A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction
Lisa K. Mullany, Aarti D. Rohira, John P. Leach, Jong Hoon 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
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.