Researchers from Karolinska Institutet, AstraZeneca, University of Würzburg, Science for Life Institute and Uppsala University show that oxidative stress in heart failure differs by sex, and that the hearts of female mice have stronger natural defenses against oxidative damage. discovered.

This study could enable new approaches for precision medicine and may explain why previous attempts to use antioxidants to treat heart failure have been so unsuccessful. .

This study nature communicationsled by Zaher Elbeck from the research group of Professor Christer Betzholz at the Medical Faculty of Huddinge (MedH) reveals the important role of two proteins: IDH2 (isocitrate dehydrogenase 2) and NRF2 (nuclear factor erythroid 2-related factor 2). I made it. Protects the heart from oxidative damage through a mechanism involving mitochondrial nuclear metabolites.

This study used a multipronged approach to analyze metabolites, gene expression, and epigenetics in mouse and human heart tissue samples, alongside analysis of a large public database. Many innovative methods have also been developed to accurately measure the heart’s natural antioxidant capacity.

After identifying the unique regulation of IDH2 expression, the researchers investigated its underlying antioxidant mechanisms and key molecules using human heart cells and animal models. Testing of AstraZeneca’s novel experimental compound in a mouse heart failure model further reveals the potential for targeted and effective antioxidant therapy.

Hearts from female mice showed superior antioxidant capacity compared to males. When targeting oxidative stress in a mouse model of heart failure, only males had improved cardiac function, whereas females, who usually have sufficient innate antioxidant capacity, experienced side effects from the treatment. These results highlight the need for “personalized” antioxidant therapy in heart failure, taking into account individual antioxidant levels.

“Previous attempts to use antioxidants to treat heart failure and other diseases have generally had limited success. Our study clears up some of the misconceptions that exist in this field. “We identified and uncovered a possible reason for the lack of druggability: the heart’s natural and powerful antioxidant defenses,” Elbeck said.

The findings challenge past concepts by highlighting the heart’s powerful natural antioxidant defenses and distinguishing between states of oxidative stress and oxidative damage.

Free radicals are part of normal biological reactions

Oxidative stress occurs as part of normal biological reactions when cells break down nutrients to produce energy and the building blocks for cellular function. These reactions also generate free radicals, which can harm cells if not controlled. Our cells have strong natural defenses against these radicals, but in disease states such as heart failure, this defense may be inadequate.

When a cell’s ability to handle these free radicals is weakened, it creates stress in the cell known as oxidative stress, which can ultimately lead to oxidative damage. Furthermore, certain important biological functions in our cells require low levels of free radicals to function effectively, and maintaining adequate levels of free radicals is also essential.

Although oxidative stress occurs in heart failure, most heart cells have sufficient antioxidants to ameliorate and prevent oxidative damage. The challenge is that fighting oxidative stress is metabolically demanding, especially for hearts weakened by energy and metabolic deficiencies. Therefore, personalized antioxidant therapy based on individual antioxidant levels assessed through biomarkers could support more effective treatment and management.

Precision medicine and antioxidant therapy

Dilated cardiomyopathy is a condition in which the heart chambers enlarge and become less able to pump blood, especially during exercise. Although heart disease is more common in men, it can also occur in women as they get older.

This study aimed to understand how gender differences influence oxidative stress in dilated cardiomyopathy. The results of this study provide valuable insights for improving heart failure treatment and highlight potential opportunities for precision medicine approaches in the design of effective antioxidant therapies. Future efforts will focus on developing specific biomarkers for antioxidant capacity assessment and therapeutic targets for precision medicine.