Document Detail

Local angiotensin II aggravates cardiac remodeling in hypertension.
MedLine Citation:
PMID:  20833959     Owner:  NLM     Status:  MEDLINE    
Angiotensin II (ANG II) contributes to hypertension, cardiac hypertrophy, fibrosis, and dysfunction; however, it is difficult to separate the cardiac effect of ANG II from its hemodynamic action in vivo. To overcome the limitations, we used transgenic mice with cardiac-specific expression of a transgene fusion protein that releases ANG II from cardiomyocytes (Tg-ANG II) and treated them with deoxycorticosterone acetate (DOCA)-salt to suppress their systemic renin-angiotensin system. Using this unique model, we tested the hypothesis that cardiac ANG II, acting on the angiotensin type 1 receptor (AT(1)R), increases inflammation, oxidative stress, and apoptosis, accelerating cardiac hypertrophy and fibrosis. Male Tg-ANG II mice and their nontransgenic littermates (n-Tg) were uninephrectomized and divided into the following three groups: 1) vehicle-treated normotensive controls; 2) DOCA-salt; and 3) DOCA-salt + valsartan (AT(1)R blocker).Under basal conditions, systolic blood pressure (SBP) and cardiac phenotypes were similar between strains. In DOCA-salt hypertension, SBP increased similarly in both n-Tg and Tg-ANG II, and cardiac function did not differ between strains; however, Tg-ANG II had 1) greater ventricular hypertrophy as well as interstitial and perivascular fibrosis; 2) a higher number of deoxynucleotidyl-transferase-mediated dUTP nick end labeling-positive cells and infiltrating macrophages; 3) increased protein expression of NADPH oxidase 2 and transforming growth factor-β(1); and 4) downregulation of phosphatidylinositol 3-kinase (PI 3-kinase) and protein kinase B (Akt) phosphorylation. Valsartan partially reversed these effects in Tg-ANG II but not in n-Tg. We conclude that, when hemodynamic loading conditions remain unchanged, cardiac ANG II does not alter heart size or cardiac functions. However, in animals with hypertension, cardiac ANG II, acting via AT(1)R, enhances inflammation, oxidative stress, and cell death (most likely via downregulation of PI 3-kinase and Akt), contributing to cardiac hypertrophy and fibrosis.
Jiang Xu; Oscar A Carretero; Tang-Dong Liao; Hongmei Peng; Edward G Shesely; Junxiao Xu; Thomas S Liu; James J Yang; Timothy L Reudelhuber; Xiao-Ping Yang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-09-10
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  299     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-01     Completed Date:  2010-11-29     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1328-38     Citation Subset:  IM    
Hypertension & Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202-2689, USA.
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MeSH Terms
Angiotensin II / genetics,  metabolism*
Angiotensin II Type 1 Receptor Blockers / pharmacology
Apoptosis / physiology
Collagen / metabolism
Desoxycorticosterone / adverse effects,  analogs & derivatives
Dinoprost / analogs & derivatives,  metabolism
Disease Models, Animal
Heart Rate / physiology
Hypertension / chemically induced,  metabolism*,  physiopathology
Membrane Glycoproteins / metabolism
Mice, Transgenic
Myocardium / metabolism*,  pathology
Myocytes, Cardiac / drug effects,  metabolism*
NADPH Oxidase / metabolism
Oxidative Stress / physiology
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Receptor, Angiotensin, Type 1 / metabolism
Renin-Angiotensin System / drug effects,  physiology
Tetrazoles / pharmacology
Transforming Growth Factor beta1 / metabolism
Valine / analogs & derivatives,  pharmacology
Grant Support
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/Membrane Glycoproteins; 0/Receptor, Angiotensin, Type 1; 0/Tetrazoles; 0/Transforming Growth Factor beta1; 11128-99-7/Angiotensin II; 137862-53-4/valsartan; 27415-26-5/8-epi-prostaglandin F2alpha; 551-11-1/Dinoprost; 64-85-7/Desoxycorticosterone; 6E0A168OB8/desoxycortone acetate; 7004-03-7/Valine; 9007-34-5/Collagen; EC protein, mouse; EC Oxidase; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC Proteins c-akt
Comment In:
Am J Physiol Heart Circ Physiol. 2010 Nov;299(5):H1304-6   [PMID:  20833955 ]

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