Northwestern Medicine scientists have revealed the role of a protein, SNRK, in cardiac tissue metabolism, which may lead to new insights in treating heart failure.
In a Nature Communications paper, the authors show that overexpression of SNRK alters heart tissue by reducing its metabolism of fatty acids and glucose, while retaining normal function.
“This was quite surprising to us,” said lead author Hossein Ardehali, MD, PhD, professor of Medicine in the Division of Cardiology and of Pharmacology. “The heart usually uses about 70 percent fatty acids and 30 percent glucose and under disease conditions, this ratio reverses. It has never been shown that the metabolism of both of these substrates are reduced simultaneously in a normal heart.”
Amy Rines, ’12 PhD, first author on the paper added, “the function of this protein wasn’t characterized but the family of proteins that SNRK is in, which includes AMPK kinases, is interesting and studying those proteins has had implications for many diseases including heart disease and cancer.”
Using mouse models, the scientists further demonstrated that mice overexpressing SNRK were also protected against ischemic heart disease, which restricts blood flow to the heart, damaging cardiac tissue by reducing the amount of nutrients such as oxygen, fatty acids and glucose.
The scientists also investigated the mechanisms behind this improved metabolic efficiency in the heart and found that mitochondria become more metabolically efficient and leak less electrons in the presence of increased levels of SNRK. They also showed the opposite effect on the mitochondria occurs in mice without SNRK protein, in addition to an increased use of both glucose and fatty acid.
“Under normal conditions, there is some inefficiency in energy production in the mitochondria, and overexpression of this protein appears to make the mitochondria more efficient in energy production,” said Ardehali, also the director of the Center for Molecular Cardiology in the Feinberg Cardiovascular Research Institute.
To better understand how the SNRK protein affects mitochondria and proteins involved in metabolism, Ardehali and his team used a yeast two-hybrid system and identified another protein involved in this pathway, called Trib3.
“Our goal is to activate this pathway and by activating it, improve metabolic efficiency of the heart,” Ardehali said. “We would like to find the mechanism on how to activate this protein, and if we can find a chemical that activates it, then it could be translated to clinical practice. There is a great deal of effort to identify AMPK activators.”
Ardehali is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
The study was supported by National Institutes of Health grants HL107448, HL087149, HL104181, HL108795, HL108379 and the American Heart Association.
