This Article Full Text (PDF) All Versions of this Article: 43/6/1164    most recent 01.HYP.0000128620.57061.67v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Díez, J. Search for Related Content PubMed PubMed Citation Articles by Díez, J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Remodeling Hypertrophy

(Hypertension. 2004;43:1164.)
© 2004 American Heart Association, Inc.

Editorial Commentaries

Profibrotic Effects of Angiotensin II in the Heart

A Matter of Mediators

Javier Díez

From the Area of Cardiovascular Pathophysiology, Centre for Applied Medical Research and University Clinic, School of Medicine, University of Navarra, Pamplona, Spain.

Correspondence to Dr Javier Díez, CIMA-Facultad de Medicina, C/ Irunlarrea 1, 31008 Pamplona, Spain. E-mail jadimar{at}unav.es

In response to mechanical and/or metabolic stress the myocardium undergoes structural remodeling involving cardiomyocyte hypertrophy and interstitial and perivascular fibrosis.¹ Cardiomyocyte hypertrophy includes an increase in contractile and embryonic protein content, which appears largely on the activation of transcription of the corresponding cardiac genes that encode these proteins. Myocardial fibrosis is the result of the exaggerated deposition of collagen types I and III fibers as a consequence of the predominance of the synthesis over the degradation of collagen molecules. Myocardial remodeling is accompanied by a progressive decline in cardiac function over time, which underlies the pathogenesis of heart failure in patients with chronic cardiac conditions.²

It is now accepted that a number of systemic and locally expressed factors have key roles in the process of myocardial remodeling.¹ One of these factors is angiotensin II (Ang II). Whereas the role of Ang II in cardiomyocyte hypertrophy is well established,³ emerging experimental and clinical evidence is providing support for the notion that this peptide induces myocardial fibrosis.⁴ Several potential pathways may mediate the profibrotic effects of Ang II on the heart. On the one hand, a number of findings indicate that the interaction of Ang II with the Ang II type-1 (AT₁) receptor located in cardiac fibroblasts results in induction of fibroblast hyperplasia, activation of collagen biosynthetic pathways, and inhibition of collagen degradative pathways.⁵ On the other hand, more recent findings suggest that fibrosis may represent the reparative response to myocardial inflammation induced by Ang II through the interaction with AT₁ receptors present in cells from the cardiac microvasculature.^6,7

Whatever the pathway is, available data indicate that the profibrotic effect of Ang II results from synergistic cooperation between this peptide and other profibrotic factors. For instance, the ability of Ang II to stimulate fibroblasts and alter the metabolism of fibrillar collagen may be mediated by transforming growth factor-ß₁, endothelin-1, and plasminogen activator inhibitor-1.⁸ In addition, several lines of evidence point to osteopontin as a critical mediator of the proinflammatory and profibrotic cardiac effects of Ang II. First, monoclonal antibodies directed against osteopontin have been found completely to block the stimulatory effects of Ang II on cultured rat cardiac fibroblasts.⁹ Second, elevated osteopontin mRNA expression has been detected in the hypertrophied and fibrotic left ventricle in rat models characterized by high myocardial Ang II concentrations such as the Ren2 rat,¹⁰ rats with renovascular hypertension,¹¹ and spontaneously hypertensive rats with heart failure.¹² Third, myocardial inflammation and fibrosis have been associated with the expression of osteopontin in coronary walls of rats with Ang II/salt-induced hypertension.¹³ Fourth, Matsui et al¹⁴ report in this issue of Hypertension that mice lacking osteopontin do not develop myocardial fibrosis in response to Ang II-induced hypertension. Finally, human myocardium with extensive fibrosis and cardiomyocyte hypertrophy have shown substantial immunoreactivity for osteopontin.¹¹

Osteopontin is a cell-secreted adhesive glycophosphoprotein found as a component of the extracellular matrix in a diversity of tissues. Osteopontin binds to integrin receptors (vß3, vß5, vß1) to regulate cell responses and is also a ligand for certain variant forms of CD44 receptor (v6 and/or v7), through which it acts as a chemoattractant factor for various cell types, notably monocytes/macrophages.¹⁵ In addition, it has been shown that osteopontin interacts with fibronectin and collagen, which suggests a possible role in matrix organization and stability.^16,17

