpression improved glucose uptake and insulin signaling.
- CD36 disrupted the InsR-HSP90α interaction by suppressing HSP90α transcription (via HSF1) and competitively displacing HSP90α.
- CD36 promoted InsR plasma membrane localization, counteracting pathological trapping in the cytosol.
Conclusions:
- CD36 mitigates pressure overload-induced IR through dual mechanisms involving HSF1 and HSP90α.
- CD36 enhances InsR membrane localization, stabilizing insulin signaling and restoring metabolic homeostasis.
- CD36 represents a promising therapeutic target for heart failure associated with metabolic dysfunction.
Background:
Insulin resistance (IR) is an early hallmark of pressure overload-induced myocardial injury and heart failure. Although CD36, a fatty acid transporter, regulates systemic insulin sensitivity, its role in myocardial insulin resistance under pressure overload remains unclear. This study aimed to elucidate CD36's cardioprotective mechanisms in this context.
Methods:
Myocardial tissues from dilated cardiomyopathy patients, transverse aortic constriction (TAC) mice, and cultured hypertrophic cardiomyocytes were analyzed for CD36 expression and insulin sensitivity. CD36 overexpression was induced via rAAV9-tnt-CD36. InsR-interacting proteins in CD36-overexpressing cells were profiled using tandem mass spectrometry, identifying HSP90α as the key partner. HSP90α agonists were used in rescue experiments. Glucose uptake (2-NBDG assay) and InsR/Akt phosphorylation were measured. Mechanistic studies included immunofluorescence, subcellular fractionation, and HSF1 transcriptional regulation analysis.
Results:
CD36 levels and insulin sensitivity were reduced in dilated cardiomyopathy patients, TAC mice, and hypertrophic cardiomyocytes. CD36 overexpression enhanced glucose uptake and insulin signaling. Mass spectrometry identified HSP90α (not HSP90β) as the critical InsR partner modulated by CD36. HSP90α agonists reversed CD36-mediated improvements in glucose uptake and InsR/Akt phosphorylation. Mechanistically, CD36 disrupted HSP90α-InsR binding via (1) HSF1-dependent transcriptional suppression of HSP90α and (2) competitive displacement of HSP90α from InsR. Pathological conditions increased cytosolic InsR-HSP90α trapping, while CD36 redistributed InsR to the plasma membrane.
Conclusion:
CD36 mitigates pressure overload-induced insulin resistance by dual mechanisms: suppressing HSP90α expression via HSF1 inhibition and competitively displacing HSP90α to promote InsR membrane localization. This stabilizes insulin signaling and restores metabolic homeostasis, highlighting CD36 as a therapeutic target for heart failure involving metabolic-cardiac crosstalk.
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