Study shows oestrogen’s role in protecting from cardiomyopathy
Oestrogen may protect diabetes patients from cardiomyopathy, according to research led by a Texas A&M AgriLife scientist and published in the June issue of the American Heart Association journal Circulation: Heart Failure
https://doi.org/10.1161/CIRCHEARTFAILURE.121.008758
The study showed that severe insulin resistance in the heart causes cardiomyopathy and death in male mice. It also showed the sex hormone oestrogen protected female mice.“Cardiovascular disease is the major cause of morbidity and mortality for diabetic patients,” said Shaodong Guo, Ph.D., primary investigator for the study. Guo is a professor and Presidential Impact Fellow in the Texas A&M Department of Nutrition at the College of Agriculture and Life Sciences, Bryan-College Station.
“Previous studies have shown that while there’s a lower instance of both cardiovascular disease and Type 2 diabetes in premenopausal women than in their age-matched male counterparts, these incidences rise sharply after female menopause,” Guo said. He said this indicates that the ovaries and ovarian hormones, such as oestrogen, may protect from Type 2 diabetes and cardiovascular diseases.
The recently published study, Guo said, investigated the role of ovaries and oestrogen in cardiac function and energy metabolism by using genetically engineered mouse models. In these mice, the cardiac insulin receptor substrate, IRS, had been modified or suppressed to mimic cardiac insulin resistance. “Our previous studies reported that impaired cardiac insulin signalling with loss of insulin receptor substrate IRS1 and IRS2 genes leads to death of male mice,” he said. “In this study, we wanted to know how the removal of the ovaries might affect cardiomyopathy in female mice and also what other impacts the loss of insulin receptors might have on energy metabolism and mitochondrial function.”
The study was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health in the United States. It was a part of an ongoing project called “Targeting Insulin Resistance by Estrogen Receptor in Control of Type2 Diabetes Mellitus,” which is being led by Guo in his laboratory.
Insulin resistance
About 90-95% of patients with Type 2 diabetes suffer from insulin resistance, a risk factor for heart failure. In healthy tissue, insulin binds to insulin receptors, which then work to activate a network of intracellular signalling pathways. Disruptions in these signalling pathways have been linked to mitochondrial dysfunction, cardiomyopathy, and impaired glucose and fatty acid metabolism, among other health issues. In this study, mice that lacked the IRS developed dilated cardiomyopathy. Additional gene-chip analysis showed lowered activity of genes important for mitochondrial function and energy metabolism. “Type 2 diabetes patients and insulinresistant patients exhibit mitochondrial dysfunction,” Guo explained.” The study fills in some blanks in understanding the role of insulin and oestrogen signalling in mitochondrial function.
Study findings
Guo said there were four important findings from the study:
• All female mice that lacked insulin receptor substrates survived for more than a year.
• Female mice without insulin receptor substrates were less likely to experience severe cardiac dysfunction and death if they had ovaries. If the mice also lacked ovaries but received oestrogen, it prolonged their lifespans. Doses of oestrogen also protected IRS-altered male mice from heart dysfunction.
Guo said oestrogen also prevents cardiomyopathy induced by loss of cardiac insulin receptor substrates. “Removal of the ovaries leads to the death of female cardiac IRS1 and IRS2 double genes knockout mice if there is no reintroduction of oestrogen,” he said.
• Loss of IRS1 and IRS2 genes in heart tissue disrupts cardiac energy metabolism, gene activity involved in mitochondrial function, and whole-body energy metabolism. On the other hand, oestrogen partially reverses these effects.
• Oestrogen is important for healthy cellular signalling pathways and promotes mitochondrial function.
Guo said the study shows that oestrogen enhances cardiac function, promotes energy metabolism, prevents cardiomyopathy and prolongs survival in both male and ovariectomy female mice lacking the insulin receptor substrates.
“This study provides evidence for the gender difference for the incidence of cardiovascular disease and implies that oestrogen replacement therapy is feasible for the treatment of diabetic cardiomyopathy through enhancement of mitochondrial function and energy metabolism,” he said. “It also reveals some of the signalling pathways that may be potential therapeutic targets for the prevention or treat ment of cardiovascular diseases in patients with Type 2 diabetes.”
Implications for diet
Guo also noted that the study shows a high potential for dietary interventions to promote human health. “The study implies that food-derived oestrogens or phytoestrogens may play similar roles to oestrogen, as observed in mice,” he said. “This may help us reshape our knowledge of nutrient and food sciences related to plant hormones that can modulate chronic metabolic diseases such as Type 2 diabetes and associated cardiovascular complications.”
Shaodong Guo, Ph.D.
CREDIT: Texas A&M AgriLife
