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European Journal of Heart Failure 2006 8(1):16-22; doi:10.1016/j.ejheart.2005.05.014
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© 2005 European Society of Cardiology

Mechanical stretch-induced hypertrophy of neonatal rat ventricular myocytes is mediated by β1-integrin-microtubule signaling pathways

Xi Yutao, Wu Geru, Bai Xiaojun, Geng Tao and Ma Aiqun*

Cardiology Department of No.1 Hospital of Xi'an Jiaotong University 1 Jiankang Road, Xi'an, Shaanxi, China Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education Xi'an, Shaanxi 710061, China

* Corresponding author. Tel.: +86 29 85261809; fax: +86 29 85396990. E-mail address: maaiqun{at}medmail.com.cn


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Background: Mechanical stress plays a crucial role in tissue morphogenesis and remodeling. These processes depend in part on force transmission mediated through integrins and the cytoskeleton.

Methods: Ventricular myocytes isolated from neonatal Sprague–Dawley rats (NRVMs) were exposed to persistent centrifugal force stretch for 12 or 24 h. The NRVMs were exposed to colchicine (4 µmol/ml) and anti-integrin β1 specific antibody (10 µg/ml). Cell viability was assessed by MTT assay and lactate dehydrogenase (LDH) activity. Incorporation of 3H-leucine, and atrial natriuretic peptide (ANP) and angiotensin II (Ang II) levels were assessed. Pixel intensity and distribution of the microtubule were estimated from laser scanning confocal images.

Results: Changes in LDH release and the MTT assay showed that 180 rpm. centrifugal force had minimal effect on the viability and number of NRVMs. Mechanical stretch significantly increased 3H-leucine incorporation into cardiomyocytes. Anti-integrin β1 blocking antibody effectively inhibited the increase in 3H-leucine incorporation and release of ANP (p<0.05). Following anti-integrin-β1-blocking antibody, the pixel intensity of the microtubule image was decreased after both12 and 24 h stretch, this was similar to the effect of colchicine. Both treatments also inhibited the secretion of Ang II induced by stretch (p<0.05).

Conclusions: Anti-integrin-β1-blocking antibody and colchicine had similar effects, partly inhibiting the stretch-induced increase in microtubule polymerization and the secretion of Ang II in hypertrophic cardiac myocytes.

Key Words: Mechanical stretch • β1-integrin • Microtubule • Cardiomyocyte • Hypertrophy

Received December 8, 2004; Accepted May 25, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Mechanical stress plays a crucial role in tissue morphogenesis and remodeling. Changes in cell morphology, which rely on the organization of cytoskeletal components and the modulation of cell adhesion, evoke specific intracellular signals and induce the expression of specific genes [1,2].

Integrins were initially considered solely as molecules necessary for adhesive interactions between cells and the extracellular matrix (ECM). Recent work has indicated that integrins are bidirectional signaling molecules [5]. Integrins can also act as mechanical transduction receptors; stimulation of integrins has been shown to modulate cellular growth and gene expression [6]. Over 20 different types of integrins exist, and their binding specificity (e.g., for collagen and fibronectin) depends on the specific pairing combination of interacting P and β subunits [7,8]. The external portion of these transmembrane receptors binds to specific peptide sequences (e.g., RGD) in ECM molecules, while their intracellular domains physically associate with actin-associated proteins, forming a molecular bridge between the ECM and the cytoskeleton [9]. Importantly, integrins provide a preferred site for mechanical signal transfer across the cell surface. This has been demonstrated directly by applying mechanical forces to surface membrane receptors of cultured cells [10,11]. Thus, integrins appear to function as cell surface mechanoreceptors, in that they are among the first molecules to sense a mechanical stress applied at the cell surface, and they transmit this signal across the plasma membrane and to the cytoskeleton over a specific molecular pathway.

The cytoskeletal network provides a scaffold where signaling proteins can anchor and become involved in signaling transduction pathways. The activation of signaling systems associated with the cytoskeleton is fundamentally dependent on the clustering of transmembrane integrins that act as linkers between extracellular matrix protein and the intracellular cytoskeletal network [12-14]. We and others have developed an in vitro system by which cultured cardiomyocytes are subjected to mechanical stress, and have demonstrated that mechanical stress induces a variety of hypertrophic responses such as the proliferation and disorder of cytoskeletal components and an increase in protein synthesis and angiotensin II [3,4]. However, the mechanisms by which hypertrophic stimuli, including mechanical stress, lead to signaling events in the cardiac cell are poorly understood.

