Phosphorylation of Hsp20 Promotes Fibrotic Remodeling and Heart Failure
| Autor: | George Gardner, Evangelia G. Kranias, Guo-Chang Fan, Guan-Sheng Liu, Jiang Qian, Yutian Li, Nathan Robbins, Kobra Haghighi, Jack Rubinstein, Burns C. Blaxall, Min Jiang, Joshua G. Travers |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
inorganic chemicals
0301 basic medicine WT wild type STAT3 signal transducer and activator of transcription 3 heart failure I/R ischemia/reperfusion 030204 cardiovascular system & hematology environment and public health TUNEL terminal deoxynucleotidyl transferase dUTP nick end labeling fibroblast Ccl2 C-C motif chemokine ligand 2 03 medical and health sciences Paracrine signalling PRECLINICAL RESEARCH 0302 clinical medicine Downregulation and upregulation In vivo TG transgenic Col1a1 collagen 1A1 medicine Hsp heat shock protein Col3A1 collagen 3A1 Fibroblast Postn periostin TGF transforming growth factor remodeling Hsp20 IL-6 TNF tumor necrosis factor business.industry fungi medicine.disease 3. Good health Cell biology Blockade ECM extra-cellular matrix IL interleukin enzymes and coenzymes (carbohydrates) 030104 developmental biology medicine.anatomical_structure Ccl3 C-C motif chemokine ligand 3 Heart failure bacteria Phosphorylation SMA smooth muscle actin Cardiology and Cardiovascular Medicine business Ex vivo |
| Zdroj: | JACC: Basic to Translational Science |
| ISSN: | 2452-302X |
| Popis: | Visual Abstract Highlights • PKA-phosphorylation of Hsp20 is elevated in human failing hearts. • Increases in phosphorylated Hsp20 in vivo are associated with fibrotic remodeling and reduced left ventricular function. • The phosphorylated Hsp20 in cardiomyocyte promotes upregulation of IL-6 and its subsequent paracrine actions on the cardiac fibroblast. • Blockade of IL-6 effects ex vivo and in vivo reduces the pro-fibrotic effects of phosphorylated Hsp20. • Targeting phosphorylated Hsp20 in the cardiomyocyte may represent a potential therapeutic strategy to mitigate fibrotic remodeling and preserve function in the failing heart. Summary Cardiomyocyte-specific increases in phosphorylated Hsp20 (S16D-Hsp20) to levels similar to those observed in human failing hearts are associated with early fibrotic remodeling and depressed left ventricular function, symptoms which progress to heart failure and early death. The underlying mechanisms appear to involve translocation of phosphorylated Hsp20 to the nucleus and upregulation of interleukin (IL)-6, which subsequently activates cardiac fibroblasts in a paracrine fashion through transcription factor STAT3 signaling. Accordingly, treatment of S16D-Hsp20 mice with a rat anti-mouse IL-6 receptor monoclonal antibody (MR16-1) attenuated interstitial fibrosis and preserved cardiac function. These findings suggest that phosphorylated Hsp20 may be a potential therapeutic target in heart failure. |
| Databáze: | OpenAIRE |
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