Rho-associated coiled-coil-containing kinase 2 deficiency in bone marrow-derived cells leads to increased cholesterol efflux and decreased atherosclerosis

Qian Zhou, Yu Mei, Takuhito Shoji, Xinbing Han, Karol Kaminski, Goo Taeg Oh, Pat P. Ongusaha, Kunzhong Zhang, Hannah Schmitt, Martin Moser, Christoph Bode, James K. Liao

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Background-Macrophages play a central role in the development of atherosclerosis. However, the signaling pathways that regulate their function are not well understood. The Rho-associated coiled-coil-containing kinases (ROCK1 and ROCK2) are serine-threonine protein kinases that are involved in the regulation of the actin cytoskeleton. Recent studies suggest that ROCK1 in macrophages and bone marrow-derived cells mediates atherogenesis. However, a similar role for ROCK2-/- in the pathogenesis of atherosclerosis has not been determined. Methods and Results-The bone marrows from wild-type, ROCK2-/-, and ROCK2-/- mice were transplanted into irradiated recipient low-density lipoprotein receptor mice, and atherosclerosis was induced with a 16-week high-cholesterol diet. Compared with wild-type bone marrow-transplanted mice, ROCK2-/- bone marrow-transplanted and ROCK2-/- bone marrow-transplanted mice showed substantially less lipid accumulation in the aorta (8.46±1.42% and 9.80±2.34% versus 15.64±1.89%; P<0.01 for both) and decreased atherosclerotic lesions in the subaortic sinus (158.1±44.4 and 330.1±109.5×10μm versus 520.2±125.7×10μm; P<0.01 for both). These findings correlated with decreased foam cell formation (2.27±0.57 versus 4.10±0.3; P<0.01) and increased cholesterol efflux (17.65±0.6 versus 9.75±0.8; P<0.05) in ROCK2-/--deficient mice that are mediated, in part, through the peroxisome proliferator-activated receptor-γ/liver X receptor/ATP-binding cassette transporter A1 pathway in macrophages. Conclusions-ROCK2-/- contributes to atherosclerosis, in part, by inhibiting peroxisome proliferator-activated receptor-γ-mediated reverse cholesterol transport in macrophages, which contributes to foam cell formation. These findings suggest that inhibition of ROCK2-/- in macrophages may have therapeutic benefits in preventing the development of atherosclerosis.

Original languageEnglish
Pages (from-to)2236-2247
Number of pages12
JournalCirculation
Volume126
Issue number18
DOIs
StatePublished - 30 Oct 2012

Keywords

  • Rho kinase
  • Rho-associated kinases
  • atherogenesis
  • atherosclerosis
  • macrophage

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