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Endothelial γ-protocadherins inhibit KLF2 and KLF4 to promote atherosclerosis.
Joshi, Divyesh; Coon, Brian G; Chakraborty, Raja; Deng, Hanqiang; Yang, Ziyu; Babar, Muhammad Usman; Fernandez-Tussy, Pablo; Meredith, Emily; Attanasio, John; Joshi, Nikhil; Traylor, James G; Orr, Anthony Wayne; Fernandez-Hernando, Carlos; Libreros, Stephania; Schwartz, Martin A.
Afiliación
  • Joshi D; Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA.
  • Coon BG; Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA.
  • Chakraborty R; Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA.
  • Deng H; Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA.
  • Yang Z; Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA.
  • Babar MU; Department of Pathology, Yale University, New Haven, CT, USA.
  • Fernandez-Tussy P; Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA.
  • Meredith E; Department of Pathology, Yale University, New Haven, CT, USA.
  • Attanasio J; Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA.
  • Joshi N; Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA.
  • Traylor JG; Department of Immunobiology, Yale University, New Haven, CT, USA.
  • Orr AW; Department of Immunobiology, Yale University, New Haven, CT, USA.
  • Fernandez-Hernando C; Department of Pathology and Translational Pathobiology, LSU Health Shreveport, Shreveport, LA, USA.
  • Libreros S; Department of Pathology and Translational Pathobiology, LSU Health Shreveport, Shreveport, LA, USA.
  • Schwartz MA; Vascular Biology and Therapeutics Program, Yale University, New Haven, CT, USA.
Nat Cardiovasc Res ; 3(9): 1035-1048, 2024 Sep.
Article en En | MEDLINE | ID: mdl-39232138
ABSTRACT
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide. Laminar shear stress from blood flow, sensed by vascular endothelial cells, protects from ASCVD by upregulating the transcription factors KLF2 and KLF4, which induces an anti-inflammatory program that promotes vascular resilience. Here we identify clustered γ-protocadherins as therapeutically targetable, potent KLF2 and KLF4 suppressors whose upregulation contributes to ASCVD. Mechanistic studies show that γ-protocadherin cleavage results in translocation of the conserved intracellular domain to the nucleus where it physically associates with and suppresses signaling by the Notch intracellular domain. γ-Protocadherins are elevated in human ASCVD endothelium; their genetic deletion or antibody blockade protects from ASCVD in mice without detectably compromising host defense against bacterial or viral infection. These results elucidate a fundamental mechanism of vascular inflammation and reveal a method to target the endothelium rather than the immune system as a protective strategy in ASCVD.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Aterosclerosis / Factores de Transcripción de Tipo Kruppel / Factor 4 Similar a Kruppel Límite: Animals / Humans / Male Idioma: En Revista: Nat Cardiovasc Res Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Aterosclerosis / Factores de Transcripción de Tipo Kruppel / Factor 4 Similar a Kruppel Límite: Animals / Humans / Male Idioma: En Revista: Nat Cardiovasc Res Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido