Angiotensin II AT1 Receptor Antagonism Downregulates Stress-Related Gene Expression in Brain Microvessels from Spontaneously Hypertensive and Normotensive Rats

Authors

  • J ZHOU,

    Corresponding author
    1. Section on Pharmacology, Division of Intramural Research Programs, National of Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA
      Address for correspondence: Jin Zhou, M.D., Ph.D., Section on Pharmacology, DIRP, NIMH, NIH, DHHS, 10 Center Drive, MSC 1514, Bldg. 10, Room 2D57, Bethesda, MD 20892, USA. Voice: 301-402-6859; fax: 301-402-0337. e-mail: zhouj@intra.nimh.nih.gov
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  • M JEZOVA,

    1. Section on Pharmacology, Division of Intramural Research Programs, National of Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA
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  • A G ELKAHLOUN,

    1. Microarray Unit, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA
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  • J M SAAVEDRA

    1. Section on Pharmacology, Division of Intramural Research Programs, National of Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA
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Address for correspondence: Jin Zhou, M.D., Ph.D., Section on Pharmacology, DIRP, NIMH, NIH, DHHS, 10 Center Drive, MSC 1514, Bldg. 10, Room 2D57, Bethesda, MD 20892, USA. Voice: 301-402-6859; fax: 301-402-0337. e-mail: zhouj@intra.nimh.nih.gov

Abstract

Abstract: We studied the effect of treatment with the Angiotensin II AT1 receptor antagonist candesartan (0.3 mg/kg/day via osmotic minipumps for 4 weeks compared with administration of vehicle) in brain microvessels in adult spontaneously hypertensive rats (SHR) that were vulnerable to stroke and normotensive control rats (WKY). At the dose administered, candesartan normalized blood pressure in SHR without significantly affecting blood pressure in WKY rats. We performed the gene expression analysis in rat brain microvessels using the Affymetrix Gene Chip Expression Analysis Technique. From a total of 8,799 probe array sets analyzed, we found abundant abnormalities in gene expression in SHR. Because stress has been suggested as a precipitant factor in brain ischemia and treatment with AT1 receptor antagonist candesartan prevents the hormonal and sympathoadrenal reaction to isolation stress and protects from stress-induced gastric ulcers, we focused on the expression of stress-related genes. We found a higher number of probe array sets modified by candesartan treatment in normotensive WKY rats than in hypertensive SHR. AT1 receptor blockade decreased the transcription levels of the stress-related tyrosine kinase receptor, stathmin, and fibroblast growth receptor genes in WKY and SHR rats. Our results indicate that Angiotensin II and its AT1 receptors can influence gene expression independently of the effects on blood pressure. In addition, AT1 receptor regulation of stress-related genes in brain microvessels may explain the proposed association between stress and ischemic disorders of the brain.

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