Study Identifies Potential Targets for Prevention of Post-MI Heart Failure

Lisa Mullany, PhD

New findings presented at the Endocrine Society’s Annual Meeting (ENDO 2021) showed that treatment with MCB-613, a small molecule activator of steroid receptor co-activators (SRCs), can potentially repair heart tissue following a severe heart attack.

As such, damage leading to heart failure may be prevented.

Previous research has demonstrated that MCB-613 can stimulate SRCs, proteins that are responsible for cellular changes and growth.

“Members of the p160 SRC family, SRC-1 (NCOA1), SRC-2 (NCOA2/TIF2/GRIP1) and SRC-3 (NCOA3/AIB1/ACTR/pCIP), interact with nuclear receptors and other transcription factors to drive target gene expression by assembling transcriptional coactivator complexes to increase transcription,” explained the investigators, led by Lisa Mullany, PhD, Baylor College of Medicine, Houston.

“This indicates a potential for SRC targeting drugs pertinent to cell migration, proliferation and survival- promoting paracrine interactions in cardiac tissue injury responses,” they continued.

They explained that MCB-613 selectively and reversibly binds to SRCs and can enhance SRC transcriptional activity, as demonstrated in mice.

“We postulated that MCB-613 could enable wound repair and preservation of cardiac function after an acute MI by reducing the extent of injury-related fibrosis and the subsequent chronic loss of cardiac function associated with non-contracting scar tissue,” Mullany and team wrote.

Thereforw, they administered MCB-613 to a mouse model 2 hours following ischemic injury.

They assessed measurements of functional cardiac output and damage as well as cell-type specific responses that are responsible for MCB-613’s cardio-protective effects. They did so by using single cell transcriptomics of cardiac interstitial cells so they could characterize the effects of SRC stimulation on cardiac function following myocardial infarction.

Promising Results

The team demonstrated that the SRC stimulator has the ability to attenuate pathological remodeling following myocardial infarction.

They observed that MCB-613 decreased infarct size, apoptosis, hypertrophy, and fibrosis. All the more, the investigators noted, significant cardiac function was maintained.

MCB-613 granted long-lasting protection from adverse remodeling while inhibiting macrophage inflammatory signaling and IL-2 signaling, attenuating fibroblast differentiation, and promoting Tsc22d3 expressing macrophages.

Doing so has the potential to reduce the acute inflammatory response and limit inflammatory damage.

“This is a remarkable discovery that may lead to effective and safe treatments to prevent the progression to heart failure after a heart attack,” Mullany said in a statement.  “Our findings show us that we can directly modulate heart tissue repair to prevent heart failure.”

These findings add to the growing body of research that indicates further analysis of SRCs as potential drug targets for the management of myocardial injury response outcomes is warranted. 

The study, “A Steroid Receptor Coactivator Stimulator MCB-613 Attenuates Adverse Remodeling After Myocardial Infarction,” was presented at ENDO 2021.