Researchers from Case Western Reserve University have found a new target for drug developers looking for ways to improve cardiac function in heart failure patients.
The study, published in Science Advances, examined the efficacy of bypassing complex cell signaling pathways not regulated in failing hearts by targeting proteins responsible for contracting the heart’s muscles.
Results showed that modifying myosin binding protein-C (MyBP-C), a protein shown to significantly enhance cardiac output in mice, could be used to improve heart function in humans.
"Phosphorylation of MyBP-C enhances both the magnitude and rate of cardiomyocyte contraction, which at the whole heart level translates to enhanced systolic left-ventricular pressures, and ultimately cardiac output," said Julian E. Stelzer, PhD, an associate professor in the department of physiology and biophysics at Case Western, in a statement. "Our findings show that a specific amino acid on MyBP-C, serine 302, can be directly targeted to enhance the rate and magnitude of cardiac pump function, which would be of benefit to a large number of heart failure patients."
In the study, the researchers explored their findings in several models, including isolated heart muscle fibers and in mouse hearts.
"In the intact heart, phosphorylation of serine 302 increased the rate and magnitude of pressure development, and therefore cardiac output, but this effect was abolished in mice with modified serine 302 MyBP-C," said Ranganath Mamidi, PhD, an author on the study and a postdoctoral scholar in the department of physiology and biophysics at Case Western, in a statement. "Therefore, our studies have identified a critical downstream target of stress signaling that can modulate cardiac output in vivo."
Ultimately, findings suggest that medications which help phosphate molecules bind to serine 301 and MyBP-C could significantly improve cardiac function in people suffering from heart failure.
"Now that serine 302 in MyBP-C has been identified as a molecular target to boost cardiac performance, efforts are underway to design small molecules that can elicit similar functional effects in the intact human heart,” Stelzer said.