(Hypertension. 2001;37:833.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Role of Myocytes in Myocardial Collagen Production
From the Department of Molecular Cardiology, The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Subha Sen, PhD, DSc, Department of Molecular Cardiology/NB50, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail sens{at}ccf.org
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Abstract |
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Excessive collagen deposition may cause abnormal stiffness of the heart during hypertrophy and heart failure. The potent vasoconstrictor angiotensin II seems, via an unknown mechanism, to stimulate collagen production. This study describes the in vitro and ex vivo effects of [Sar1]Ang II on collagen production by fibroblasts in culture and in beating, nonworking heart preparations. The effects of [Sar1]Ang II on isolated rat hearts or rat heart fibroblasts were determined by quantifying transcript levels of collagen phenotypes I and III through videodensitometry after Northern blot analysis with specific cDNA probes (collagen [P
2r2] rat
2[I] probe for type I and human skin
fibroblast 1[III] probe for type III). When
[Sar1]Ang II was added in vitro to
neonatal or adult 28-week-old Wistar-Kyoto rat heart fibroblasts,
questionable stimulation in the mRNAs of types I and III
occurred. In contrast, when 10-8 mol/L
[Sar1]Ang II was added to beating,
nonworking Wistar-Kyoto rat heart preparation ex vivo, a 1.5- to
2.5-fold stimulation of collagen mRNAs of phenotypes I and III
was observed. When neonatal fibroblasts were cocultured with neonatal
myocytes in vitro, with 10-10 mol/L
[Sar1]Ang II added, there was no
stimulation of either phenotype. However, significant
stimulation of both collagen transcripts was recorded when
10-10 mol/L
[Sar1]Ang II was added to adult
fibroblasts cocultured with either neonatal or adult myocytes. Our data
suggest that factors produced by myocytes are necessary for
upregulation of collagen genes in vitro and demonstrate that
fibroblast-myocyte cross-talk is required for Ang II–induced collagen
upregulation.
Key Words: angiotensin II • cardiac myocytes • collagen • fibroblasts • hypertrophy
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Introduction |
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Biosynthesis of the heart’s collagen matrix has been shown to be regulated under various physiological and pathologic conditions. Excessive deposition of collagen may be responsible for abnormal tissue stiffness and altered cardiac function during hypertrophy and heart failure. Workers at our laboratory have shown that during the development of hypertrophy in hypertension, the alteration of collagens and their phenotypes occurs especially during the chronic phase of hypertrophy in both humans and rats.1 Mukherjee and Sen2 first showed the diverse effects of antihypertensive treatment on collagen metabolism. They showed that captopril causes regression of hypertrophy associated with reduction and normalization of blood pressure and reversal of the alteration of collagen phenotypes. The molecular mechanism of such a process is not known. Butt et al3 observed that collagen production was stimulated by some of the growth factors tested (in order of potency, transforming growth factor [TGF]-1> platelet-derived growth factor>insulin-like growth factor>basic fibroblast growth factor). Recently, evidence has been presented that defines a role of angiotensin II (Ang II), a potent vasoconstrictor, in stimulation of collagen gene expression and protein turnover in cultured cardiac fibroblasts.4 5 6 In addition to having a potent vasoconstrictive effect, Ang II seems to work as an autocrine/paracrine factor that regulates the growth of local tissues such as blood vessel, kidney, and heart.7 8 9 10 A close relationship has been suggested between Ang II generated at sites of injury and expression of the profibrotic cytokine represented by the TGF-ß family of peptides. The binding of TGF-ß1 with its receptors on fibroblasts regulates their expression of type I collagen and tissue-induced metalloprotease and favors fibrous tissue formation.11 12 Recently, Kim et al13 showed that Ang II induces collagen type I and type III mRNA expression in vivo in rats when they were infused with 200 ng Ang II · kg-1 · min-1. Stimulation could be observed only after 3 days of continuous infusion and gradually plateaued after 7 days. Zeydel et al14 have shown that the deposition of type I collagen occurred only when the medium was supplemented with ascorbate and was independent of the age of the animals.
To date, no data on the effects of Ang II on collagen gene expression are available from cardiac fibroblasts of adult (>20 weeks old) rats or from isolated whole rat heart preparation. However, research on older animals is important because altered cardiac function and heart failure do not usually occur in young animals. Thus, the objectives of the present study were to examine, in parallel, the effect of [Sar1]Ang II on collagen phenotypes in vitro with fibroblasts in culture and ex vivo with an isolated beating, nonworking heart preparation in 28-week-old rats. Our data showed a distinct and significant difference between ex vivo and in vitro results with fibroblasts alone in culture and combinations of fibroblasts and myocytes, the 2 major types of cells present in the heart, from both neonatal and adult rats, in which a significant stimulation of collagen transcripts was observed; this suggests the participation of myocytes in modulation of collagen production.
