(Hypertension. 1998;31:176.)
© 1998 American Heart Association, Inc.
Workshop on Vascular Biology & Hypertension: From Molecules to Humans |
Integrins, Adhesion, and Cardiac Remodeling
From University of California at Los Angeles, School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Los Angeles, Calif.
Correspondence to Willa A. Hsueh, MD, UCLA School of Medicine, Division of Endocrinology, Diabetes and Hypertension, 900 Veteran Avenue, Suite 24-130, Box 957073, Los Angeles, CA 90095-7073
 |
Abstract |
|---|
 Top Abstract IntroductionIntegrins and Cardiac RemodelingReferences |
|---|
Integrins are heterodimeric cell surface receptors that mediate a cell’s ability to perceive its environment, respond to changed in its environment, and alter its environment. When activated, these receptors form focal adhesions, which are areas of close attachment of the cells to extracellular matrix proteins in which colocalization of cytoskeletal proteins, intracellular signaling molecules, and growth factor receptors occurs. In cardiac fibroblasts, integrins mediate cell growth and adhesion. Growth factors such as angiotensin II regulate DNA synthesis, protooncogene expression, extracellular matrix production, adhesion, and other actions of cardiac fibroblasts, many of which require integrin activation. In addition to controlling growth factor and hemodynamic effects, regulation of integrin activity may be useful to affect cardiac fibrosis and the remodeling process.
Key Words: integrins • extracellular matrix • cardiac fibroblasts • angiotensin II • fibrosis
Abbreviations: ACEI = angiotensin-converting enzyme inhibitors • AII = angiotensin II • ANP = atrial natriuretic peptide • ECM = extracellular matrix • EGF = epidermal growth factor • ET = endothelin • FACK = focal adhesion kinase • JNK = jun N-terminal kinase • LVH = left ventricular hypertrophy • MAPK = mitogen-activated protein kinase • MEK = APK-ERK-kinase • NE = norepinephrine • NO = nitric oxide • OP = osteopontin • PDGF = platelet-derived growth factor • RGD = arginine-glycine-aspartic acid motif • TGF-ß = transforming growth factor beta
|
Introduction |
|---|
|
TopAbstractIntroductionIntegrins and Cardiac RemodelingReferences |
|---|
Integrins are a family of a transmembrane receptors that mediate a variety of cell functions including adhesion, growth, and motility. They are composed of
and ß subunit heterodimers that consist of a large extracellular domain, a transmembrane region, and a relatively short cytoplasmic domain.1-3 The extracellular domain binds to proteins that form the ECM such as fibronectin, collagen, vitronectin, osteopontin, and others, while the cytoplasmic domains interact with cytoskeletal proteins and intracellular signaling molecules. Thus, integrins have a unique role, transmitting information from the external environment of the cell that then influences structural changes within the cell and thus ultimately regulates cell activity. The engagement of integrins by certain ECM proteins initiates the localization of cytoskeletal proteins into focal adhesions, which are areas of tight association between the plasma membrane and the ECM.4 Focal adhesions represent the colocalization of cytoskeletal proteins such as talin and -actinin, FAK, integrins, growth factor receptors, and other signaling molecules.1,5,6 In general, this colocalization is dependent on the integrin ß-cytoplasmic domain, which is highly conserved between species and for each of the ß subtypes.7 Signaling molecules such as c-src, FAK, phosphotidylinositol 3 kinase, phospholipase C
, MAPK, MEK, JNK, Ras, Raf, and others are associated with focal adhesions.5,6 The colocalization of all these molecules is likely an important means of facilitating their interactions. In addition to the presence of growth factor receptors, growth factor receptor substrates are also present in focal adhesions. For example, the insulin receptor substrate 1 that is phosphorylated in response to tyrosine phosphorylation of the insulin receptor associates with the integrin v ß3 on activation of the insulin receptor.8 The attachment and spreading of cells are functionally important for their growth, survival, and motility. Prevention of attachment leads to cell death.9 Activation of integrins can induce protooncogene expression and regulate the production of cell cycle proteins.10,11 Current data suggest that integrins may act at two points in the cell cycle: regulation of the G0/G1 transition and G1/S transition.12,13 