Osteopontin expression is induced in cardiovascular cells in response to a number of stimuli, including cytokines, growth factors, and hormones. Cell culture studies have shown that Ang II stimulates osteopontin mRNA expression in cardiac cells, including fibroblasts^9,18 and microvascular endothelial cells.¹⁹ Reactive oxygen species and activation of members of the mitogen-activated protein kinases super family would mediate this effect.^18,19 In addition, Ang II has been shown to increase osteopontin mRNA expression in fresh samples of human myocardium.²⁰ Interestingly, it has been shown that myocardial osteopontin expression is markedly attenuated in Ang II–infused rats treated either with adrenalectomy or with the selective aldosterone blocker eplerenone.¹³ These preliminary findings are partly confirmed by data reported by Matsui et al¹⁴ in this issue showing that eplerenone does tend to decrease the cardiac osteopontin mRNA level in wild-type Ang II–infused mice. Thus, aldosterone may mediate the stimulatory effect of Ang II on cardiac osteopontin, providing additional support to the proposal that aldosterone activation of cardiac mineralocorticoid receptors critically contributes to cardiac damage induced by Ang II.²¹

In summary, although blood pressure dependent effects of Ang II are difficult to separate from blood pressure independent effects in most studies, including the present one by Matsui et al,¹⁴ this peptide emerges as an important determinant of the fibrotic response of the myocardium to injury. Data reviewed in this commentary illustrate the complex network of mediators and interactions potentially involved in Ang II–induced myocardial fibrosis. Osteopontin seems to play a central role in this network and, thus, may be considered as a target for possible therapeutic strategies aimed to block the development of myocardial fibrosis and, in turn, to prevent heart failure in chronic cardiac diseases.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

1. Swynghedauw B. Molecular mechanisms of myocardial remodeling. Physiol Rev. 1999; 79: 215–262.[Abstract/Free Full Text]
2. Takano H, Hasegawa H, Nagai T, Komuru I. Implication of cardiac remodeling in heart failure: mechanisms and therapeutic strategies. Intern Med. 2003; 42: 465–469.[Medline] [Order article via Infotrieve]
3. Lijnen P, Petrov V. Renin-angiotensin system, hypertrophy and gene expression in cardiac myocytes. J Mol Cell Cardiol. 1999; 31: 949–970.[CrossRef][Medline] [Order article via Infotrieve]
4. Lijnen PJ, Petrov VV. Role of intracardiac renin-angiotensin-aldosterone system in extracellular matrix remodeling. Methods Find Exp Clin Pharmacol. 2003; 25: 541–564.[CrossRef][Medline] [Order article via Infotrieve]
5. González A, López B, Querejeta R, Díez J. Regulation of myocardial fibrillar collagen by angiotensin II. A role in hypertensive heart disease? J Mol Cell Cardiol. 2002; 34: 1585–1593.[CrossRef][Medline] [Order article via Infotrieve]
6. Tokuda K, Kai H, Kuwahara F, Yasukawa H, Tahara N, Kudo H, Takemiya K, Koga M, Yamamoto T, Imaizumi T. Pressure-independent effects of angiotensin II on hypertensive myocardial fibrosis. Hypertension. 2004; 43: 499–503.[Abstract/Free Full Text]
7. Behr TH, Willette RN, Coatney RW, Berova M, Angermann CE, Anderson K, Sackner-Bernstein J, Barone FC. Eprosartan improves cardiac performance, reduces cardiac hypertrophy and mortality and downregulates myocardial monocyte chemoattractant protein-1 and inflammation in hypertensive heart disease. J Hypertens. 2004; 22: 583–592.[CrossRef][Medline] [Order article via Infotrieve]
8. Dostal DE. Regulation of cardiac collagen. angiotensin and cross-talk with local growth factors. Hypertension. 2001; 37: 841–844.[Free Full Text]
9. Ashizawa N, Graf K, Do YS, Nunohiro T, Giachelli CM, Meehan WP, Tuan TL, Hsueh WA. Osteopontin is produced by rat cardiac fibroblasts and mediates AII-induced DNA synthesis and collagen gel contraction. J Clin Invest. 1996; 98: 2218–2227.[Medline] [Order article via Infotrieve]
10. Rothermund L, Kreutz R, Kossmehl P, Fredersdorf S, Shakibaei M, Schulze-Tamzil G, Paul M, Grimm D. Early onset of chondroitin sulfate and osteopontin expression in angiotensin II-dependent left ventricular hypertrophy. Am J Hypertens. 2002; 15: 644–652.[CrossRef][Medline] [Order article via Infotrieve]
11. Graf K, Do YS, Ashizawa N, Meehan WP, Giachelli CM, Marboe CC, Fleck E, Hsueh WA. Myocardial osteopontin expression is associated with left ventricular hypertrophy. Circulation. 1997; 96: 3063–3071.[Abstract/Free Full Text]
12. Singh K, Sirokman G, Communal C, Robinson KG, Conrad CH, Brooks WW, Bing OHL, Colucci WS. Myocardial osteopontin expression coincides with the development of heart failure. Hypertension. 1999; 33: 663–670.[Abstract/Free Full Text]
13. Rocha R, Martin-Berger CL, Yang P, Scherrer R, Delyani J, McMahon E. Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart. Endocrinology. 2002; 143: 4828–4836.[Abstract/Free Full Text]
14. Matsui Y, Jia N, Okamoto H, Kon S, Onozuka H, Akino M, Liu L, Morimoto J, Riyyling, Denhardt D, Kitabatake A, Uede T. Role of osteopontin in cardiac fibrosis and remodeling in angiotensin II-induced cardiac hypertrophy. Hypertension. 2004; 43: 1195–1201.[Abstract/Free Full Text]
15. Denhardt DT, Noda M, O’Regan AW, Pavlin D, Berman JS. Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest. 2001; 107: 1055–1061.[Medline] [Order article via Infotrieve]
16. Mukherjee BB, Nemir M, Beninati S, Cordella-Miele E, Singh K, Chackalaparampil I, Shanmugam V, DeVougue MW, Mukherjee AB. Interaction of osteopontin with fibronectin and other extracellular matrix molecules. Ann N Y Acad Sci. 1995; 760: 201–212.[Medline] [Order article via Infotrieve]
17. Kaartinen MT, Pirhonen A, Linnala-Kankhunen A, Maenpaa PH. Cross-linking of osteopontin by tissue transglutaminase increases its collagen binding properties. J Biol Chem. 1999; 274: 1729–1735.[Abstract/Free Full Text]
18. Xie Z, Singh M, Singh K. ERK1/2 and JNKs, but not p38 kinase, are involved in reactive oxygen species-mediated induction of osteopontin gene expression by angiotensin II and interleukin-1ß in adult rat cardiac fibroblasts. J Cell Physiol. 2004; 198: 399–407.[CrossRef][Medline] [Order article via Infotrieve]
19. Xie Z, Pimental DR, Lohan S, Vasertriger A, Pligavko C, Colucci WS, Singh K. Regulation of angiotensin II-stimulated osteopontin expression in cardiac microvascular endothelial cells: role of p42/44 mitogen-activated protein kinase and reactive oxygen species. J Cell Physiol. 2001; 188: 132–138.[CrossRef][Medline] [Order article via Infotrieve]
20. Kupfahl C, Pink D, Friedrich K, Zurbrügg HR, Neuss M, Warnecke C, Fielitz J, Graf K, Fleck E, Regitz-Zagrosek V. Angiotensin II directly increases transforming growth factor ß1 and osteopontin and indirectly affects collagen mRNA expression in the human heart. Cardiovasc Res. 2000; 46: 463–475.[Abstract/Free Full Text]
21. Struthers AD, MacDonald TM. Review of aldosterone- and angiotensin II-induced target organ damage and prevention. Cardiovasc Res. 2004; 61: 663–670.[Abstract/Free Full Text]

