UB-Yale Study Finds Molecule Reduces Heart Attack Damage

The in vivo study paves the way for possible new pharmaceutical agents.

This research signals a new approach to limiting ischemic injury caused by restricted blood flow, and possibly reducing the severity of heart attacks in people over 70, says Ji Li, PhD, assistant professor of pharmacology and toxicology.

“Our data show that mice treated with MIF20 had around a 40 percent reduction in dead myocardium when compared to untreated mice,” says Li.

“We can use this molecule to enhance activation of a key cardioprotective pathway, AMP-activated protein kinase (AMPK),” he explains.

MIF20 optimally activates this pathway by increasing the binding between the regulatory protein MIF (migration inhibitory factor) and its cardiac receptor.

Small-molecular MIF agonists may compensate for age-related or genetic deficiencies in the pathway’s ability to respond to ischemic injury, the researchers conclude.

Therefore, “pharmacological interventions that restore MIF-AMPK signaling in the aged heart may be a useful means to reduce cardiac damage caused by ischemic injury,” says Li.

Li’s group performed key in vivo studies. Richard Bucala, MD, PhD, of Yale, led the overall study.

The next step will be to replicate the findings in larger mammals.

The UB-Yale team has been collaborating since 2007, when Li was on the faculty in Yale’s Department of Medicine.

In a previous study published in Nature, the researchers found that MIF initiates the protective pathway by activating AMPK.

The study demonstrates that protective MIF-AMPK signaling is under genetic control and therefore can be pharmacologically targeted to ameliorate the severity of ischemic heart disease. It was led by Lawrence H. Young, MD, professor of cardiology at Yale.

In an earlier study, the UB-Yale team found that MIF action decreases with age, which could help explain why myocardial infarction is so common after age 70.

The researchers hypothesize that aging is associated with a decline in the ability of the heart to activate the protective pathway in response to ischemia.

MIF20 was identified by Yale chemists, led by William L. Jorgenson, PhD. A related study by Bucala’s group found that this small molecule increases MIF action through its receptor.

As a first step toward developing new pharmaceuticals, Yale has filed patent applications on small-molecule MIF modulators.

The Circulation paper is entitled “Limiting Cardiac Ischemic Injury by Pharmacological Augmentation of Macrophage Migration Inhibitory Factor-AMP-Activated Protein Kinase Signal Transduction.”

UB co-authors from Li’s lab include first author Jingying Wang, PhD; second author Chao Tong, PhD; third author Xiaoyan Yan, PhD; Changxing Ma, PhD, associate professor of biostatistics; and Eddie Yeung.

Yale co-authors, in addition to Jorgenson, Bucala and Young, are Sunilkumar Gandavadi, PhD; Alissa A. Hare, PhD; Xin Du, MD; and Lin Leng, PhD. Colleagues from the Icahn School of Medicine at Mount Sinai also contributed.

National funders have supported the research, including the American Heart Association, the American Diabetes Association and the Brookdale Foundation.