HSPA12B Protects Against Age-Related Endothelial Cell Senescence by Regulating STING Degradation

Area of Science:

• Cardiovascular Biology
• Cellular Aging
• Molecular Mechanisms

Background:

• Cardiovascular diseases are a leading cause of death, with aging as a primary risk factor.
• Endothelial cell (EC) dysfunction and senescence are central to age-related cardiomyopathy.
• Molecular drivers of endothelial senescence are not fully understood.

Purpose of the Study:

• Investigate the role of endothelial-specific heat shock protein family A member 12B (HSPA12B) in age-related endothelial senescence.
• Elucidate the molecular pathways through which HSPA12B influences EC function and vascular aging.
• Identify HSPA12B as a potential therapeutic target for cardiovascular dysfunction.

Main Methods:

• Assessed HSPA12B expression in aging cardiovascular tissues.
• Utilized HSPA12B deficient and overexpressing mouse models to study EC senescence and cardiac function.
• Investigated the impact of HSPA12B on the X-box binding protein 1 (XBP1) pathway, endoplasmic reticulum-associated degradation (ERAD), and the cGAS-STING pathway.
• Employed pharmacological interventions targeting STING and XBP1 activity.

Main Results:

• HSPA12B expression declines with age, accelerating EC senescence and cardiac dysfunction in mice.
• HSPA12B overexpression mitigates EC senescence and protects against vascular aging.
• HSPA12B deficiency impairs XBP1 activity, reducing SEL1L and HRD1 expression, leading to ERAD defects and STING pathway activation.
• Pharmacological inhibition of STING or enhancement of XBP1 activity reversed HSPA12B deficiency-induced senescence.

Conclusions:

• HSPA12B plays a crucial protective role in maintaining endothelial homeostasis during aging.
• HSPA12B regulates the XBP1-mediated ERAD of STING, thereby controlling EC senescence.
• HSPA12B represents a promising therapeutic target for age-related cardiovascular diseases.