Integrins may also affect the apoptotic process.14 The tyrosine kinase, FAK, is phosphorylated in various cells when the cells are attached to fibronectin, laminin, vitronectin, collagen, and other ECM proteins.15,16 Activation requires integrity of the actin cytoskeleton and an intact ß-cytoplasmic domain.17 Four tyrosine sites in FAK can be phosphorylated; phosphorylation of specific sites can activate certain signaling pathways.18 FAK appears to be an important regulator in the movement of cells, since cells that are deficient in FAK have reduced motility in vitro, while overexpression of FAK is associated with increased motility.19,20 FAK is not only activated by integrins, since growth factors such as endothelin, angiotensin II, vasopressin, and others can stimulate phosphorylation of FAK.21,22
While ECM proteins can influence integrin activity, integrin activation can in turn regulate components of the ECM. For example, collagen and fibronectin, through their binding to integrins, can induce the expression of metalloproteinases, collagenase, gelatinase, and other enzymes that regulate the amount and type of protein in the ECM.23 The cellular response is dictated by which ECM protein activates which specific integrin. In addition, activation of integrins affects the inflammatory response through regulation of NF-
B activity, which itself can control integrin-mediated gene expression.24
Increasing evidence suggests that integrins play an important role in cardiovascular remodeling. Integrins that bind to the RGD motif, such as v ß3 and others, are important in the angiogenic process.25 Inhibitors of these integrins inhibit angiogenesis and may limit tumor growth by thus limiting their blood supply.26 In addition, the IIb ß3 antagonists, which inhibit platelet aggregation, also inhibit the v ß3 integrins.27 This effect is thought to play a role in the ability of IIb ß3 antagonists to inhibit restenosis after vascular injury, thus implying a role for v ß3 in vascular remodeling.28 RGD-dependent integrins also appear to play a role in cardiac fibroblasts actions that contribute to remodeling in the heart.29 The following will review the role of growth factors and integrins in cardiac remodeling.
|
Integrins and Cardiac Remodeling |
|---|
|
TopAbstractIntroductionIntegrins and Cardiac RemodelingReferences |
|---|
When cardiac mass and shape are altered in response to increased workload or stress, two major cell types are involved: myocytes and interstitial fibroblasts.30 The myocytes hypertrophy; this process is accompanied by an alteration of gene expression. In the rodent adult heart, this response involves an induction of ANP, protooncogenes, and a switch from the adult pattern of contractile protein gene expression to the fetal pattern.31 In the human adult heart, ANP is also induced, and ß-myosin heavy chain, ß-skeletal actin, and phospholaban are upregulated.32 A phenotypic alteration occurs in cardiac fibroblasts, so they assume a myofibroblast character, such as expression of
-smooth muscle actin.33,34 The stimulated myofibroblast proliferates and increases its production of ECM proteins, including fibronectin, laminin, and collagen I and III. As the process continues, there is progressive fibrosis, which is a major component of the remodeling process.35 The volume of the heart that is fibrotic is increased relative to the volume that is muscle compared to these volumes in normal heart.35 The fibrosis impairs myocyte contractility, oxygenation, and metabolism, thus contributing to ventricular dysfunction.36 Ultimately, compensated hypertrophy becomes decompensated, resulting in ventricular failure, although events that trigger decompensation are unknown. It is likely that fibrosis contributes to the decompensation. Boluyt et al37 demonstrated that hearts from spontaneous hypertensive rats with failure expressed increased TGF-ß, fibronectin, and collagen compared to hearts from spontaneous hypertensive rats without failure. Autocrine and paracrine, as well as endocrine, growth factors mediate the remodeling process. NE and ET increase ANP and induce fetal contractile protein gene and protooncogene expression in cultured adult rat cardiac myocytes.31 All has similar effects in stretched cardiomyocytes but has lesser effects in cells grown only on plastic-coated dishes.38 In addition, AII indirectly promotes myocyte hypertrophy by increasing ET production from endothelial and endocardial cells39 and by stimulating NE secretion from cardiac nerve endings.40 In contrast, other growth factors contribute to cardiac fibroblast growth and ECM production. AII, EGF, and PDGF stimulate protooncogene expression and DNA synthesis in rat and human cardiac fibroblasts, but only AII substantially enhances ECM production, including fibronectin and laminin.41 ET and NE affected neither growth nor ECM production in the cardiac fibroblast.41 AII is likely an important contributor to the cardiac fibrotic process. TGF-ß appears to mediate actions of AII to increase ECM protein production.42
