Document Detail

Role of angiotensin II in the regulation of a novel vascular modulator, hepatocyte growth factor (HGF), in experimental hypertensive rats.
MedLine Citation:
PMID:  9403566     Owner:  NLM     Status:  MEDLINE    
Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor that regulates cell growth, cell motility, and morphogenesis of various types of cells, and is thus considered a humoral mediator of epithelial-mesenchymal interactions responsible for morphogenic tissue interactions. We have previously reported that HGF is a novel member of endothelium-specific growth factors whose serum concentration is positively associated with blood pressure in humans. Therefore, we speculated that serum HGF secretion might be elevated in response to high blood pressure as a counter-system against endothelial dysfunction. However, it is difficult to elucidate the role of circulating and tissue HGFs in human hypertension. To address this issue, we measured circulating and tissue HGF concentrations in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at different ages. Serum HGF concentration in SHR was significantly higher than that in WKY at 6, 15, and 25 weeks of age (P<.01). Serum HGF concentration was also significantly positively correlated with blood pressure in SHR (P<.02, r=.455). In contrast, tissue HGF concentrations in heart, aorta, and kidney were significantly decreased in SHR as compared with WKY at 25 weeks of age, when these organs showed hypertrophic changes induced by hypertension (P<.01). Cardiac HGF mRNA was also decreased in SHR as compared with WKY at 25 weeks of age. Moreover, cardiac HGF concentration showed a significant negative correlation with left ventricular (LV) weight (P<.01), whereas serum HGF concentration showed a significant positive correlation with LV weight (P<.05). Interestingly, concentrations of cardiac and vascular angiotensin II, a suppressor of HGF, were increased in SHR as compared with WKY at 25 weeks of age (P<.01). Therefore, we examined the effects of angiotensin blockade on circulating and tissue HGF concentrations, to study the role of angiotensin II in HGF regulation. Administration of an angiotensin-converting enzyme inhibitor (enalapril) and angiotensin II type 1 receptor antagonists (losartan and HR 720) for 6 weeks resulted in a significant increase in cardiac HGF concentration, accompanied by increased cardiac HGF mRNA, and a significant decrease in serum HGF concentration, accompanied by lowered blood pressure and reduced LV weight (P<.01). Here, we demonstrated increased circulating HGF and decreased vascular, cardiac, and renal HGF in SHR as compared with WKY at the maintenance stage of hypertension. Decreased tissue HGF in target organs of hypertension may be due to increased tissue angiotensin II. These results suggest that decreased local HGF production may have an important role in the cardiovascular remodeling of target organs in hypertension, since HGF prevented endothelial injury and promoted angiogenesis. Blockade of angiotensin augmented local decreased cardiovascular HGF in hypertension, potentially resulting in the improvement of endothelial dysfunction.
N Nakano; A Moriguchi; R Morishita; I Kida; N Tomita; K Matsumoto; T Nakamura; J Higaki; T Ogihara
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Hypertension     Volume:  30     ISSN:  0194-911X     ISO Abbreviation:  Hypertension     Publication Date:  1997 Dec 
Date Detail:
Created Date:  1998-01-08     Completed Date:  1998-01-08     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1448-54     Citation Subset:  IM    
Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan.
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MeSH Terms
Aging / physiology
Angiotensin II / physiology*
Angiotensin-Converting Enzyme Inhibitors / pharmacology
Aorta / metabolism
Biphenyl Compounds / pharmacology*
Blood Pressure
Enalapril / pharmacology
Gene Expression Regulation, Developmental / drug effects,  physiology*
Heart / growth & development
Hepatocyte Growth Factor / biosynthesis*
Hypertension / blood,  metabolism*,  physiopathology*
Imidazoles / pharmacology*
Losartan / pharmacology*
Lung / metabolism
Myocardium / metabolism
Organ Specificity
Rats, Inbred SHR
Rats, Inbred WKY
Receptors, Angiotensin / antagonists & inhibitors
Regression Analysis
Reg. No./Substance:
0/Angiotensin-Converting Enzyme Inhibitors; 0/Biphenyl Compounds; 0/Imidazoles; 0/Receptors, Angiotensin; 0/fonsartan; 11128-99-7/Angiotensin II; 114798-26-4/Losartan; 67256-21-7/Hepatocyte Growth Factor; 75847-73-3/Enalapril

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