In the present study, the in vitro centrifugal force stretch model was used to investigate stretch stimulated protein synthesis, pixel intensity and the distribution of the microtubule image, following integrin-microtubule pathway inhibition by β1-integrin blocking antibody and colchicine.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1. Materials
Anti-β1-integrin antibody was purchased from BD Biosciences (Cat. no. 555002, San Jose, CA, U.S.A.); Anti-β1-Tubulin was purchased from NeoMarkers (Fremont, CA, U.S.A.); Colchicine and 3H-leucine (50 Ci/mmol) were purchased from Sigma Chemical Co. (St. Louis, MO, U.S.A.); The test kits for Ang II and LDH were purchased from Beijing Nuclear Inc. (Beijing, China), and for ANP from Peninsula Lab Inc. (Belmont, CA., U.S.A.). Medium 1640 and fetal bovine serum (FBS) were from GIBCO BRL (Carlsbad, CA, U.S.A.).

2.2. Preparation of neonatal rat ventricular myocytes (NRVMs)
NRVMs from the ventricles of 3-to 5-day-old Sprague-Dawley rats (from animal facilities of Xi’an Jiaotong University, Xi'an, Shaanxi, China) were cultured as previously described [4]. Rat ventricular myocardium was isolated by collagen enzyme (Type I collagen, Sigma co., St. Louis, MO, U.S.A.) and incubated (5% CO2, 37 °C) for 10 min. Cells were then suspended in M1640 medium, supplemented with 5% fetal calf serum (FCS) and antibiotics (ampicillin 34 µg/ml and streptomycin 3 µg/ml) and pre-plated for 90 min to remove non-cardiomyocytes. The NRVMs were plated at a density of 2x106 cell/ml in M1640 supplemented with 10% FCS on 24-well plates. Cells were incubated at 37 °C in a humidified atmosphere containing 5% CO2. An affixing monolayer of spontaneously beating cells was formed in 24 h. Using this method, we routinely obtained cultures with <5% non-cardiomyocytes. For experiments, NRVMs were plated on 24-well plates which were coated with laminin (20 µg/ml), at least overnight, with substrates at 4 °C before use.

2.3. Mechanical stretch
NRVMs were subjected to persistent stretch by means of the centrifugal force stretch device described previously [4]. NRVMs on culture plates were subjected to a 180 rev per min (rpm.) centrifugal force for either 12 or 24 h in a 37 °C, 5% CO2 incubator. Parallel culture plates, which were not subjected to stretch, served as controls.

2.4. Determination of MTT formazan formation
The MTT assay was used to determine the viability of NRVMs. The MTT assay is based on the ability of mitochondria to reduce MTT (a yellow tetrazolium dye) to MTT formazan (a blue mitochondrial by-product.). This reduction is mediated by mitochondrial dehydrogenases which are present in living but not in dead cells. This assay is therefore one of the most appropriate ways to assess the viability of mitochondria-rich cells, including cardiac myocytes. Over the final 4 h of the 12 or 24 h period of persistent stretch, the culture medium in each well was replaced by 20 µl of the MTT solution (5 mg/ml phosphate buffer) and incubated for 4 h at 37 °C. After removal of the MTT-mixture, 1 ml of dimethyl sulfoxide (DMSO) was added to each well to dissolve the MTT formazan, and the amount of MTT formazan in DMSO was then measured at a wavelength of 490 nm, using a Powerwave 2000 (Bio-Tek. Int., Vermont, NE, U.S.A.). Five wells in each group were chosen. The amount of MTT formazan in the stretched myocytes was expressed as a percentage of that in the non-stretched NRVMs.

2.5. Measurement of 3H-Leucine incorporation
Incorporation of 3H-leucine was measured over the final 4 h of the 12 or 24 h period of persistent stretch, in six wells in each group. NRVMs were subjected to mechanical stress in the presence of 1.0 µCi/ml 3H-leucine. The medium was aspirated and the cells washed twice with ice-cold PBS and once with 10% trichloroacetic acid (TCA; Sigma Co.) and then fixed for 45 min at 4 °C with 10% TCA. The cells were then washed twice with cold 95% ethanol, and the radioactivity incorporated into the TCA-perceptible material was determined by liquid scintillation counting.

