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Unexpected protein key to estrogen’s protective effect on right heart function, IU researchers find

INDIANAPOLIS—For years, scientists have observed that women with pulmonary hypertension have better survival rates than men with the same condition. It wasn’t clear exactly why this is true—until now. 

Indiana University School of Medicine researchers studying a type of pulmonary hypertension called pulmonary arterial hypertension (PAH) found that estrogen, its receptor ER-α, and a protein called BMPR2 work together to increase an abundance of another protein called apelin, which exerts a protective effect on the right heart. 

This team is the first to identify and characterize a protective pathway that is able to prevent and even reverse right heart failure, said Andrea Frump, PhD, an Assistant Professor of Medicine at IU School of Medicine and the paper’s first author. 

The researchers shared their discovery in an article published in the Journal of Clinical Investigation last month.  

According to Tim Lahm, MD, an Associate Professor of Medicine at IU School of Medicine and the paper’s senior author, the researchers expected to find that estrogen increased the production of beneficial proteins. They did not expect the key protein to be apelin, however.

Lahm describes apelin as “pro-contractile,” which means that it increases the force generated by the muscle cells of the heart (called cardiomyocytes). In other words, he said, apelin helps the heart beat more strongly. 

“Apelin has previously been shown to play a role in other cell types, so we were surprised and excited to learn that it plays a prominent role in cardiomyocytes,” he said. “We were also surprised that this effect is mediated by BMPR2. This protein has previously been identified as a signaling mediator in blood vessels, rather than a mediator in the adult heart.” 

The study, which began in 2014 and also involved researchers from other institutions in the United States and Canada, relied on right heart tissue from patients with PAH and right heart failure, as well as on animal models and cell culture studies.

While the study primarily focused on PAH, which is relatively rare, the findings are also pertinent for right heart failure caused by other, more common types of pulmonary hypertension, said Lahm.

He said that these other forms of pulmonary hypertension frequently occur in people with chronic lung disease, heart disease, and sleep-disordered breathing, meaning that about70 million people in the U.S. either have right heart dysfunction or are at risk for it.

“Ultimately, our goal is to harness this newly identified mechanism to develop new therapeutic interventions for patients with right heart failure from PAH and other types of pulmonary hypertension,” said Lahm. “And those treatments could be beneficial to both women and men.” 


IU School of Medicine is the largest medical school in the U.S. and is annually ranked among the top medical schools in the nation by U.S. News & World Report. The school offers high-quality medical education, access to leading medical research and rich campus life in nine Indiana cities, including rural and urban locations consistently recognized for livability.