Article

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: 3.96). 08/2008; 88(7):731-9. DOI: 10.1038/labinvest.2008.42
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
84 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The renin-angiotensin system plays a critical role in the pathogenesis of several cardiovascular diseases, largely through activation of type I angiotensin (AT(1)) receptors by angiotensin II. Treatment with AT(1) receptor blockers (ARBs) is a proven successful intervention for hypertension and progressive heart and kidney disease. However, the divergent actions of AT(1) receptors on individual cell lineages in hypertension may present novel opportunities to optimize the therapeutic benefits of ARBs. For example, T lymphocytes make important contributions to the induction and progression of various cardiovascular diseases, but new experiments indicate that activation of AT(1) receptors on T cells paradoxically limits inflammation and target organ damage in hypertension. Future studies should illustrate how these discrepant functions of AT(1) receptors in target organs versus mononuclear cells can be exploited for the benefit of patients with recalcitrant hypertension and other cardiovascular diseases.
    Current Hypertension Reports 11/2012; DOI:10.1007/s11906-012-0318-z · 3.90 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background/Aims: To examine the role of the angiotensin II (ATII) type 1a receptor (AT1-R) pathway in renal tissue damage and repair, we investigated reversible glomerular injury in a mouse model of habu snake venom (HSV)-induced glomerulonephritis using AT1-R-deficient (AT1a-/-) mice and AT1-R antagonist-treated mice. Methods: Experimental glomerulonephritis was induced by single administration of HSV to AT1a+/+ mice (HSV group) and AT1a-/- mice (KO-HSV group) and AT1-R antagonist-treated BL6 mice (HSV-ARB group). Morphological change and expression levels of type IV collagen, CD31, and vascular endothelial growth factor (VEGF) were analyzed. Results: The HSV group showed increased mesangial matrix expansion on day 7, which returned to preinjection levels by day 56, while mes-angial matrix expansion and increased type IV collagen expression were seen throughout days 7 to 56 in the KO-HSV group. The KO-HSV group showed fewer CD31-positive capillary loops and a marked decrease in the number of VEGF-positive cells in the glomeruli than the HSV group. VEGF administration to the KO-HSV group facilitated glomerular capillary repair and reconstruction. The HSV-ARB group showed the same delay in glomerular repair as that seen in the KO-HSV group. Conclusion: Our results indicate that blocking of the ATII-AT1R pathway delays glomerular repair via angiogenesis inhibition, followed by reduced induction of VEGF.
    Nephron Experimental Nephrology 02/2013; 122(1-2):13-22. DOI:10.1159/000346954 · 1.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Whole body genetic deletion of AT1a receptors in mice uniformly reduces hypercholesterolemia and angiotensin II-(AngII) induced atherosclerosis and abdominal aortic aneurysms (AAAs). However, the role of AT1a receptor stimulation of principal cell types resident in the arterial wall remains undefined. Therefore, the aim of this study was to determine whether deletion of AT1a receptors in either endothelial cells or smooth muscle cells influences the development of atherosclerosis and AAAs. AT1a receptor floxed mice were developed in an LDL receptor -/- background. To generate endothelial or smooth muscle cell specific deficiency, AT1a receptor floxed mice were bred with mice expressing Cre under the control of either Tie2 or SM22, respectively. Groups of males and females were fed a saturated fat-enriched diet for 3 months to determine effects on atherosclerosis. Deletion of AT1a receptors in either endothelial or smooth muscle cells had no discernible effect on the size of atherosclerotic lesions. We also determined the effect of cell-specific AT1a receptor deficiency on atherosclerosis and AAAs using male mice fed a saturated fat-enriched diet and infused with AngII (1,000 ng/kg/min). Again, deletion of AT1a receptors in either endothelial or smooth muscle cells had no discernible effects on either AngII-induced atherosclerotic lesions or AAAs. Although previous studies have demonstrated whole body AT1a receptor deficiency diminishes atherosclerosis and AAAs, depletion of AT1a receptors in either endothelial or smooth muscle cells did not affect either of these vascular pathologies.
    PLoS ONE 12/2012; 7(12):e51483. DOI:10.1371/journal.pone.0051483 · 3.53 Impact Factor

Preview

Download
0 Downloads
Available from