Adhesion is important to cell growth and the woundhealing process.43 We identified the RGD-binding integrins v, ß1, ß3, and ß5 on the surface of rat and human cardiac fibroblasts. Growth factors such as AII increased mRNA levels of 
ß3 and ß5 in the rat cardiac fibroblast, but little effect of AII was seen on these integrin message levels in human cardiac fibroblasts (Hsueh WA, Do YS, unpublished observations). ß3 binds to a variety of RGD-containing ligands such as fibronectin, thrombin, fibrinogen, collagen, thrombospondin, and others, while ß1 more commonly binds to collagen and ß5 to vitronectin.44 Activation of ß3 by fibronectin or ß1 by collagen enhances MAP kinase activity in rat cardiac fibroblasts. Furthermore, adhesion to collagen or fibronectin increases the stimulation of MAP kinase activity by AII and enhances the effect of AII to induce protooncogene expression (Hsueh WA, Do YS, unpublished observations). Thus, ECM proteins work in conjunction with growth factors such as AII to stimulate intracellular signaling pathways that promote growth in the cardiac fibroblast, a feature suggesting that the ECM plays a dynamic rather than a passive role in the cardiac remodeling process.
OP is a large acidic phosphoprotein that contains calcium binding domains and a RGD motif that contributes to adhesion, growth, and motility in vascular smooth muscle cells.44 OP levels are increased in calcified atherosclerotic plaques. This protein is present in low quantities in normal adult rat and human heart, but OP message and protein are readily detectable in neonatal or hypertrophied adult rat heart and in hypertrophied human heart.45 AII is a potent stimulator of OP production on cultured rat cardiac fibroblasts; TGF-ß and PDGF can also enhance OP production in these cells.45 Human cardiac fibroblasts, however, contain low levels of OP that do not respond to treatment of cells with AII or PDGF. Immunohistochemical studies and in situ hybridization indicate that cardiomyocytes in hypertrophied rat and human heart are a major source of OP in the heart, and in hypertrophied rat heart, OP message levels correlate with ANP message levels.29 ET and NE, but not AII, stimulate OP production in cultured rat cardiomyocytes.29 Antibodies to OP inhibit AII-induced cardiac fibroblast growth (Fig 1) and the ability of cardiac fibroblasts to adhere to and contract collagen gels (Fig 2). Antibodies against ß3 and ß1 also inhibit these functions of cardiac fibroblasts.29 Thus, OP interacting with ß3 and possibly ß1 that bind to RGD sequences on OP mediates AII growth effects and collagen contraction, which in the skin is the last important step in wound healing.43 The effects of OP and the role of integrins in cardiomyocytes has yet to be determined; OP appears to be a paracrine means by which growing or hypertrophied myocytes influence fibroblast growth and other behaviors that are intimately involved in the development of cardiac fibrosis.
|
|
The relationship between the effect of growth factors and the ECM is summarized in Fig 3. ET from endothelial cells and the endocardium and NE from cardiac nerve endings stimulate myocyte hypertrophy. AII has a modest direct effect on myocytes but stimulates both ET, and NE production. AII, PDGF, FGF, and EGF stimulate myofibroblast growth; AII can also enhance ET production in the myofibroblast that promotes myocyte hypertrophy and TGF-ß production that mediates ECM biosynthesis.42 The ECM provides the external milieu for the myofibroblast to control growth and adhesion. OP is secreted from the myocyte, particularly in the hypertrophic state, and from the myofibroblast in response to growth factors (AII) and mediates growth and adhesion of the myofibroblast. The ECM also affects myocyte contractility, oxygenation, and likely its hypertrophic responses. Integrins are intimately involved in mediating OP and ECM effects and synergize with growth factor effects through focal adhesions.
