CLINICAL STUDY: VALVE DISEASE
Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease
Jens Fielitz, MD*,
Stefan Hein, MD ,
Veselin Mitrovic, MD,
Rainer Pregla, MD ,
Heinz R. Zurbrügg, MD,
Christina Warnecke, VMD*,
Jutta Schaper, MD ,
Eckart Fleck, MD* and
Vera Regitz-Zagrosek, MD*
* Innere Medizin, Kardiologie, Charite, Campus Virchow Klinikum, Humboldt Universität Berlin und Deutsches Herzzentrum, Berlin, Germany
Kerkhoff-Klinik, Abt für Herz-, Gefäß- und Thoraxchirurgie, Bad Nauheim, Germany
Klinik für Herz-, Gefäß- und Thoraxchirurgie, DHZB?2, Germany
MPI für experimentelle Kardiologie, Bad Nauheim, Germany
Manuscript received July 20, 2000;
revised manuscript received December 8, 2000,
accepted December 28, 2000.
Reprint requests and correspondence: Prof. Dr. Regitz-Zagrosek, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
zagrosek{at}dhzb.de
OBJECTIVES
We sought to determine whether the cardiac renin-angiotensin system (RAS) is activated in human aortic valve disease depending on left ventricular function, and we analyzed the concomitant regulation of the extracellular matrix components.
BACKGROUND
In animal models with pressure or volume load, activation of the cardiac RAS increases fibrosis. In human aortic valve disease, the ventricular collagen protein content is increased, but only scarce data on the activation state of the cardiac RAS and its effects on collagen and fibronectin messenger ribonucleic acid (mRNA) are available.
METHODS
In left ventricular biopsies from patients with aortic valve stenosis (AS) and aortic valve regurgitation and from control subjects, we quantitated mRNAs for angiotensin-converting enzyme (ACE), chymase, transforming growth factor-beta1 (TGF-beta1), collagen I, collagen III and fibronectin by reverse-transcription polymerase chain reaction. Proteins were localized by immunohistochemistry; ACE activity was determined by high performance liquid chromatography; and TGF-beta protein by quantitative enzyme immunoassay.
RESULTS
Protein, ACE and TGF-beta1 mRNA were significantly increased in patients with AS and AR (1.5- to 2.1-fold) and correlated with each other. The increase occurred also in patients with normal systolic function. Collagen I and III and fibronectin mRNAs were both upregulated about twofold in patients with AS and AR. In AS, collagen and fibronectin mRNA expression levels were positively correlated with left ventricular end-diastolic pressure and inversely with left ventricular ejection fraction (LVEF).
CONCLUSIONS
In human hearts, pressure and volume overload increases cardiac ACE and TGF-beta1 in the early stages. This activation of the cardiac RAS may contribute to the observed increase in collagen I and III and fibronectin mRNA expression. The increase in extracellular matrix already exists in patients with a normal LVEF, and it increases with functional impairment.
|
Abbreviations and Acronyms
| | ACE | = angiotensin-converting enzyme | | AR | = aortic (valve) regurgitation | | AS | = aortic (valve) stenosis | | GAPDH | = glyceraldehyde-3-phosphate dehydrogenase | | hHC | = human heart chymase | | LVEDP | = left ventricular end-diastolic pressure | | LVEF | = left ventricular ejection fraction | | mRNA | = messenger ribonucleic acid | | PDH | = pyruvic dehydrogenase | | RAS | = renin-angiotensin system | | RT-PCR | = reverse-transcription polymerase chain reaction | | TGF-beta1 | = transforming growth factor-beta1 |
|
This article has been cited by other articles:
|
|
|
|
 
A. Della Corte, G. Salerno, E. Chiosi, D. Iarussi, G. Santarpino, M. Miraglia, S. Naviglio, and M. De Feo
Preoperative, postoperative and 1-year follow-up N-terminal pro-B-type natriuretic peptide levels in severe chronic aortic regurgitation: correlations with echocardiographic findings
Interactive CardioVascular and Thoracic Surgery,
June 1, 2008;
7(3):
419 - 424.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Mihaljevic, M. R. Sayeed, S. C. Stamou, and S. Paul
Pathophysiology of Aortic Valve Disease
Card. Surg. Adult,
January 1, 2008;
3(2008):
825 - 840.
[Full Text]
|
|
|
|
|
|
|
J. Fielitz, S. Philipp, L. R. Herda, E. Schuch, B. Pilz, C. Schubert, V. Gunzler, R. Willenbrock, and V. Regitz-Zagrosek
Inhibition of prolyl 4-hydroxylase prevents left ventricular remodelling in rats with thoracic aortic banding
Eur J Heart Fail,
April 1, 2007;
9(4):
336 - 342.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Philipp, J. S. Jurgensen, J. Fielitz, W. M. Bernhardt, A. Weidemann, A. Schiche, B. Pilz, R. Dietz, V. Regitz-Zagrosek, K.-U. Eckardt, et al.
