A City of Hope investigator has shown that a key protein may protect the heart, which suggests that therapies targeting this protein might delay the progression of heart disease.
In a study of mice, Janice Huss, Ph.D., assistant professor in the Department of Gene Regulation and Drug Discovery, and her postdoctoral advisor, Daniel Kelly, Ph.D., of Washington University School of Medicine in St. Louis, recently showed that loss of a factor regulating how cells generate energy can accelerate cardiac dysfunction. They published these findings in July’s Cell Metabolism.
The investigators analyzed mice that were engineered to lack a nuclear receptor protein called estrogen-related receptor alpha (ERRa). When those mice underwent surgery to constrict the aorta — a procedure that places an increased workload on the heart and produces localized hypertension — the mice developed heart failure symptoms more rapidly than did normal mice undergoing the same procedure.
ERRa activates muscle cell genes involved in energy production. “Depletion of this important regulatory factor sets those hearts up to be unable to maintain their energetic capacity and contractile function,” said Huss. If heart muscle cells do not get enough energy over a long period, those cells may die.
Generally, when heart muscle works harder, the muscle cells enlarge, a process known as “hypertrophy.” Cardiac hypertrophy can be either beneficial or deadly.
Cells mint their chemical currency — the energy to keep them going — in intracellular factories called mitochondria. “In ‘good’ hypertrophy, which occurs in response to exercise, mitochondria actually increase in number and activity to keep up with energy demands,” explained Huss. But in “bad” hypertrophy — which occurs with chronic hypertension — cells enlarge, but mitochondrial numbers fail to increase. That can be a little like powering a Hummer with a Geo engine — an overwhelming burden that can lead to heart failure.
“We observed that in ‘bad’ hypertrophy, the energy-generation program, governed in part by ERRa, fails,” said Huss.
Decreased mitochondrial function also occurs in metabolic syndrome, the collection of symptoms that includes high triglycerides, insulin resistance, hypertension and obesity, all of which increase the risk of type 2 diabetes or cardiovascular disease.
Huss, who joined City of Hope in October, just won her first major National Institutes of Health (NIH) grant as an independent investigator to continue ERRa studies in skeletal and cardiac muscle. One question she will address is whether ERR pathways could be modulated to treat metabolic syndrome.
So why do that in a cancer hospital? About 80 years ago, Nobel Prize-winning physiologist Otto Warburg showed that metabolic changes similar to those seen in the diseased heart muscle cells of ERRa mutant mice also occur in tumor cells, she noted.
Some cells in myosarcoma (a muscular-tissue tumor) downregulate ERRa — meaning they become less sensitive to the protein, Huss said. “I am interested in looking at ERR signaling in muscle sarcomas to see if activating that pathway alters tumor cell metabolism and growth,” she said. “And I am very open to interfacing with basic cancer biology groups here to look for metabolic alterations in cancer models.”
Huss has long been fascinated by nuclear receptor regulation and energy metabolism, two fields receiving a lot of attention. “These fields are relevant to obesity, atherosclerosis, diabetes and perhaps even Alzheimer’s,” she said. “At the core of many of these diseases is the idea that cell metabolism is disrupted.”
Study colleagues included Vincent Giguere, Ph.D., and Catherine Dufour of McGill University in Montreal, Carla Weinheimer, Michael Courtois, and Atilla Kovacs, M.D., of Washington University, Ken-ichi Imahashi of Takeda Pharmaceutical Company in Osaka, Japan, and Elizabeth Murphy, Ph.D., at the National Heart, Lung, and Blood Institute of the NIH.
The NIH and the Canadian Institutes for Health Research funded the research.