SRC-3 deficiency prevents atherosclerosis development by decreasing endothelial ICAM-1 expression to attenuate...

Area of Science:

• Cardiovascular Biology
• Molecular Endocrinology
• Immunology

Background:

• Steroid receptor coactivator 3 (SRC-3) is a p160 family member involved in gene regulation.
• The role of SRC-3 in atherosclerosis remains largely unknown.
• Atherosclerosis involves inflammation, macrophage recruitment, and endothelial dysfunction.

Purpose of the Study:

• To investigate the role of SRC-3 in the development of atherosclerosis.
• To elucidate the molecular mechanisms by which SRC-3 influences atherosclerotic plaque formation.
• To evaluate the therapeutic potential of targeting SRC-3 in atherosclerosis.

Main Methods:

• Utilized SRC-3 knockout (SRC-3-/-) and ApoE knockout (ApoE-/-) mouse models fed a Western diet.
• Performed RNA-sequencing and Western blot analysis on aortic tissues.
• Employed siRNA-mediated knockdown of SRC-3 in endothelial cells and AAV9-shSRC-3 viral delivery.
• Administered SRC-3 inhibitor bufalin to ApoE-/- mice.

Main Results:

• SRC-3-/-ApoE-/- mice exhibited significantly reduced atherosclerotic lesions and necrotic areas compared to controls.
• SRC-3 deficiency led to decreased expression of ICAM-1, a key mediator of macrophage recruitment.
• Knockdown of SRC-3 in endothelial cells and bufalin treatment attenuated atherosclerotic plaque development.
• SRC-3 was found to coactivate NF-κB p65, thereby increasing ICAM-1 transcription in endothelial cells.

Conclusions:

• SRC-3 plays a critical role in promoting atherosclerosis development.
• Inhibition of SRC-3 ameliorates atherosclerosis by suppressing endothelial activation and ICAM-1 expression.
• Targeting SRC-3, possibly via its interaction with NF-κB signaling, represents a potential therapeutic avenue for atherosclerosis.