Published online February 10 in Nature Medicine, the research could have unique clinical application for treating diastolic heart failure.
Within heart cells, calcium plays a major role in orchestrating normal heart pump function. However, in diastolic failure the calcium signaling process is slowed; calcium levels rise to the peak needed for the squeezing action of the heart but don’t then drop quickly enough for an efficient relaxation period – the condition known as diastolic heart failure.
With help from Potter and his former post-doctoral fellow Qi Li, Ph.D., researchers led by Joseph M. Metzger, Ph.D., professor and chair of the University of Minnesota’s Department of Integrative Biology and Physiology, pinpointed a specific protein, parvalbumin – which aids in high-speed relaxation of fast-twitching muscles in nature – and optimized it to become a calcium sponge for the heart muscle. As a result, the optimized protein, ParvE101Q, soaks up excess calcium at a precise instant, allowing the heart to relax efficiently after contraction.
Described in the study, “Noncanonical EF-hand motif strategically delays Ca2+ buffering to enhance cardiac performance,” the advance offers a solid conceptual step forward in solving the puzzle of diastolic heart failure. The next step will be determining the best possible small molecule or gene delivery mechanism for the protein, which should allow the discovery to be used in clinics.
Potter and Li contributed to the study by engineering parvalbumin to alter its calcium and magnesium binding properties in such a way as to lower its calcium affinity and raise its magnesium affinity.
“Interestingly, when this was expressed in vitro in cardiac myocytes and in vivo in mice, it enhanced cardiac relaxation,” Potter said. “In disease models of diastolic dysfunction, it corrected the abnormal relaxation associated with these models. Thus, this modified protein can serve as a model to develop new therapeutic strategies for biological systems with Ca2+ handling abnormalities, especially those found in the heart, and may usher in a novel new therapeutic approach for many diseases.”
Metzger, the Maurice B. Visscher Endowed Chair in Physiology, said the sponge mechanism works as a temporary depot for calcium along its normal pathway. It increases productivity in the relaxation phase of the heart cycle without negatively impacting the contracting phase.
“In nature, there are unique organisms known to be able to contract and relax muscles quickly,” he said. “We hoped research and discovery could help identify what was promoting this highly efficient activity so we could harness it for use in the heart. We’ve discovered that our optimized variation of parvalbumin can fulfill that role by treating diastolic heart failure.”
If researchers can develop an ideal delivery system for the optimized protein, they believe they may have found a unique clinical application to treat diastolic heart failure. Heart failure is a common killer of both men and women across the country and the rate of heart failure is increasing as our population ages and as the survival rate after recovery from first heart attack goes up.
Researchers at The Ohio State University College of Medicine also contributed to the study.
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