BAG3 expression and sarcomere localization in the human heart are linked to HSF-1 and are differentially affected by sex and disease
Autor: | Toni R. Pak, Christine S. Moravec, Sara Tawfik, Thomas G Martin, Jonathan A. Kirk |
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Rok vydání: | 2021 |
Předmět: |
Adult
Cardiomyopathy Dilated Male Sarcomeres 0301 basic medicine endocrine system medicine.medical_specialty Myofilament Physiology medicine.drug_class Heart Ventricles Ovariectomy Cardiomyopathy Gene Expression 030204 cardiovascular system & hematology Biology BAG3 Sarcomere 03 medical and health sciences Sex Factors 0302 clinical medicine Heat Shock Transcription Factors Myofibrils Physiology (medical) Internal medicine Gene expression medicine Animals Humans Myocytes Cardiac Adaptor Proteins Signal Transducing Aged Myocardium Dilated cardiomyopathy Middle Aged medicine.disease Rats 030104 developmental biology Endocrinology Microscopy Fluorescence Estrogen Heart failure cardiovascular system Female Apoptosis Regulatory Proteins Cardiology and Cardiovascular Medicine Research Article |
Zdroj: | Am J Physiol Heart Circ Physiol |
ISSN: | 1522-1539 0363-6135 |
Popis: | Mutations to the sarcomere-localized cochaperone protein Bcl2-associated athanogene 3 (BAG3) are associated with dilated cardiomyopathy (DCM) and display greater penetrance in male patients. Decreased protein expression of BAG3 is also associated with nongenetic heart failure; however, the factors regulating cardiac BAG3 expression are unknown. Using left ventricular (LV) tissue from nonfailing and DCM human samples, we found that whole LV BAG3 expression was not significantly impacted by DCM or sex; however, myofilament localized BAG3 was significantly decreased in males with DCM. Females with DCM displayed no changes in BAG3 compared with nonfailing. This sex difference appears to be estrogen independent, as estrogen treatment in ovariectomized female rats had no impact on BAG3 expression. BAG3 gene expression in noncardiac cells is primarily regulated by the heat shock transcription factor-1 (HSF-1). We show whole LV HSF-1 expression and nuclear localized/active HSF-1 each displayed a striking positive correlation with whole LV BAG3 expression. We further found that HSF-1 localizes to the sarcomere Z-disc in cardiomyocytes and that this myofilament-associated HSF-1 pool decreases in heart failure. The decrease of HSF-1 was more pronounced in male patients and tightly correlated with myofilament BAG3 expression. Together our findings indicate that cardiac BAG3 expression and myofilament localization are differentially impacted by sex and disease and are linked to HSF-1. NEW & NOTEWORTHY Myofilament BAG3 expression decreases in male patients with nonischemic DCM but is preserved in female patients with DCM. BAG3 expression in the human heart is tightly linked to HSF-1 expression and nuclear translocation. HSF-1 localizes to the sarcomere Z-disc in the human heart. HSF-1 expression in the myofilament fraction decreases in male patients with DCM and positively correlates with myofilament BAG3. |
Databáze: | OpenAIRE |
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