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J Cell Physiol ; 236(6): 4403-4419, 2021 06.
Article in English | MEDLINE | ID: mdl-33184863

ABSTRACT

Prolonged endoplasmic reticulum (ER) stress is the key driving force behind diabetic cardiomyopathy (DCM). Autophagy is extensively implicated in adaptive mechanisms for cell survival. Interleukin-33 (IL-33) is known to be a potent cardiac protector, but its roles in DCM, ER stress, and autophagy are currently unknown. We aimed to explore the effects of IL-33 on DCM and characterize the roles that ER stress and autophagy play in DCM. The effects of IL-33 on DCM, ER stress, and autophagy were characterized both in db/db mice and in palmitic acid (PA)-treated cardiomyocytes. The manipulators of ER stress and autophagy were used to clarify their roles in DCM remittance conferred by IL-33. Gene expression analysis was used to identify IL-33-dependent regulators of ER stress and autophagy. Both db/db mice and PA-treated cells presented with enhanced levels of ER stress, apoptosis, and lipid deposition, as well as impaired autophagy, all of which could be reversed by IL-33. Treatment with IL-33 improved the cardiac diastolic function of diabetic mice. Nonselective autophagy inhibitors, such as 3-methyladenine (3-MA) or wortmannin, abolished the protective effects of IL-33, resulting in an increase in both ER stress and apoptosis. Strikingly, insulin-like growth factor-binding protein 3 (IGFBP3) was identified as the gene most significantly differentially expressed between IL-33 and control groups. Knockdown of IGFBP3 expression, similar to the effect of nonselective autophagy inhibitors, resulted in high levels of ER stress, impaired autophagy, and apoptosis that were not rescued upon treatment with IL-33. IL-33 abates DCM by alleviating ER stress and promoting autophagy. IGFBP3 is essential for IL-33-induced ER stress resolution and autophagic enhancement during DCM.


Subject(s)
Autophagy/drug effects , Diabetes Mellitus, Type 2/drug therapy , Diabetic Cardiomyopathies/prevention & control , Endoplasmic Reticulum Stress/drug effects , Insulin-Like Growth Factor Binding Protein 3/metabolism , Interleukin-33/pharmacology , Myocytes, Cardiac/drug effects , Animals , Apoptosis Regulatory Proteins/metabolism , Autophagy-Related Proteins/metabolism , Cells, Cultured , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Diabetic Cardiomyopathies/etiology , Diabetic Cardiomyopathies/metabolism , Diabetic Cardiomyopathies/pathology , Disease Models, Animal , Insulin-Like Growth Factor Binding Protein 3/genetics , Male , Mice , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Palmitic Acid/toxicity , Rats, Sprague-Dawley , Signal Transduction
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