| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 1997;30:1448-1454.)
© 1997 American Heart Association, Inc.
Articles |
Role of Angiotensin II in the Regulation of a Novel Vascular Modulator, Hepatocyte Growth Factor (HGF), in Experimental Hypertensive Rats
From the Department of Geriatric Medicine, Osaka University Medical School, and the Division of Biochemistry, Department of Oncology (K.M., T.M.), Biomedical Research Center, Osaka University Medical School, Osaka, Japan.
Correspondence to Toshio Ogihara, MD, PhD, Chairman and Professor, Department of Geriatric Medicine, Osaka University Medical School, 2-2 Yamada-oka, Suita 565, Japan.
Abstract 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.
Key Words: arteriosclerosis • cardiovascular hepatocyte growth factor system • remodeling • endothelial cell
This article has been cited by other articles:
 |
|
 |
|
  F. Sanada, Y. Taniyama, K. Iekushi, J. Azuma, K. Okayama, H. Kusunoki, N. Koibuchi, T. Doi, Y. Aizawa, and R. Morishita Negative Action of Hepatocyte Growth Factor/c-Met System on Angiotensin II Signaling via Ligand-Dependent Epithelial Growth Factor Receptor Degradation Mechanism in Vascular Smooth Muscle Cells Circ. Res., September 25, 2009; 105(7): 667 - 675. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Silvestre and B. I. Levy Circulating progenitor cells and cardiovascular outcomes: latest evidence on angiotensin-converting enzyme inhibitors Eur. Heart J. Suppl., August 1, 2009; 11(suppl_E): E17 - E21. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. You, C. Cochain, C. Loinard, J. Vilar, B. Mees, M. Duriez, B. I. Levy, and J.-S. Silvestre Combination of the Angiotensin-Converting Enzyme Inhibitor Perindopril and the Diuretic Indapamide Activate Postnatal Vasculogenesis in Spontaneously Hypertensive Rats J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 766 - 773. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. You, C. Cochain, C. Loinard, J. Vilar, B. Mees, M. Duriez, B. I. Levy, and J.-S. Silvestre Hypertension Impairs Postnatal Vasculogenesis: Role of Antihypertensive Agents Hypertension, June 1, 2008; 51(6): 1537 - 1544. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Takeshita, H. Tomiyama, N. Yokoyama, Y. Kawamura, T. Furukawa, Y. Ishigai, T. Shibano, T. Isshiki, and T. Sato Angiotensin-converting enzyme inhibition improves defective angiogenesis in the ischemic limb of spontaneously hypertensive rats Cardiovasc Res, November 1, 2001; 52(2): 314 - 320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Matsumoto, R. Morishita, A. Moriguchi, N. Tomita, M. Aoki, H. Sakonjo, K. Matsumoto, T. Nakamura, J. Higaki, and T. Ogihara Inhibition of Neointima by Angiotensin-Converting Enzyme Inhibitor in Porcine Coronary Artery Balloon-Injury Model Hypertension, February 1, 2001; 37(2): 270 - 274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Taniyama, R. Morishita, H. Nakagami, A. Moriguchi, H. Sakonjo, Shokei-Kim, K. Matsumoto, T. Nakamura, J. Higaki, and T. Ogihara Potential Contribution of a Novel Antifibrotic Factor, Hepatocyte Growth Factor, to Prevention of Myocardial Fibrosis by Angiotensin II Blockade in Cardiomyopathic Hamsters Circulation, July 11, 2000; 102(2): 246 - 252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yasuda, Y. Goto, T. Baba, T. Satoh, H. Sumida, S. Miyazaki, and H. Nonogi Enhanced secretion of cardiac hepatocyte growth factor from an infarct region is associated with less severe ventricular enlargement and improved cardiac function J. Am. Coll. Cardiol., July 1, 2000; 36(1): 115 - 121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. B Strawn, R. H Dean, and C. M Ferrario Novel mechanisms linking angiotensin II and early atherogenesis Journal of Renin-Angiotensin-Aldosterone System, March 1, 2000; 1(1): 11 - 17. [PDF]
|
|
|
|
 |
|
 R. Busse and I. Fleming A critical look at cardiovascular translational research Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1655 - H1660. [Full Text] [PDF]
|
|
|
|
 |
|
 M.A. Breider, A.W. Gough, J.R. Haskins, G. Sobocinski, and F.A. De La Iglesia Troglitazone-Induced Heart and Adipose Tissue Cell Proliferation in Mice Toxicol Pathol, September 1, 1999; 27(5): 545 - 552. [Abstract] [PDF]
|
|
|
|
|
|
K. Matsumoto, R. Morishita, A. Moriguchi, N. Tomita, Y. Yo, T. Nishii, K. Matsumoto, T. Nakamura, J. Higaki, and T. Ogihara Prevention of Renal Damage by Angiotensin II Blockade, Accompanied by Increased Renal Hepatocyte Growth Factor in Experimental Hypertensive Rats Hypertension, August 1, 1999; 34(2): 279 - 284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yoshitomi, S. Kojima, T. Umemoto, K. Kubo, Y. Matsumoto, M. Yano, T. Sugi, and M. Kuramochi Serum Hepatocyte Growth Factor in Patients with Peripheral Arterial Occlusive Disease J. Clin. Endocrinol. Metab., July 1, 1999; 84(7): 2425 - 2428. [Abstract] [Full Text]
|
|
|
|
|
|
S. Yasuda, Y. Goto, H. Sumida, T. Noguchi, T. Baba, S. Miyazaki, and H. Nonogi Angiotensin-Converting Enzyme Inhibition Restores Hepatocyte Growth Factor Production in Patients With Congestive Heart Failure Hypertension, June 1, 1999; 33(6): 1374 - 1378. [Abstract] [Full Text] [PDF]
|
|