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Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis

Romeo Ricci1, Grzegorz Sumara, Izabela Sumara

  • 1Cardiovascular Research, Institute of Physiology, and Division of Cardiology, University Hospital Zurich, CH-8057 Zurich, Switzerland. romeo.ricci@cell.biol.ethz.ca

Science (New York, N.Y.)
|November 30, 2004
PubMed

Insights

c-Jun N-terminal kinases (JNKs) play a role in atherosclerosis. JNK2 deficiency in mice reduced plaque formation by affecting lipid uptake in macrophages, highlighting JNK2 as a potential therapeutic target for atherosclerosis.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Immunology

Background:

  • In vitro studies implicate c-Jun N-terminal kinases (JNKs) in cellular processes contributing to atherosclerosis.
  • Atherosclerosis is a complex inflammatory disease characterized by plaque buildup in arteries.

Purpose of the Study:

  • To investigate the specific roles of JNK1 and JNK2 in the development of atherosclerosis.
  • To determine the molecular mechanisms by which JNKs regulate macrophage function in atherogenesis.

Main Methods:

  • Utilized apolipoprotein E-deficient (ApoE-/-) mice lacking JNK1 or JNK2.
  • Administered pharmacological JNK inhibitors.
  • Examined macrophage foam cell formation and scavenger receptor A (SR-A) expression and phosphorylation.
  • Performed macrophage-specific JNK2 deletion studies.

Main Results:

  • ApoE-/- mice lacking JNK2, but not JNK1, exhibited significantly reduced atherosclerosis.
  • Pharmacological JNK inhibition effectively decreased atherosclerotic plaque formation.
  • Macrophages deficient in JNK2 showed impaired foam cell formation due to defective modified lipoprotein handling.
  • JNK2 deficiency led to increased scavenger receptor A (SR-A) levels and decreased its phosphorylation.
  • Macrophage-specific JNK2 deletion was sufficient to attenuate atherogenesis.

Conclusions:

  • JNK2, but not JNK1, plays a critical role in promoting atherosclerosis.
  • JNK2-dependent phosphorylation of SR-A is essential for lipid uptake by macrophages, driving foam cell formation.
  • Targeting JNK2 offers a potential therapeutic strategy for reducing atherosclerosis progression.

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