cGAS/STING/NLRP3 Signaling Pathway-Mediated Pyroptosis in Hypertrophic Cardiomyopathy Radiotherapy.

Area of Science:

• Cardiology
• Oncology
• Molecular Biology

Background:

• Radiotherapy is a cancer treatment, but its effects on hypertrophic cardiomyopathy (HCM) are unknown.
• Radiation activates the cGAS-STING pathway, linked to NLRP3 inflammasomes and pyroptosis, a cell death mechanism.
• The precise role of this pathway in radiation-induced cardiomyocyte pyroptosis in HCM requires elucidation.

Purpose of the Study:

• To investigate the role of the cGAS/STING/NLRP3 pathway in cardiomyocyte pyroptosis during radiotherapy for HCM.
• To understand the molecular mechanisms linking radiation, oxidative stress, and cell death in HCM.

Main Methods:

• Established a mouse model of pressure overload-induced HCM via transverse aortic constriction, followed by radiotherapy.
• Utilized an in vitro HL-1 cell model of HCM subjected to radiation, with or without NLRP3 inhibition or cGAS overexpression.
• Assessed cardiac function, hypertrophy, cell viability, inflammatory cytokines, mitochondrial potential, and key protein expression (cGAS, STING, NLRP3).

Main Results:

• Radiotherapy improved cardiac function and reduced hypertrophy and fibrosis in HCM mice.
• Radiation induced pyroptosis and reduced viability in HL-1 cells, an effect mitigated by NLRP3 inhibition and exacerbated by cGAS overexpression.
• Radiation triggered mitochondrial dysfunction and DNA release, activating the cGAS-STING-NLRP3 pathway and leading to pyroptosis, evidenced by increased inflammatory markers.

Conclusions:

• Radiation therapy can improve cardiac function and reduce myocardial hypertrophy in HCM.
• Radiation induces oxidative stress, leading to mitochondrial DNA leakage.
• This leakage activates the cGAS/STING/NLRP3 pathway, ultimately causing cardiomyocyte pyroptosis.