|
An important question is when and how to control the cardiac remodeling response. Myocyte hypertrophy and cardiac fibrosis are both potentially reversible.46 Decreasing the workload is critically important. Lowering blood pressure induces regression of LVH.47,48 Afterload reduction in heart failure improves cardiac performance.47,48 In end-stage heart failure, left ventricular assist devices decrease the high levels of ANP produced by the stressed myocyte,49 and in patients who are placed on these devices, the improved cardiac function that results may be permanent.50,51 Local factors that are produced in the heart, such as ANP and NO, impair cell growth and ECM production and serve as a natural mechanism to balance the local effects of growth factors and vasoconstrictors.52 Whether enhancing the production of these counterbalancing factors (eg, ACEI increase tissue production of bradykinin that stimulates NO) is useful in the heart remains to be determined. Inhibition of AII production by ACEI or its action by AT1 receptor blockade induces regression of hypertrophy in hypertension by mechanisms that appear to extend beyond blood pressure-lowering effects.47,48 In post-myocardial infarction models, timing of control of fibrosis is critical, since wound healing after the acute event is necessary. However, continuation of the wound-healing process leads to progressive hypertrophy, dilation, and fibrosis of the ventricular wall, even in the noninfarcted segments, leading to globular heart fibrosis and failure.47,48 Inhibition of the renin-angiotensin system impairs this post-myocardial infarction response, improves cardiac function, and importantly decreases mortality.47,48 Several other potential approaches exist to control fibrosis: regulate TGF-ß activity, control enzymes such as metalloproteinases that degrade fibrillar collagen and matrix, inhibit integrin receptors or OP, control signaling and nuclear pathways that regulate matrix production, and others. Further investigation will be necessary to characterize the fibrotic process in different models of cardiac remodeling and to define the molecular, cellular, biochemical, and mechanical factors involved to identify the most useful and safest approaches to regulate ventricular wall composition, structure, and, ultimately, function.
Received September 26, 1997; first decision October 16, 1997; accepted October 29, 1997.
|
References |
|---|
|
TopAbstractIntroductionIntegrins and Cardiac RemodelingReferences |
|---|
1. Meredith JE Jr, Winitz S, McArthur Lewis J, Hess S, Ren X-D, Renshaw MW, and Schwartz MA. The regulation of growth and intracellular signaling by integrins. Endocrine Rev. 1996; 17 : 207 .
2. Hynes RO. "Integrins" versatility, modulation and signaling in cell adhesion. Cell. 1992; 69 : 11 –25.[Medline] [Order article via Infotrieve]
3. Schwartz MA, Schaller MD, Ginsberg MH. Integrins: emerging paradigms of signal transduction. Annu Rev Cell Biol. 1995; 11 : 543 –599.
4. Lin CQ, Bissell MJ. Multi-faceted regulation of cell differentiation by extracellular matrix. FASEB J. 1993; 7 : 737 –743.[Abstract]
5. Miyamoto S, Termoto H, Coso OA, Gutkind JS, Burbelo PD, Akiyama SK, Yamada KM. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules.
J Cell Biol. 1995;
131
: 791
–805.
6. Plopper GE, McNamee HP, Kike LE, Bojanowski K, Ingber DE. Convergence of integrin and growth factor receptor signaling pathways within the focal adhesion complex. Mol Biol Cell. 1995; 6 : 1349 –1365.[Abstract]
7. DeSimone DW, Hynes RO. Structural conservation and evolutionary divergence of integrin ß subunits.
J Biol Chem. 1988;
263
: 5333
–5340.
8. Vuori K, Ruoslahti E. Association of insulin receptor substrate-1 with integrins.
Science. 1994;
266
: 1576
–1578.
9. Stoker M, O’Neill C, Berryman S, Waxman V. Anchorage and growth regulation in normal and virus-transformed cells. Int J Cancer. 1968; 3 : 683 –693.[Medline] [Order article via Infotrieve]
10. Dike LE, Farmer Sr. Cell adhesion induces expression of growth-associated genes in suspension-arrested fibroblasts.
Proc Natl Acad Sci U S A. 1988;
85
: 6792
–6796.
11. Guadagno TM, Ohtsubo M, Roberts JM, Assoian RK. A link between cyclin A expression and adhesion-dependent cell cycle progression.
Science. 1993;
262
: 1572
–1575.
