A Steroid Receptor Coactivator Stimulator (Mcb-613) Attenuates Adverse Remodeling After Myocardial Infarction

Authors

Lisa K Mullany
Aarti D Rohira
John P Leach
Jong H Kim
Tanner O Monroe
Andrea R Ortiz
Brittany Stork
M Waleed Gaber
Poonam Sarkar
Andrew G Sikora
Todd K Rosengart
Brian York
Yongcheng Song
Clifford C Dacso
David M Lonard
James F Martin
Bert W O'Malley

Publication Date

12-8-2020

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2011614117

PMID

33229578

PMCID

PMC7733826

PubMedCentral® Posted Date

11-23-2020

Published Open-Access

yes

Keywords

Animals, Cell Differentiation, Cyclohexanones, Fibroblasts, Fibrosis, Heart Function Tests, Inflammation, Macrophages, Mice, Myocardial Infarction, Pyridines, RAW 264.7 Cells, RNA, Receptors, Steroid, Transcription, Genetic, Ventricular Remodeling

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.

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