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A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Dec 08; Vol. 117 (49), pp. 31353-31364. Date of Electronic Publication: 2020 Nov 23. - Publication Year :
- 2020
-
Abstract
- Progressive remodeling of the heart, resulting in cardiomyocyte (CM) loss and increased inflammation, fibrosis, and a progressive decrease in cardiac function, are hallmarks of myocardial infarction (MI)-induced heart failure. We show that MCB-613, a potent small molecule stimulator of steroid receptor coactivators (SRCs) attenuates pathological remodeling post-MI. MCB-613 decreases infarct size, apoptosis, hypertrophy, and fibrosis while maintaining significant cardiac function. MCB-613, when given within hours post MI, induces lasting protection from adverse remodeling concomitant with: 1) inhibition of macrophage inflammatory signaling and interleukin 1 (IL-1) signaling, which attenuates the acute inflammatory response, 2) attenuation of fibroblast differentiation, and 3) promotion of Tsc22d3-expressing macrophages-all of which may limit inflammatory damage. SRC stimulation with MCB-613 (and derivatives) is a potential therapeutic approach for inhibiting cardiac dysfunction after MI.<br />Competing Interests: The authors declare no competing interest.<br /> (Copyright © 2020 the Author(s). Published by PNAS.)
- Subjects :
- Animals
Cell Differentiation drug effects
Fibroblasts drug effects
Fibroblasts metabolism
Fibroblasts pathology
Fibrosis
Heart Function Tests
Inflammation pathology
Macrophages drug effects
Macrophages pathology
Mice
Myocardial Infarction genetics
Myocardial Infarction pathology
RAW 264.7 Cells
RNA genetics
RNA metabolism
Transcription, Genetic drug effects
Cyclohexanones pharmacology
Myocardial Infarction physiopathology
Pyridines pharmacology
Receptors, Steroid metabolism
Ventricular Remodeling drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 117
- Issue :
- 49
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 33229578
- Full Text :
- https://doi.org/10.1073/pnas.2011614117