12. Hansen LK, Mooney DJ, Vacanti JP, Ingber DE. Integrin binding and cell spreading on extracellular matrix act at different points in the cell cycle to promote hepatocyte growth. Mol Biol Cell. 1994; 5 : 967 –975.[Abstract]
13. Tucker RW, Butterfield CE, Folkman J. Interaction of serum and cell spreading affects growth of neoplastic and nonneoplastic cells. J Supramol Struct. 1981; 15 : 29 –40.
14. Ellis RE, Yuan J, Horvitz HR. Mechanisms and functions of cell death. Ann Rev Cell Biol. 1991; 7 : 663 –698.
15. Burridge K, Turner CE, Romer LH. Tyrosine phosphorylation of paxillin and pp125 FAK accompanies cell adhesion to extracellular matrix: a role in cytoskeletal assembly.
J Cell Biol. 1992;
119
: 893
–903.
16. Hanks SK, Calalb MB, Harper MC, Patel SK. Focal adhesion protein tyrosine kinase phosphorylated in response to cell spreading on fibronectin.
Proc Natl Acad Sci U S A. 1992;
89
: 8487
–8489.
17. Guan J-L, Trevithick JE, Hynes RO. Fibronectin/integrin interaction induces tyrosine phosphorylation of a 120 kD protein. Cell Regul. 1991; 2 : 951 –964.[Medline] [Order article via Infotrieve]
18. Calalb MB, Polte TR, Hands SK. Tyrosine phosphorylation of focal adhesion kinase at sites in the catlytic domain regulates kinase activity: a role for src family kinases. Mol Cell Biol. 1995; 15 : 954 –963.[Abstract]
19. Illic D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N, Nomura S, Fujimoto J, Okada M, Yamamoto T, Aizawa S. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature. 1995; 377 : 539 –544.[Medline] [Order article via Infotrieve]
20. Akasaka T, van Leeuwen IG, Yoshinaga IG, Mihm MC, Byers HR. Focal adhesion kinase (p125FAK) expression correlates with motility of human melanoma cell lines. J. Invest Dermatol. 1995; 105 : 104 –108.[Medline] [Order article via Infotrieve]
21. Zachary I, Sinnett-Smith J, Rozengurt E. Bombesin, vasopressin and endothelin stimulation of tyrosine phosphorylation in Swiss 3T3 cells.
J Biol Chem. 1992;
267
: 19031
–19034.
22. Schorb W, Peeler TC, Madigan NN, Conrad KM, Baker KM, Angiotensin II-induced protein tyrosine phosphorylation in neonatal rat cardiac fibroblasts.
J Biol Chem. 1994;
269
: 19626
–19632.
23. Tremble P, Damsky CH, Werb Z. Components of the nuclear signaling cascade that regulate collagenase gene expression in response to integrinderived signals.
J Cell Biol. 1995;
129
: 1707
–1720.
24. Haskill S, Beg AA, Tompkins SM, Moriss JS, Yurochko AD, Sampson-Johannes A, Mondal K, Ralph P, Baldwin AS. Characterization of an intermediate-early gene induced in adherent monocytes that encodes IB-like activity.
Cell. 1991;
65
: 1281
–1289.[Medline]
[Order article via Infotrieve]
25. Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis.
Science. 1994;
264
: 569
–571.
26. Brooks PC, Montgomery AM, Rosenfeld M, Reisfeld RA, Hu T, Klier G, Cheresh DA. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell. 1994; 79 : 1157 –1164.[Medline] [Order article via Infotrieve]
27. Hammes H-P, Brownlee M, Jonczyk A, Sutter A, Preissner KT. Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization. Nature Med. 1996; 2 : 529 .[Medline] [Order article via Infotrieve]
28. Choi ET, Engel L, Callow AD, Sun S, Trachtenberg J, Santoro S, Ryan US. Inhibition of neointimal hyperplasia by blocking alpha V beta 3 integrin with a small peptide antagonist GpenGRGDSPCA. J Vasc Surgery. 1994; 19 : 125 –134.[Medline] [Order article via Infotrieve]
29. 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 A(II) - induced DNA synthesis and collagen gel contraction. J Clin Invest. 1996; 98 : 2218 –27.[Medline] [Order article via Infotrieve]
30. Gvozdjak J, Bada V, Niederland TR. The role of myocardial fibrosis in the development of cardiac insufficiency in cardiomyopathies. Cor Vasa. 1969; 11 : 229 –234.[Medline] [Order article via Infotrieve]
31. Chien KR, Knowlton KU, Zhu H, Chien S. Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response. FASEB J. 1991; 5 : 3037 –3046.[Abstract]
32. Feldman AM, Ray PE, Silan CM, Mercer JA, Minobe W. Selective gene expression in failing human heart: quantification of steady-state levels of messenger RNA in endomyocardial biopsies using the polymerase chain reaction.
