Lack of frataxin protein in the heart muscles of mice with Friedreich’s ataxia leads to low levels of another protein that protects against heart damage, a study reports.
The heart-protecting protein, Nrf2, regulates oxidative stress, an imbalance between the body’s production of potentially harmful free radicals and the antioxidant system’s ability to counter them. When present in high levels, free radicals can cause significant damage to cell structures. Low levels of Nrf2 prevent the antioxidant system from working properly.
Researchers published their study in the American Journal of Pathology. It is titled, “Molecular Alterations in a Mouse Cardiac Model of Friedreich Ataxia: An Impaired Nrf2 Response Mediated via Upregulation of Keap1 and Activation of the Gsk3β Axis.”
Friedreich’s ataxia, or FA, causes heart as well as nerve damage. Lack of frataxin in the heart causes a heart muscle disease known as cardiomyopathy that claims many patients’ lives.
Unfortunately, scientists know little about the molecular dysfunction in FA, especially in the heart. They know that Nrf2 controls the body’s antioxidant response and that there are low levels of the protein in animal models of FA. What they haven’t known is what mechanisms lead to the reduction in Nrf2’s levels.
This prompted researchers to try to identify Nrf2’s role in the oxidative stress that leads to FA patients’ cardiomyopathy.
The team discovered a significantly higher level of free radicals in the hearts of mice with FA than in normal mice. Another finding was that Nrf2 levels were much lower in mice with FA than in healthy mice.
Scientists know that two protein signaling pathways reduce Nrf2 activity. One is for a protein called Keap1 and the other a protein called Gsk3b.
The research team discovered higher Keap1 and Gsk3b signaling in mice with FA. This explained the reduction in the mice’s levels of Nrf2. It also explained a decrease in the activity of the antioxidant genes that Nrf2 controls.
Interestingly, while levels of protein-coding microRNA were lower in the genes, levels of the proteins that the genes generate were not. Because microRNA codes for protein, this finding suggested that other pathways could compensate for the lower Nrf2 levels involved in the genes’ protein production.
Despite evidence of compensating pathways, researchers found oxidative damage in the hearts of the mice that had FA. This indicated that antioxidant therapy could help treat their heart condition.
“The major antioxidant mechanism mediated by Nrf2 is dysfunctional, and this could play a role in the cardiac pathology observed in FA,” the authors concluded.