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Methods |
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Materials
All tissue culture reagents used in this study were purchased from Life Technologies, Inc. All radiochemicals were obtained from DuPont-New England Nuclear. All restriction enzymes were from Boehringer Mannheim GmbH. All other chemicals and reagents were from Sigma Chemical Co. All rats used in this study were obtained from Taconic Farms. The investigation conforms with the "Guide for the Care and Use of Laboratory Animals" (US National Institutes of Health, NIH publication No. 85-23, revised 1996).
Preparation of Fibroblasts in Culture
Rat cardiac fibroblasts were isolated from normal
28-week-old Wistar-Kyoto (WKY) rats according to the method of Sil and
Sen.15 The flasks containing
pure fibroblasts were then maintained at 37°C until the cells were
confluent; they were subsequently passaged. The cells were used at 70%
to 75% confluency and kept in serum-free medium for 24 hours before
each experiment.
Beating, Nonworking Rat Heart
Preparation
For the beating, nonworking heart preparation, normal
28-week-old WKY rats were heparinized with 500 U heparin and
anesthetized with 20 mg/kg pentobarbital IP. The heart was
taken out and washed with modified Krebs’ buffer (pH 7.35) The buffer
was bubbled with 95% O2/5%
CO2 for 30 minutes. The heart was then
cannulated through the aorta and was perfused with buffer at 37°C at
the rate of 135 mL/min. The heart was kept beating with a Grass
electrical stimulator (frequency 8 Hz, duration 15 ms, 2.5 V).The
positive and negative terminals were connected to the atria of the
heart. A constant pressure of 75 mm Hg was maintained throughout
the experimental period. [Sar1]Ang II was
perfused with a small peristaltic pump and allowed to mix with the
buffer. Proper concentrations of [Sar1]Ang
II were carefully maintained. For a typical experiment, hearts were
perfused with the buffer alone for 30 minutes and then perfused with
[Sar1]Ang II for 2 hours. At the end of
the experiment, the hearts were removed and kept frozen in liquid
nitrogen.
Preparation of Rat Myocytes in Culture
Neonatal rat myocytes were isolated and cultured on
laminin-coated glass coverslips placed in the standard 6-well
plates according to the procedure described by Sil and
Sen.15 Adult myocytes were
prepared on laminin-coated cover glasses according to the method of
Bugaisky and Zak16 with some
modifications.
Experiment With Myocytes on Coverslips Added to
Neonatal and Adult Fibroblasts in Culture
Both neonatal and adult fibroblast cells
(2x106 per well of standard 6-well plates)
were incubated for 24 hours at 37°C in the absence (control) or
presence (treated) of [Sar1]Ang II.
Six-well plates, each containing neonatal and adult rat fibroblasts,
respectively, were kept for incubation with neonatal and adult myocytes
separately on coverslips or coculture inserts for 2 to 10 hours without
the addition of [Sar1]Ang II. In the
treated cultures (experimental), fibroblasts were incubated in the
presence of 10-10 mol/L
[Sar1]Ang II with coverslips and inserts
that contained myocytes. The cellular combination of fibroblasts and
myocytes was incubated for 2 to 4 hours alone and then with
10-10 mol/L
[Sar1]Ang II for 20 hours at 37°C. The
same amount of Ang II was replenished every 6 hours during the
experiment.
Extraction of RNA and Northern
Hybridization
Total RNA from fibroblast cells (in 6-well plates
with or without myocytes) was isolated using the RNeasy minikit
following the Qiagen protocol. RNA from each sample was then run on a
1% agarose-formaldehyde gel with DEPC-treated 1[times] MOPS as a
running buffer, transblotted onto a GeneScreen membrane, and
crosslinked in a UV crosslinker. The membrane was then subjected to
prehybridization for 6 hours, followed by hybridization at 42.5°C for
16 hours. The hybridization of the same membrane was performed with 3
different radiolabeled probes: (1) collagen
P2r2 type I rat cDNA
probe, (2) collagen 1 type III human
skin fibroblast cDNA probe, and (3) 18S rRNA oligoprobe. Hybridization
and washing were performed according to Sambrook et
al.17 The membrane then was
subjected to autoradiography. For estimation, the
intensity of the bands was quantified with videodensitometry. The 18S
RNA oligoprobe was used to normalize our results.
Quantification of Collagen
Total collagen was quantified from each rat heart by
measuring hydroxyproline with a modified Stagemann
procedure.18 The amount of
hydroxyproline in unknown samples was calculated with a standard curve.
