Deterioration of atherosclerosis in mice lacking angiotensin II type 1A receptor in bone marrow-derived cells

Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Ibaraki, Japan.
Laboratory Investigation (Impact Factor: 3.68). 08/2008; 88(7):731-9. DOI: 10.1038/labinvest.2008.42
Source: PubMed


The renin-angiotensin system (RAS) modulates end-organ damages, resulting in cardiovascular and kidney diseases. Experiments both in vitro and in vivo demonstrate that the angiotensin II (Ang II) type 1 (AT1) receptor pathway also exerts pro-inflammatory and pro-atherogenic effects on bone marrow-derived cells (BMDCs). Here, we investigated how AT1 receptor expression by BMDCs contributes to atherosclerosis and kidney injury in vivo by transplanting BM into RAS-activated transgenic mice. There was no difference in the extent of kidney damage between mice receiving BM transplants from mutant mice lacking the angiotensin II type 1a receptor (AT1a) gene and mice receiving transplants from wild-type (WT) mice. However, mice receiving transplants from AT1a 'knockout' (KO) mice displayed accelerated lethality and atherosclerotic lesions. These results indicated that the effects of AT1a receptor on BMDCs are organ dependent. Microarray expression profiling of macrophages from AT1a-KO mice revealed significant changes in the mRNA levels for a number of genes implicated in atherosclerosis. In accordance with the in vivo atherosclerosis results, AT1a-KO macrophages exhibited greater uptake of modified lipoproteins relative to macrophages from WT mice. We propose that the expression of AT1a receptor by BMDCs limits atherosclerosis in vivo.

Download full-text


Available from: Takeshi Sugaya, Sep 21, 2015
  • Source
    • "Images were captured at 48-h intervals until day 18 using equal-exposure conditions. The images were analyzed with the Developer Toolbox 1.7 software (GE Healthcare, Buckinghamshire, UK) as described (Kato et al., 2008). The invasion index was calculated using the following formula: DiI-positive invasion area (B)/initial sphere area (A). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Glioblastomas (GBMs) are the most common and aggressive type of brain tumor. GBMs usually show hyperactivation of the PI3K-Akt pathway, a pro-tumorigenic signaling cascade that contributes to pathogenesis. Girdin, an actin-binding protein identified as a novel substrate of Akt, regulates the sprouting of axons and the migration of neural progenitor cells during early postnatal-stage neurogenesis in the hippocampus. Here, we show that Girdin is highly expressed in human glioblastoma (GBM). Stable Girdin knockdown in isolated GBM stem cells resulted in decreased expression of stem cell markers, including CD133, induced multilineage neural differentiation, and inhibited in vitro cell motility, ex vivo invasion, sphere-forming capacity and in vivo tumor formation. Furthermore, exogenous expression of the Akt-binding domain of Girdin, which competitively inhibits its Akt-mediated phosphorylation, diminished the expression of stem cell markers, SOX2 and nestin, and migration on the brain slice and induced the expression of neural differentiation markers glial fibrillary acidic protein/βIII Tubulin. Our results reveal that Girdin is required for GBM-initiating stem cells to sustain the stemness and invasive properties.
    Oncogene 10/2011; 31(22):2715-24. DOI:10.1038/onc.2011.466 · 8.46 Impact Factor
  • Source
    • "These reports suggest the ameliorative function of AT1 receptor blockade in vascular cells for the AT1 receptor blocker- (ARB-) mediated atherosclerosis inhibition. In conjunction with the latter reports, the study by Kato et al. [124] also demonstrates that the beneficial effects of ARB in end-organ injuries are due to the blockade of AT1 receptor expressed in the end organs, but not in bone-marrow-derived cells. They proposed that distinct results observed in the kidney injury and atherosclerosis is possibly from the differences in the pathogenesis of mouse models. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Local hematopoietic bone marrow (BM) renin-angiotensin system (RAS) affects the growth, production, proliferation differentiation, and function of hematopoietic cells. Angiotensin II (Ang II), the dominant effector peptide of the RAS, regulates cellular growth in a wide variety of tissues in pathobiological states. RAS, especially Ang II and Ang II type 1 receptor (AT1R), has considerable proinflammatory and proatherogenic effects on the vessel wall, causing progression of atherosclerosis. Recent investigations, by analyzing several BM chimeric mice whose BM cells were positive or negative for AT1R, disclosed that AT1R in BM cells participates in the pathogenesis of atherosclerosis. Therefore, AT1R blocking not only in vascular cells but also in the BM could be an important therapeutic approach to prevent atherosclerosis. The aim of this paper is to review the function of local BM RAS in the pathogenesis of atherosclerosis.
    Cardiology Research and Practice 12/2010; 2011(1):714515. DOI:10.4061/2011/714515
  • Source
    • "Unlike the uniform demonstration of whole body AT1a receptor deficiency decreasing atherosclerosis, the literature using bone marrow transplantation has produced inconsistent results. AT1a receptor deficiency in bone marrow–derived cells has been demonstrated to attenuate [32, 34], have no effect [7, 31, 35], or increase atherosclerosis [36] in hypercholesterolemic mice, either induced by hypercholesterolemia alone or augmented with AngII infusion. The basis for this inconsistency is not readily apparent. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The renin angiotensin system (RAS) has profound effects on atherosclerosis development in animal models, which is partially complimented by evidence in the human disease. Although angiotensin II was considered to be the principal effector of the RAS, a broader array of bioactive angiotensin peptides have been identified that have increased the scope of enzymes and receptors in the RAS. Genetic interruption of the synthesis of these peptides has not been extensively performed in experimental or human studies. A few studies demonstrate that interruption of a component of the angiotensin peptide synthesis pathway reduces experimental lesion formation. The evidence in human studies has not been consistent. Conversely, genetic manipulation of the RAS receptors has demonstrated that AT1a receptors are profoundly involved in experimental atherosclerosis. Few studies have reported links of genetic variants of angiotensin II receptors to human atherosclerotic diseases. Further genetic studies are needed to define the role of RAS in atherosclerosis.
    Current Atherosclerosis Reports 05/2010; 12(3):167-73. DOI:10.1007/s11883-010-0109-4 · 3.42 Impact Factor
Show more