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Gene Siegal 3 original scrBy Christina Crowe

Adam Wende, Ph.D., Associate Professor, Division of Molecular and Cellular Pathology, has received a R01 grant from the National Heart, Lung, and Blood Institute of the NIH to study new roles of specific proteins called pyruvate dehydrogenase kinases, or PDKs, in heart failure. The $2.3 million grant runs through 2028.

Cardiovascular disease is the number one cause of mortality in the United States. Wende’s research examines the heart’s metabolism and fuel utilization. One of the key functions of a cell is the entry of nutrients into the mitochondria, which is highly regulated. That regulation, by a family of kinases called pyruvate dehydrogenase kinases, or PDKs, is induced by exercise, but suppressed in heart failure, mimicking a “switch.”

Wende’s grant aims to test the hypothesis that PDKs play distinct roles beyond this mitochondrial oxidative metabolism in impact mortality and cardiac hypertrophy through novel signaling to transcriptional pathways in the nucleus. More specifically by regulating epigenetics through histone acetylation. These studies will further examine whether loss of different PDK isoforms, specifically PDK2, but not PDK4, is cardioprotective through differential epigenetic and transcriptional regulation, in response to pressure overload-induced heart failure.

“We’re trying to determine if PDK2 is a good target to prevent heart failure,” he says. “We think this altered fuel utilization, through histone acetylation, regulates gene expression,” Wende says. “We’re looking at why and how this is occurring, and if we can figure out what it’s regulating can we also figure out what’s making it adaptive—making it a potentially therapeutic target.”

Wende’s team has developed two novel mouse models to test this hypothesis, working to determine the role of each PDK isoform in heart failure progression, and to identify the molecular mechanisms of these differences.

“We made mice models that have either or neither of these two isoforms—they have different effects, suggesting they have roles just beyond the switch,” he says. “Metabolism feeds into a lot of things. Your heart burns these fuels to generate adenosine triphosphate (ATP), however as sugars and fats are broken down, they make metabolic intermediates that can be used for a whole bunch of different things.”

One of these other pathways is the modification of proteins. Sugar first breaks down into pyruvate, then breaks down again into acetyl CoA. This last product can be used for ATP production or for the modification of proteins and we found this differed in the two mouse models, Wende explains.

“When we removed PDK2 from the hearts, it improved survival and decreased heart failure indicators,” he says, “where when we removed PDK4, the mice had worse survival and outcomes. That was kind of a surprise to us—we thought they had similar roles.”

If these kinases are going to serve as a target, trying to develop specific drugs to only hit one of these proteins will be very difficult, Wende admits.

Wende’s collaborators on the grant include Martin Young, Ph.D., Professor of Medicine, Vice-Director for Research in the Division of Cardiovascular Disease, and Min Xie, M.D., Associate Professor, Division of Cardiovascular Disease in the UAB Department of Medicine.