Dysregulated Cardiac IGF-1 Signaling and Antioxidant Response Are Associated with Radiation Sensitivity

Area of Science:

• Radiation biology
• Cardiovascular research
• Molecular mechanisms of radiation sensitivity

Background:

• Acute exposure to ionizing radiation causes Hematopoietic Acute Radiation Syndrome (H-ARS).
• Inter-strain differences in radiosensitivity exist, with Gottingen minipigs (GMP) being more sensitive than Sinclair minipigs (SMP).
• Insulin-like Growth Factor-1 (IGF-1) signaling plays a role in radiation sensitivity and cardiovascular homeostasis.

Purpose of the Study:

• To investigate the link between cardiac IGF-1 signaling dysregulation and radiosensitivity in minipigs.
• To explore the cellular and molecular mechanisms underlying inter-strain differences in H-ARS.
• To determine the role of oxidative stress and antioxidant response in radiation sensitivity.

Main Methods:

• Adult male GMP (n=48) and SMP (n=24) minipigs were exposed to total body irradiation (TBI) with gamma photons (1.7-2.3 Gy).
• Animals were categorized as survivors (survived to day 45) or decedents (euthanized before day 45 due to illness).
• Cardiac tissue analysis was performed on unirradiated and irradiated animals.

Main Results:

• Inter-strain radiosensitivity and survival outcomes in H-ARS were associated with the activation status of cardiac IGF-1 signaling.
• Nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated induction of antioxidant gene expression was linked to radiosensitivity.
• Dysregulation of cardiac IGF-1 signaling was observed in H-ARS.

Conclusions:

• Cardiac IGF-1 signaling dysregulation is linked to H-ARS.
• Oxidative stress and the cardiac antioxidant response are critical factors in radiation sensitivity.
• Understanding these mechanisms can inform strategies to mitigate radiation effects.