Studies Show Brain and Heart Cells Control Thyroid Hormone for Self-Protection
Underscoring the body’s remarkable ability to protect itself, Miller School researchers have published two studies that indicate the brain and heart each create a localized state of hypothyroidism to decrease energy metabolism during a stroke or heart attack.
Under normal conditions, hormones produced by the thyroid gland control energy use by stimulating oxygen consumption and accelerating metabolism at the cellular level. But during ischemic or hypoxic events, two independent teams of international researchers led by Antonio C. Bianco, M.D., Ph.D., professor of medicine and chief of the Division of Endocrinology, Diabetes and Metabolism, reported in The Journal of Neuroscience and Molecular Endocrinology that the brain and heart both deactivate hormone thyroid action to reduce energy expenditure and oxygen consumption, thereby minimizing tissue damage.
“If blood and oxygen are not getting to the tissue, you want that tissue to function at a very low level so it doesn’t use too much oxygen,” Bianco explained. “This is sort of nature’s version of induced coma. It promotes a state of hypothyroidism so metabolism slows down significantly, putting the organ, or the damaged area, in a sort of torpor, so recovery is better.”
Published June 20 in The Journal of Neuroscience, the study on the brain, “Neuronal Hypoxia Induces Hsp-40-Mediated Nuclear Import of Type 3 Deiodinase As an Adaptive Mechanism to Reduce Cellular Metabolism,” found that the enzyme type 3 deiodinase (D3) is redistributed subcellularly to inactivate thyroid hormone in brain neurons during stroke.
By occluding the carotid artery for an hour in rat models, the researchers specifically found that D3, which normally floats in the periphery of brain cells, migrates to and concentrates in the nucleus of neurons, blocking access to the thyroid hormone receptor and rapidly creating a state of localized hypothyroidism.
“The enzyme makes sure the thyroid hormone receptor, which is located in the nucleus of the neurons, is empty and remains unoccupied,’’ Bianco said. “Thyroid hormone molecules that try to diffuse to the nucleus are inactivated by D3, so it minimizes the damage caused by the stroke by reducing oxygen consumption and energy metabolism.”
Having previously shown that similar mechanisms happen in the heart during hypoxia or myocardial infarction, another Bianco team published the study in Molecular Endocrinology proving the enzyme’s importance in cardiac remodeling. In that study, “Absence of Myocardial Thyroid Hormone Inactivating Deiodinase Results in Restrictive Cardiomyopathy in Mice,” the researchers showed that increased D3 levels observed in the sick heart are associated with survival and improved cardiac function.
For that study, published in the May issue of The Endocrine Society journal, Bianco’s team knocked out the D3 gene in one set of mice and, with the assistance of Joshua M. Hare, M.D., the Louis Lemberg Professor of Medicine and director of the Interdisciplinary Stem Cell Institute, compared the knock-out mice to normal mice undergoing adrenergic overdrive. The result: the mortality rate among the D3 knock-out mice was more than twice as high as the mice that produced the enzyme.
The mice lacking the D3 enzyme also started life at a distinct disadvantage. The researchers found the knock-out mice quickly developed left ventricular hypertrophy, a common disease in which the overtaxed heart becomes enlarged. As such, they were more vulnerable to cardiac insufficiency when their hearts underwent adrenergic overdrive.
The studies collectively underscore the body’s innate ability to protect itself by customizing thyroid hormone action at the cellular level, a mechanism that Bianco has spent years unraveling. As he notes, the level of thyroid hormones circulating in the blood remains fairly constant through a healthy individual’s life, raising the question: How can a hormone that hardly ever changes its plasma values control important metabolic pathways in different tissues?
The answer, Bianco says in summary, is D3. The enzyme enables specific tissues to regulate and customize their own levels of thyroid hormone, and thus their metabolism, on an as-needed basis. “Every time you have a sick organ, or one damaged by hypoxia or ischemia, that organ develops a mechanism by which it becomes hypothyroid, and the mechanism is customized for that organ – thanks to this enzyme, D3,’’ he said. “That probably happens to many organs, but the heart and brain are the ones we most care about.”
Also contributing to the brain study from the Miller School were lead author Sungro Jo, Ph.D., senior research associate, and Rafael Arrojo e Drigo, Ph.D., post-doctoral fellow, both in the Division of Endocrinology, Diabetes and Metabolism; and Vance P. Lemmon, Ph.D., professor of neurological surgery and the Walter G. Ross Distinguished Chair in Developmental Neuroscience, and John L. Bixby, professor of molecular and cellular pharmacology and neuroscience, both of The Miami Project to Cure Paralysis. Led by Balazc Gerben, Ph.D., formerly a post-doctoral associate in Bianco’s lab, researchers from the Institute of Experimental Medicine at the Hungarian Academy of Sciences in Budapest, Hungary, also contributed.
In addition to Bianco and Hare, other Miller School contributors to the heart study were Cintia B. Ueta, graduate student, Emerson L. Olivares, Ph.D., visiting scholar from Brazil, Mayrin M. Correa, M.D., Ph.D., assistant scientist, and Gordana Simovic, technician, from the Division of Endocrinology, Diabetes and Metabolism; and Behzad N. Oskouei, M.D., fellow from the Interdisciplinary Stem Cell Institute; and Jose R. Pinto, Ph.D., former assistant professor of molecular and cellular pharmacology. Researchers from the Institute for Cardiovascular Research at VU University Medical Center Amsterdam in the Netherlands also contributed.