Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Cellular Stress Response

Background:

• Thrombospondins (Thbs) are secreted proteins involved in cellular dynamics and matrix production during stress and injury.
• The specific role of Thbs family members in cardiac homeostasis and pathology remains incompletely understood.

Purpose of the Study:

• To investigate the role of Thbs1 in cardiac function and identify the molecular mechanisms underlying its effects.
• To determine if Thbs1 mediates cardiac atrophy and explore its interaction with stress response pathways.

Main Methods:

• Overexpression of Thbs1 in transgenic mice and analysis of cardiac phenotype.
• Investigating the role of PERK, ATF4, and autophagy in Thbs1-induced cardiac atrophy.
• Gene deletion studies targeting Thbs1 effectors/receptors (ATF6α, CD36, CD47, PERK).
• AAV9-mediated gene transfer of PERK or ATF4 in mice.

Main Results:

• Thbs1 overexpression, but not other Thbs family members, induced lethal cardiac atrophy.
• Thbs1 activated the endoplasmic reticulum stress pathway via PERK and ATF4, triggering autophagy.
• Thbs1 deficiency exacerbated cardiac hypertrophy and reduced atrophy under stress.
• Deletion of PERK, but not ATF6α, CD36, or CD47, rescued Thbs1-induced atrophy.
• Overexpression of PERK or ATF4 mimicked Thbs1's effects, causing atrophy and lethality.

Conclusions:

• Thbs1 is a critical mediator of cardiac atrophy through the PERK-eIF2α-ATF4-autophagy pathway.
• This pathway represents a key regulator of cardiomyocyte size in response to cardiac stress.
• Targeting the Thbs1-PERK-ATF4 axis may offer therapeutic strategies for cardiac diseases.