Collagen content was estimated by multiplying the hydroxyproline
content by a factor of 8.2 and was expressed as micrograms of collagen
per milligram of heart tissue.
Statistical Analysis
Results are expressed as mean±SEM. Data were
analyzed by 2-way ANOVA, and the differences between groups
were determined by the least-square means test (SUPERNOVA). Differences
were considered statistically significant at
P<0.05.
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Results |
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Effect of [Sar1]Ang II on Beating, Nonworking Heart Preparation Ex Vivo
As shown in Figure 1A, both the transcripts of collagen type I and the 5.3-kb transcript of collagen type III were significantly upregulated when the hearts were perfused with [Sar1]Ang II for 2 hours. After quantification with videodensitometry and normalization of results with 18S RNA, both transcripts of collagen type I were found to be upregulated more in the presence of 10-8 mol/L [Sar1]Ang II than with either 10-12 or 10-10 mol/L Ang II (Figure 1B). The stimulation was 1.5-fold (n=5, P<0.01) for the 4.5-kb transcript and 2.5-fold (n=5, P<0.004) for the 4.8-kb transcript of collagen type I mRNA, when estimated over the respective control measurements. The stimulation of the collagen type III transcript was 1.8-fold (n=5, P<0.01) over the control.
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Estimation of Total Collagen Ex Vivo
Ex vivo hearts compared with the control show an
increase in collagen content of 
33.8%, 42.06%, and 67.50%
over control when perfused with 10-12,
10-10, or
10-8 mol/L
[Sar1]Ang II,, respectively
(n=5,
P<0.01). Control heart
measurement was 9.51 g/mg, whereas hearts perfused with
10-12, 10-10,
or 10-8 mol/L
[Sar1]Ang II resulted in the values of
12.73, 13.51, and 15.93 g/mg, respectively
(Figure 2).
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Effect of [Sar1]Ang II on Neonatal and Adult
Rat Fibroblasts in Culture
When the neonatal and adult (28-week-old) WKY rat heart
fibroblasts in serum-free media were incubated for 24 hours at 37°C
in the absence (control) or presence (treated) of the 3 different
concentrations of [Sar1]Ang II
(10-10, 10-8,
and 10-6 mol/L, respectively;
n=5), there was no change over
the control in either of the 2 collagen type I transcripts for
10-10 or 10-6
mol/L Ang II
(Figure 3). There was, however, a questionable increase in
both collagen type I transcripts for 10-8
mol/L Ang II. For the same membrane, with a collagen type III cDNA
probe (n=5), no stimulation was
observed (as shown in
Figure 3). Incubation of fibroblasts for periods of 2 to 24
hours at 37°C in the presence of 10-12
to 10-6 mol/L
[Sar1]Ang II
(n=5) also did not show any
stimulation for either of the collagen transcripts (result not
shown).
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Effect of
[Sar1]Ang II on Neonatal Rat Fibroblasts
Cocultured With Neonatal or Adult Rat Myocytes
As shown in
Figure 4, in the absence or presence of
10-10 or 10-8
mol/L [Sar1]Ang II
(n=5), neonatal or adult rat
myocytes cocultured with neonatal fibroblasts did not show any
stimulation for either of the collagen
phenotypes.
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Effect of
[Sar1]Ang II on Adult Rat Fibroblasts
Cocultured With Neonatal and Adult Rat Myocytes
Fibroblasts from 28-week-old WKY rats
cocultured with either neonatal or adult rat cardiomyocytes
could upregulate the transcript levels of both collagen type I and type
III quite significantly after incubation with Ang II at the
concentration of 10-10 mol/L. The results
of these experiments are shown in
Figures 5A and 6A. Both transcripts of collagen type I and
type III transcripts were stimulated, more so when fibroblasts
cocultured with myocytes were kept for 4 hours and then incubated with
10-10 mol/L
[Sar1]Ang II for an additional 24 hours.