This article has been cited by other articles:

				E. Caglayan, B. Stauber, A. R. Collins, C. J. Lyon, F. Yin, J. Liu, S. Rosenkranz, E. Erdmann, L. E. Peterson, R. S. Ross, et al. Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator-Activated Receptor {gamma} in Cardiac Fibrosis Diabetes, September 1, 2008; 57(9): 2470 - 2479. [Abstract] [Full Text] [PDF]

				J. C. B. Ferreira, A. V. Bacurau, F. S. Evangelista, M. A. Coelho, E. M. Oliveira, D. E. Casarini, J. E. Krieger, and P. C. Brum The role of local and systemic renin angiotensin system activation in a genetic model of sympathetic hyperactivity-induced heart failure in mice Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2008; 294(1): R26 - R32. [Abstract] [Full Text] [PDF]

				G. Ruiz-Hurtado, M. Fernandez-Velasco, M. Mourelle, and C. Delgado LA419, a Novel Nitric Oxide Donor, Prevents Pathological Cardiac Remodeling in Pressure-Overloaded Rats Via Endothelial Nitric Oxide Synthase Pathway Regulation Hypertension, December 1, 2007; 50(6): 1049 - 1056. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) All Versions of this Article: 43/6/1164    most recent 01.HYP.0000128620.57061.67v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Díez, J. Search for Related Content PubMed PubMed Citation Articles by Díez, J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Remodeling Hypertrophy