Circulation. 1991;
83
: 1866
–1872.
33. Sun Y, Weber KT. Angiotensin converting enzyme and myofibroblasts during tissue repair in the rat heart. J Mol Cell Cardiol. 1996; 28 : 851 –858.[Medline] [Order article via Infotrieve]
34. Sun Y, Weber KT. Cells expressing angiotensin II receptors in fibrous tissue of rat heart. Cardiovasc Res. 1996; 31 : 518 –525.[Medline] [Order article via Infotrieve]
35. Weber KT, Janikki JS, Shroff SG, Pick R, Chen RM, Bashey RI. Collagen remodeling of the pressure-overloaded hypertrophyed: non-human private myocardium.
Circ Res. 1988;
62
: 757
–765.
36. Weber KT, Brilla CG, Campbell SE, Zhou G, Matsubara L, Guarda E. Pathologic hypertrophy with fibrosis: the structural basis for myocardial failure. Blood Press. 1992; 1 : 75 –85.[Medline] [Order article via Infotrieve]
37. Boluyt MO, O’Neill L, Meredith AL, Bing OSL, Brooks WW, Conrad CH, Crow MT, Lakatta EG. Alteration in cardiac gene expression during the transition from stable hypertrophy to heart failure.
Circ Res. 1994;
75
: 23
–32.
38. Sadoshima J, Yuhui X, Slater HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell. 1993; 75 : 977 –984.[Medline] [Order article via Infotrieve]
39. Hiroshi I, Yukio H, Susumu A, Masato T, Motoyoshi T, Akira K, Akihiko N, Fumiaki M, Michiaki H. Endothelin-1: an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest. 1993; 92 : 398 –403.[Medline] [Order article via Infotrieve]
40. Hughes J, Roth RH. Evidence that angiotensin enhances transmitter release during sympathetic nerve stimulation. Br J Phannacol. 1971; 41 : 239 –255.
41. Iwami K, Ashizawa, N, Do YS, Graf K, Hsueh WA. Comparison of angiotensin II with other growth factors on EGR-1 and matrix gene expression in cardiac fibroblasts. Am J Physiol. 1996; 39 : H2100 –H2107.
42. Kim S, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K, Inada Y, Ishimura Y, Chatani F, Iwao H. Angiotensin II type I receptor antagonist inhibits the gene expression of transforming growth factor-beta 1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats.
J Pharmacol Exp Ther. 1995;
273
: 509
–515.
43. Grinnell, F. Fibroblasts, myofibroblasts, and wound contraction.
J Cell Biol. 1994;
124
: 401
–404.
44. Liaw L, Almeida M, Hart CE, Schwartz SM, Giachelli CM. Osteopontin promotes vascular cell adhesion and spreading and is chemotactic for smooth muscle cells in vitro.
Circ Res. 1994;
74
: 214
–224.
45. 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. 1998; in press.
46. Dahloef, B, Pennert K, Hansson L. Reversal of left ventricular hypertrophy in hypertensive patients: a metaanalysis of 109 treatment studies. Am J Hypertens. 1992; 5 : 95 –110.[Medline] [Order article via Infotrieve]
47. SAVE Investigators. Effects of captopril on morbidity and mortality in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. N Engl J Med. 1992; 327 : 669 –677.[Abstract]
48. GISSI-3 Coordinating Center. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet. 1994; 343 : 1115 –1122.[Medline] [Order article via Infotrieve]
49. Altemose GT, Gritzus V, Jeevanendam V, Goldman B, Bargulies KB. Altered myocardial phenotype after mechanical support in human beings with advanced cardiomyopathy. J Heart Lung Transplant. 1997; 16 : 765 –773.[Medline] [Order article via Infotrieve]
50. Levin HR, Oz MC, Chen JM, Packer M, Rose EA, Burkhoff D. Reversal of chronic ventricular dilation in patients with end-stage cardiomyopathy by prolonged mechanical unloading.