Figures 5B and 6B show the quantification of 4.5-kb (1.5-fold
over the control, n=5,
P<0.001) and 4.8-kb (1.7-fold
over the control, n=5,
P<0.005) transcripts of
collagen type I and the 5.3-kb (1.4-fold over the control,
n=5,
P<0.005) transcript of
collagen type III after videodensitometry and appropriate normalization
with an 18S RNA oligoprobe. We incubated the fibroblasts with myocytes
in coculture plates for different lengths of time (2 to 6 hours) before
the addition and incubation of 10-10 mol/L
[Sar1]Ang II for 24 hours, but we found
that 4 hours of prior contact between fibroblast and myocytes results
in the maximum upregulation of the collagen
transcripts.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, we demonstrated that when Ang II was added to neonatal and adult rat fibroblasts in culture in vitro in a dose-dependent fashion, no change occurred in the transcript levels of collagen type I or type III (except some questionable increase for collagen I transcripts with 10-8 mol/L [Sar1]Ang II). In contrast, in the beating, nonworking adult heart preparation, the addition of 10-8 mol/L [Sar1]Ang II showed a significant stimulation (
2-fold) of collagen mRNAs for both phenotypes
(Figure 1). This observation suggests that the effects of Ang
II in vitro and ex vivo are different and that Ang II may have an
indirect effect on fibroblasts for collagen production. To
understand the cellular mechanism for collagen upregulation by
fibroblasts, we sought to probe into the involvement of some other
cardiac cell types in the collagen gene action. When neonatal as well
as adult myocytes were cocultured along with adult fibroblasts and
incubated in the presence of 10-10 mol/L
[Sar1]Ang II, a significant upregulation
in both collagen phenotypes was observed
(Figures 5 and 6). However, when neonatal and adult myocytes
were grown on coverslips and added to neonatal fibroblasts in culture
in the presence of Ang II, there was no stimulation of either collagen
phenotype. It has been suggested that excessive collagen deposition is a potential cause of stiffness of the heart during the chronic phase of hypertrophy, especially during its transition to heart failure. The molecular mechanism for this abnormal collagen formation during the chronic phase is not clearly understood. Ang II, a potent vasoconstrictor, is believed to play a role in the stimulation of collagen production in vivo. Our study shows that although Ang II had a significant effect in the stimulation of collagen production in vivo and ex vivo, it had no effect when added to pure fibroblasts in vitro except with cardiomyocytes (although fibroblasts are reported to be the sole producer for collagen in heart).
Collagen biosynthesis is regulated at different levels of transcription and translation. Type I and type III are the 2 major types of collagen present in the myocardium in both normal and diseased myocardial tissue. Thus, the quality rather than the quantity of the collagen would be an important marker to define the pathophysiology during the chronic phase of hypertrophy and heart failure. Therefore, a ratio of type I and type III is an important marker for determination of the quality of collagen and therefore prediction of the stiffness of the heart muscle. Our in vitro study shows that regardless of the time of exposure of fibroblasts alone to [Sar1]Ang II, the fibroblasts did not alter collagen production, whereas a 2-hour perfusion of 10-8 mol/L [Sar1]Ang II showed significant stimulation of collagen production at the transcription as well as translation levels in the whole-heart model.
Several studies in vivo have suggested that Ang II may also be a critical factor in mediation of cardiac hypertrophy.19 20 21 22 These observations are consistent with, although they do not prove, the notion that Ang II may act as an endogenous growth factor for the myocardium. Thus, Ang II, directly or in combination with other growth factors, may play an important role in the development of vascular hypertrophy and elevated arterial resistance in hypertension. It is thought that many factors play a direct role in abnormal collagen deposition, such as Ang II and TGF-ß, as well as an indirect role, such as prostaglandin A2, bradykinin, NO, and endothelin-1, as either a stimulator or an inhibitor.3 All of these other factors work indirectly through Ang II, and Ang II in turn stimulates collagen formation. Therefore, the results from our study are important in understanding Ang II–mediated collagen deposition because the myocyte-generated factor plays an important role in stimulation of collagen formation in conjunction with Ang II. Our preliminary data suggest that the factor from myocytes is soluble. When the supernatants from the myocyte cultures (neonatal and adult) were added to the fibroblasts, similar upregulation of collagen was observed (data not shown). Furthermore, results from the present study opened new doors to understanding the molecular mechanism for collagen production. The nature of such factors is not known, nor can we comment on the nature of the factors produced by the myocytes, but we know that identification and characterization of the factors and development of an inhibitor would be important steps in the control of the deposition of excessive fibrous tissue during the chronic phase of hypertrophy and its transition to heart failure.
Cardiac hypertrophy and heart failure remain major health problems in the United States. The chronically failing heart is associated with alteration in tissue composition, including fibrous tissue deposition that appears in both left and right ventricles.23 Such adverse accumulation of extracellular matrix is believed to be in part responsible for myocardial stiffness and eventually affects the contractile behavior of the heart.24 25 26 27 28 29 Therefore, understanding the cellular and molecular mechanisms responsible for the deposition of collagen (fibrous tissue) is an essential step in designing cardioprotective agents that could prevent the deposition of collagen and, therefore, fibrosis during heart failure.
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Acknowledgments |
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This study was supported by grant RO1-HL-27838 from the National Institutes of Health (to Dr Sen). We are grateful to JoAnne Holl for typing the manuscript and to Christine Kassuba for editorial assistance.
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Footnotes |
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1 Both authors participated equally in the generation of data.
Received July 6, 2000; first decision July 25, 2000; accepted September 1, 2000.
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References |
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