A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction

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

doi:10.1073/pnas.2011614117

A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction

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

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

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.

Original language	English (US)
Pages (from-to)	31353-31364
Number of pages	12
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	117
Issue number	49
DOIs	https://doi.org/10.1073/pnas.2011614117
State	Published - Dec 8 2020

Keywords

Fibrosis
MCB-613
Myocardial infarction
Cell Differentiation/drug effects
Cyclohexanones/pharmacology
Receptors, Steroid/metabolism
Myocardial Infarction/genetics
RNA/genetics
Macrophages/drug effects
Animals
Fibroblasts/drug effects
RAW 264.7 Cells
Mice
Transcription, Genetic/drug effects
Heart Function Tests
Inflammation/pathology
Pyridines/pharmacology
Ventricular Remodeling/drug effects

ASJC Scopus subject areas

General

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10.1073/pnas.2011614117

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Mullany, L. K., Rohira, A. D., Leach, J. P., Kim, J. H., Monroe, T. O., Ortiz, A. R., Stork, B., Gaber, M. W., Sarkar, P., Sikora, A. G., Rosengart, T. K., York, B., Song, Y., Dacso, C. C., Lonard, D. M., Martin, J. F., & O'Malley, B. W. (2020). A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction. Proceedings of the National Academy of Sciences of the United States of America, 117(49), 31353-31364. https://doi.org/10.1073/pnas.2011614117

Mullany, LK, Rohira, AD, Leach, JP, Kim, JH, Monroe, TO, Ortiz, AR, Stork, B, Gaber, MW, Sarkar, P, Sikora, AG, Rosengart, TK, York, B, Song, Y, Dacso, CC, Lonard, DM, Martin, JF & O'Malley, BW 2020, 'A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 49, pp. 31353-31364. https://doi.org/10.1073/pnas.2011614117

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

note = "Copyright {\textcopyright} 2020 the Author(s). Published by PNAS.",

year = "2020",

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doi = "10.1073/pnas.2011614117",

language = "English (US)",

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T1 - A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction

AU - Mullany, Lisa K.

AU - Rohira, Aarti D.

AU - Leach, John P.

AU - Kim, Jong H.

AU - Monroe, Tanner O.

AU - Ortiz, Andrea R.

AU - Stork, Brittany

AU - Gaber, M. Waleed

AU - Sarkar, Poonam

AU - Sikora, Andrew G.

AU - Rosengart, Todd K.

AU - York, Brian

AU - Song, Yongcheng

AU - Dacso, Clifford C.

AU - Lonard, David M.

AU - Martin, James F.

AU - O'Malley, Bert W.

PY - 2020/12/8

Y1 - 2020/12/8

N2 - 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.

AB - 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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KW - Myocardial infarction

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KW - Cyclohexanones/pharmacology

KW - Receptors, Steroid/metabolism

KW - Myocardial Infarction/genetics

KW - RNA/genetics

KW - Macrophages/drug effects

KW - Animals

KW - Fibroblasts/drug effects

KW - RAW 264.7 Cells

KW - Mice

KW - Transcription, Genetic/drug effects

KW - Heart Function Tests

KW - Inflammation/pathology

KW - Pyridines/pharmacology

KW - Ventricular Remodeling/drug effects

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SN - 0027-8424

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EP - 31364

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

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

IS - 49

ER -

A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction

Abstract

Keywords

ASJC Scopus subject areas

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