Abstract 17238: Hematopoietic Deficiency of the Catalytic PI 3-Kinase Isoform PI3Kdelta Aggravates the Development of Atherosclerosis in LDLR-/- Mice
Atherosclerosis is a chronic inflammatory disease of arterial blood vessels underlying myocardial infarction and ischemic stroke. Atherogenesis is characterized by infiltration of the arterial wall by macrophages, dendritic cells and T lymphocytes. Although different cell types of the innate and adaptive immune system play central pro-inflammatory roles, they exert regulatory functions in different stages of this complex disease as well. Leukocytes express the catalytic phosphoinositide 3-kinase isoform p110δ (PI3Kδ), a key enzyme involved in the regulation of immune responses. Therefore, PI3Kδ represents an interesting target for the modulation of atherogenesis.
To investigate the role of PI3Kδ in leukocytes for the orchestration of atherogenesis, lethally irradiated LDLR-/- mice were either transplanted with bone marrow from PI3Kδ-/- or PI3Kδ+/+ mice. After 4 weeks of recovery, recipient mice were challenged for 6 weeks with atherogenic diet. PI3Kδ-/- recipient LDLR-/- mice displayed a profound reduction of peripheral B and T cells as well as strongly impaired CD4+ T-cell activation and regulatory T-cell numbers in paraaortic lymph nodes and spleen compared with PI3Kδ+/+ transplanted recipients. Surprisingly, the profound impairment of the immune system by PI3Kδ-deficiency caused a considerable exacerbation of atherosclerosis in LDLR-/- mice. Atherosclerotic lesion area / aortic root area in PI3Kδ-/- recipient LDLR-/- mice was significantly augmented compared with PI3Kδ+/+ transplanted controls (0.26 ± 0.07 vs. 0.16 ± 0.04; P<0.001), as shown by staining of proximal aortic sections with Oil Red O. Furthermore, lesion area / total aortic area in PI3Kδ-/- recipients was also significantly higher than in PI3Kδ+/+ transplanted LDLR-/- mice (0.023 ± 0.009 vs. 0.01 ± 0.005; P<0.001), as confirmed by en face analysis of Sudan IV-stained whole aortas.
In summary, we demonstrate that hematopoietic PI3Kδ plays a crucial role in regulating immune responses within the arterial wall by exerting protective functions during the development and progression of atherosclerosis. Current studies aim to dissect PI3Kδ-dependent mechanisms that modulate inflammatory processes in multiple stages of atherosclerotic lesion formation.
- © 2013 by American Heart Association, Inc.