Circulation. 1995;
91
: 2717
–2724.
51. Oz MC, Argenziano M, Catanese KA, Gardocki MT, Goldstein DJ, Ashton RC, Gelijns AC, Rose EA, Levin HR. Bridge experience with long-term implantable left ventricular assist devices. Are they an alternative to transplantation?
Circulation. 1997;
95
: 1844
–1852.
52. Hou J, Kato H, Cohen RA, Chobanian AV, Brecher P. Angiotensin II-induced cardiac fibrosis in the rat is increased by chronic inhibition of nitric oxide synthase. J Clin Invest. 1995; 96 : 2469 –2477.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  A. M. Manso, L. Elsherif, S.-M. Kang, and R. S. Ross Integrins, membrane-type matrix metalloproteinases and ADAMs: Potential implications for cardiac remodeling Cardiovasc Res, February 15, 2006; 69(3): 574 - 584. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S Ross Molecular and mechanical synergy: cross-talk between integrins and growth factor receptors Cardiovasc Res, August 15, 2004; 63(3): 381 - 390. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Collins, J. Schnee, W. Wang, S. Kim, M. C. Fishbein, D. Bruemmer, R. E. Law, S. Nicholas, R. S. Ross, and W. A. Hsueh Osteopontin modulates angiotensin II- induced fibrosis in the intact murine heart J. Am. Coll. Cardiol., May 5, 2004; 43(9): 1698 - 1705. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Ross and T. K. Borg Integrins and the Myocardium Circ. Res., June 8, 2001; 88(11): 1112 - 1119. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Keller, S.-Y. Shai, C. J. Babbitt, C. G. Pham, R. J. Solaro, M. L. Valencik, J. C. Loftus, and R. S. Ross Disruption of Integrin Function in the Murine Myocardium Leads to Perinatal Lethality, Fibrosis, and Abnormal Cardiac Performance Am. J. Pathol., March 1, 2001; 158(3): 1079 - 1090. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Touyz and E. L. Schiffrin Signal Transduction Mechanisms Mediating the Physiological and Pathophysiological Actions of Angiotensin II in Vascular Smooth Muscle Cells Pharmacol. Rev., December 1, 2000; 52(4): 639 - 672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. N. Muller, E. M. A. Mervaala, F. Schmidt, J.-K. Park, R. Dechend, E. Genersch, V. Breu, B.-M. Loffler, D. Ganten, W. Schneider, et al. Effect of Bosentan on NF-{kappa}B, Inflammation, and Tissue Factor in Angiotensin II-Induced End-Organ Damage Hypertension, August 1, 2000; 36(2): 282 - 290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Schnee and W. A. Hsueh Angiotensin II, adhesion, and cardiac fibrosis Cardiovasc Res, May 1, 2000; 46(2): 264 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. N. Muller, R. Dechend, E. M. A. Mervaala, J.-K. Park, F. Schmidt, A. Fiebeler, J. Theuer, V. Breu, D. Ganten, H. Haller, et al. NF-{kappa}B Inhibition Ameliorates Angiotensin II-Induced Inflammatory Damage in Rats Hypertension, January 1, 2000; 35(1): 193 - 201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kappert, G. Schmidt, G. Doerr, B. Wollert-Wulf, E. Fleck, and K. Graf Angiotensin II and PDGF-BB Stimulate {beta}1-Integrin-Mediated Adhesion and Spreading in Human VSMCs Hypertension, January 1, 2000; 35(1): 255 - 261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kawano, R. J. Cody, K. Graf, S. Goetze, Y. Kawano, J. Schnee, R. E. Law, and W. A. Hsueh Angiotensin II Enhances Integrin and {alpha}-Actinin Expression in Adult Rat Cardiac Fibroblasts Hypertension, January 1, 2000; 35(1): 273 - 279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Walker and F. G. Spinale THE STRUCTURE AND FUNCTION OF THE CARDIAC MYOCYTE: A REVIEW OF FUNDAMENTAL CONCEPTS J. Thorac. Cardiovasc. Surg., August 1, 1999; 118(2): 375 - 382. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||