Stabilization of hypoxia inducible factor rather than modulation of collagen metabolism improves cardiac function after acute myocardial infarction in rats
Eur J Heart Fail,
June 1, 2006;
8(4):
347 - 354.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Mahmoodzadeh, S. Eder, J. Nordmeyer, E. Ehler, O. Huber, P. Martus, J. Weiske, R. Pregla, R. Hetzer, and V. Regitz-Zagrosek
Estrogen receptor alpha up-regulation and redistribution in human heart failure
FASEB J,
May 1, 2006;
20(7):
926 - 934.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Shigeyama, Y. Yasumura, A. Sakamoto, Y. Ishida, T. Fukutomi, M. Itoh, K. Miyatake, and M. Kitakaze
Increased gene expression of collagen Types I and III is inhibited by {beta}-receptor blockade in patients with dilated cardiomyopathy
Eur. Heart J.,
December 2, 2005;
26(24):
2698 - 2705.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J Jimenez-Candil, J Bermejo, R Yotti, C Cortina, M Moreno, J L Cantalapiedra, and M A Garcia-Fernandez
Effects of angiotensin converting enzyme inhibitors in hypertensive patients with aortic valve stenosis: a drug withdrawal study
Heart,
October 1, 2005;
91(10):
1311 - 1318.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Martinka, J. Fielitz, A. Patzak, V. Regitz-Zagrosek, P. B. Persson, and H. M. Stauss
Mechanisms of blood pressure variability-induced cardiac hypertrophy and dysfunction in mice with impaired baroreflex
Am J Physiol Regulatory Integrative Comp Physiol,
March 1, 2005;
288(3):
R767 - R776.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B.-J. Thiele, A. Doller, T. Kahne, R. Pregla, R. Hetzer, and V. Regitz-Zagrosek
RNA-Binding Proteins Heterogeneous Nuclear Ribonucleoprotein A1, E1, and K Are Involved in Post-Transcriptional Control of Collagen I and III Synthesis
Circ. Res.,
November 26, 2004;
95(11):
1058 - 1066.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Nordmeyer, S. Eder, S. Mahmoodzadeh, P. Martus, J. Fielitz, J. Bass, N. Bethke, H. R. Zurbrugg, R. Pregla, R. Hetzer, et al.
Upregulation of Myocardial Estrogen Receptors in Human Aortic Stenosis
Circulation,
November 16, 2004;
110(20):
3270 - 3275.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Helske, K. A. Lindstedt, M. Laine, M. Mayranpaa, K. Werkkala, J. Lommi, H. Turto, M. Kupari, and P. T. Kovanen
Induction of local angiotensin II-producing systems in stenotic aortic valves
J. Am. Coll. Cardiol.,
November 2, 2004;
44(9):
1859 - 1866.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. A. Walker, K. S. Masters, D. N. Shah, K. S. Anseth, and L. A. Leinwand
Valvular Myofibroblast Activation by Transforming Growth Factor-{beta}: Implications for Pathological Extracellular Matrix Remodeling in Heart Valve Disease
Circ. Res.,
August 6, 2004;
95(3):
253 - 260.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kostin, S. Dammer, S. Hein, W. P Klovekorn, E. P Bauer, and J. Schaper
Connexin 43 expression and distribution in compensated and decompensated cardiac hypertrophy in patients with aortic stenosis
Cardiovasc Res,
May 1, 2004;
62(2):
426 - 436.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Sakata, K. Yamamoto, T. Mano, N. Nishikawa, J. Yoshida, T. Miwa, M. Hori, and T. Masuyama
Temocapril prevents transition to diastolic heart failure in rats even if initiated after appearance of LV hypertrophy and diastolic dysfunction
Cardiovasc Res,
March 1, 2003;
57(3):
757 - 765.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Hein, E. Arnon, S. Kostin, M. Schonburg, A. Elsasser, V. Polyakova, E. P. Bauer, W.-P. Klovekorn, and J. Schaper
Progression From Compensated Hypertrophy to Failure in the Pressure-Overloaded Human Heart: Structural Deterioration and Compensatory Mechanisms
Circulation,
February 25, 2003;
107(7):
984 - 991.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. V. Petrov, R. H. Fagard, and P. J. Lijnen
Stimulation of Collagen Production by Transforming Growth Factor-{beta}1 During Differentiation of Cardiac Fibroblasts to Myofibroblasts
Hypertension,
February 1, 2002;
39(2):
258 - 263.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Fielitz, A. Dendorfer, R. Pregla, E. Ehler, H. R. Zurbrugg, J. Bartunek, R. Hetzer, and V. Regitz-Zagrosek
Neutral Endopeptidase Is Activated in Cardiomyocytes in Human Aortic Valve Stenosis and Heart Failure
Circulation,
January 22, 2002;
105(3):
286 - 289.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
