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Global heartbeat control suggests therapy for beating heart failure

Cell Press

Keeping a healthy heart beating requires the production of a constant supply of energy, a feat depending on the coordination of several genetic programs. Now, researchers report in the May issue of Cell Metabolism, a publication of Cell Press, that two closely related receptors can act together or separately to pull all of the strings. Drugs that influence these newfound global orchestrators of heart function might offer a novel approach to managing diseases of the heart muscle, according to the researchers.

"The heart is a simple pumping organ," said Vincent Giguere of McGill University in Montreal. "What it needs is energy, which it gets from different fuels¡ªglucose or fatty acids¡ªdepending on their availability. It was thought that separate programs make energy and use it through contraction, but we've revealed two receptors that control the whole setup. That's what's really new."

The orphan nuclear receptor known as ERR¦Á was known to scientists as a key regulator in the production of cellular power plants called mitochondria, the researchers explained. But whether ERR¦Á or related ERR receptors play a broader role in cardiac energetics and function remained an open question. These receptors are considered "orphans" because the molecules that normally trigger their activity have yet to be defined.

To maintain its essential function, the heart must regulate a cascade of biological processes including the uptake and processing of energy substrates, the conversion of those substrates into usable forms, the sensing of cellular energy charge, and the use of that energy for contraction, the researchers explained.

In their study, the researchers employed a powerful combination of genomic tools to identify the gene promoters to which ERR¦Á and ¦Ã bind in the adult mouse heart and to investigate changes in gene and protein expression when levels of ERR¦Á are manipulated. That investigation provided evidence that ERR¦Á and ¦Ã control most aspects of the integrated processes that fuel the heart by regulating the expression of genes involved at each step.

"The receptors control some 400 genes, and probably more," Gigu¨¨re said. Rather than being randomly distributed, "the genes fell into precise categories of well-defined energy pathways." Further study of mice lacking ERR¦Á provided evidence that the receptor plays an important role in the cardiac energy-sensing machinery.

Among the genes targeted by the receptors, the researchers uncovered several that had been linked previously to cardiomyopathies, a finding that Gigu¨¨re described as "the cherry on the sundae for us."

Those direct links to human disease suggest that drugs targeting ERR receptors might hold promise for novel heart therapies. "There are not many ways to prevent heart failure, but molecules that act on these receptors might be one," he said.

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The researchers include Catherine R. Dufour and Brian J. Wilson of McGill University Health Centre in Montreal; Janice M. Huss of City of Hope in Duarte, CA; Daniel P. Kelly of Washington University School of Medicine in St. Louis; William A. Alaynick, Michael Downes, and Ronald M. Evans of The Salk Institute for Biological Studies in La Jolla; Mathieu Blanchette of McGill Centre for Bioinformatics in Montr¨¦al; Vincent Giguere of McGill University and McGill University Health Centre in Montr¨¦al.

This work was supported by grants from the Canadian Institutes for Health Research and Genome Quebec/Canada to V.G. and the NIH to R.M.E. (R01 HD27183), J.M.H. (K01 DK063051) and D.P.K. (R01 HL058493).

Dufour et al.: "Genome-wide Orchestration of Cardiac Functions by the Orphan Nuclear Receptors ERRa and g." Publishing in Cell Metabolism 5, 345¨C356, May 2007. DOI 10.1016/j.cmet.2007.03.007 www.cellmetabolism.org

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