Discovery shows how to treat heart attacks; drug development underway | New
Vanderbilt researchers have identified the protein receptor in specialized heart cells that, when removed, preserve heart function after a heart attack. This finding has important implications for survival after heart attack, with promising therapeutic development currently underway in the United States. Warren Center for Drug Discovery in Neuroscience.
The article “5-HT targeting2B Receptor signaling prevents expansion of the border area and improves microstructural remodeling after myocardial infarction ”, was published in the review Circulation January 21.
The research was led by David merryman, Walters Family Chair Professor of Biomedical Engineering, with experiments led by Caleb Snider, former Vanderbilt graduate student and current postdoctoral fellow at Washington University in St. Louis, and others. The team used genetic and drug models to confirm that removing serotonin 2B receptors in heart fibroblasts – the “worker bee” cells that produce connective tissue in the heart – helps the organ heal in a way. significant after a heart attack.
Usually, only a small area of the heart dies in a heart attack (myocardial infarction), but over time the boundaries of the scarred area dilate. The resulting stress for the heart to do more with less induces heart failure. The researchers set out to determine what exactly the protein receptor was responsible for during heart attacks and how it might be altered for better results.
Heart health is measured by the ejection fraction, which is the heart’s pumping ability. Normally, an animal has an ejection fraction of 80 percent, which halves after a heart attack. In models in which serotonin 2B was either drug-treated or genetically suppressed, the heart had a 50% higher ejection fraction six weeks after a heart attack than models in which serotonin 2B remained in cardiac fibroblasts , explained Merryman.
The most important measure in this study was heart function, measured by echocardiography. Through the biomechanical characterization of the scar and the adjacent border area, the researchers measured the evolution of the structure and function of scar tissue. They found that early inhibition of serotonin 2B after a heart attack results in a functional scar that is less likely to extend beyond the initial wound to put additional pressure on the heart.
“We have found that the drug models have an acute and long-term effect,” Merryman said. “The drug treatment preserves heart function six weeks after a heart attack to a much greater extent than the control group, and it effectively prevents worsening of the border area of the affected area of the heart.”
Merryman collaborates with Craig lindsley, Professor of Medicine William K. Warren, Jr., University Professor of Pharmacology, Biochemistry and Chemistry and Director of WCNDD, to develop a highly targeted molecule that only impacts serotonin 2B in the cardiopulmonary system where the receptor is widespread. The molecule will be designed not to cross the blood-brain barrier, thus avoiding neurological side effects. Researchers have conducted three cycles of medicinal chemistry and are examining the effectiveness of the molecule.
“This molecule has the potential to treat not only myocardial infarction, but also pulmonary arterial hypertension, known as pulmonary arterial hypertension,” Merryman said. “We are working with many clinicians to find the best path for drug development that we believe has important implications for human health.”
Research for this study was supported by grants from the National Institutes of Health R35-HL135790, R01-HL115103, R01-HL133290, R01-HL143074, R01-HL138519, K99-HL146951, F32-HL154596, T32-HL007411, T32- EB021937, the American Heart Association scholarship 18PRE34060078 and a scholarship from the Leducq Foundation.
Therapeutic development is supported by a Vanderbilt Discovery Grant. The Discovery Grants program is designed to act as a catalyst for large external funding sources including large federal funding agencies such as the National Science Foundation, National Institutes of Health, Department of Defense, etc.