Endothelial γ-protocadherins inhibit KLF2 and KLF4 to promote atherosclerosis

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Vascular Inflammation

Background:

• Atherosclerotic cardiovascular disease (ASCVD) is a major global health concern.
• Endothelial KLF2 and KLF4 transcription factors, induced by laminar shear stress, confer vascular protection against ASCVD.
• Identifying novel regulators of these protective pathways is crucial for therapeutic development.

Purpose of the Study:

• To identify novel molecular targets that regulate KLF2 and KLF4 in the context of ASCVD.
• To investigate the role of clustered gamma-protocadherins in endothelial dysfunction and ASCVD pathogenesis.
• To evaluate the therapeutic potential of targeting gamma-protocadherins for ASCVD treatment.

Main Methods:

• Investigated clustered gamma-protocadherins as regulators of KLF2 and KLF4.
• Performed mechanistic studies involving protein cleavage, nuclear translocation, and protein-protein interactions (gamma-protocadherin and Notch intracellular domain).
• Utilized genetic deletion and antibody blockade in mouse models of ASCVD, alongside analysis of human ASCVD endothelium.

Main Results:

• Clustered gamma-protocadherins were identified as potent suppressors of KLF2 and KLF4, upregulated in ASCVD.
• Gamma-protocadherin cleavage leads to nuclear translocation of its intracellular domain, suppressing Notch signaling.
• Genetic deletion or antibody blockade of gamma-protocadherins conferred protection against ASCVD in mice without impairing immune defense.

Conclusions:

• Clustered gamma-protocadherins represent a key mechanism driving vascular inflammation in ASCVD by suppressing protective KLF2/KLF4.
• Targeting gamma-protocadherins offers a promising endothelial-centric therapeutic strategy for ASCVD.
• This approach avoids systemic immunosuppression, presenting a safer alternative to current treatments.