2.6. Confocal microscopy and immunofluorescence protocols
The cells were fixed in acetone and stored at 4 °C after stretch. The sections were then treated with Triton-X100 for 30 min, washed with PBS 3 times, and blocked with NDS for 60 min. The primary antibody, monoclonal mouse anti-β-tubulin was diluted 1:50 in normal goat serum-PBS. 100 µl of diluted antibody per section was needed. The sections were incubated with the primary antibody overnight at 4 °C. FITC, the secondary antibody, was diluted 1:200 and incubated with the sections for 60 min at room temperature. Immediately, after being washed with PBS 3 times, the sections were mounted in Vectashield mounting media and attached to slides and cover slips with nail varnish. The pattern of laser confocal microscopy was examined with a LEICA confocal microscopy system (Model TCS Laser Scanning Confocal Microscope System, LEICA, Germany). A 488 nm laser was used to excite the FITC. The confocal system was controlled by LEICA software. The laser was chosen according to the sample and compared pixel intensity and pixel distribution. Quantitative data was obtained from 10 cells in each group.

2.7. Biochemical measurements
After stretch, supernatant liquid of the culture medium (2 ml) from 6 wells in each group was collected for measurement of angiotensin II (Ang II), lactate dehydrogenase (LDH) and atrial natriuretic peptide (ANP). Samples for measurement of LDH were frozen at –70 °C and the activity of LDH was tested by ELISA. Samples for measurement of Ang II and ANP were mixed with 250 µl angiotensinase inhibitor solution (containing 125 mmol/L disodium EDTA and 25 mmol/L aprotinin) and frozen at –70 °C. Ang II and ANP were measured directly using specific radioimmunoassay.

2.8. Integrin microtubule inhibition
Cells were cultured in serum-free medium containing either colchicine, an inhibitor of microtubule polymerization (final concentration, 4 µmol/ml), or anti-integrin β1 specific antibody, an inhibitor of integrin β1 (10 µg/ml) [15], or control PBS, for 24 h.

2.9. Statistical analysis
Statistical analysis was performed using SPSS 12.0 and all data are expressed as means±SD. Analyses were performed by t test and one-way ANOVA, with comparison of different groups by Fisher's protected least significant difference test. A probability value p<0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1. Effect of mechanical stretch, colchicine and β1-Integrin blocking antibody on the viability of NRVMs
A preliminary experiment was performed to determine the extent of cellular damage induced by mechanical stretch, colchicine and β1-integrin blocking antibody. Fig. 1 shows changes in LDH release and formation of MTT formazan induced by mechanical stretch, colchicine and β1-integrin blocking antibody. Stretch increased LDH release, and decreased the formation of MTT formazan in a time-dependent way [10]. After the start of stretch exposure, the amounts of LDH released in the three groups were approximately 113%, 81%, and 135% at 12 h and 134%, 130%, and 162% at 24 h of the amounts of LDH in the non-stretched group, respectively. The amounts of MTT formazan in the stretch, colchicine and β1-integrin blocking antibody groups were approximately 70.1%, 68.3%, and 68.2% at 12 h and 53.1%, 75.7%, and 65.2% at 24 h, of those in non-stretched myocytes, respectively. This data confirmed that 180 r.p.m. centrifugal force for stretch, colchicine and β1-integrin blocking antibody had minimal effects on the viability and numbers of NRVMs.


Figure 1
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  		Fig. 1 Colchicine, β1-integrin blocking antibody and mechanical stretch had minimal effects on formation of MTT formazan in cardiac mycocytes. (A) The amounts of LDH and (B) the amounts of MTT formazan in the three groups. *p<0.05 vs. non-stretch.

 
3.2. Effects of colchicine and β1-integrin blocking antibody on mechanical stretch-induced hypertrophic response of NRVMs
Mechanical stretch significantly increased 3H-leucine incorporation into cardiomyocytes, compared with that of non-stretched cardiomyocytes [(1751.98±112.46) vs. (1122.67±51.63) at 12 h; (2015.50±79.06) vs. (1210.67±90.92) at 24 h, p<0.05]. To further elucidate the role of integrins, in particular the involvement of integrin β1 in mechanical stretch-induced hypertrophy, myocytes pretreated with a β1-integrin-blocking antibody, were subjected to centrifugal mechanical stretch. Anti-integrin β1 antibody effectively inhibited the increase in 3H-leucine incorporation [(1295.17±51.19) at 12 h; (1252.50±32.32) at 24 h, p<0.05], a similar effect was observed for colchicine [(1292.67±58.22) at 12 h; (1327.83±39.75) at 24 h, p<0.05] (Fig. 2A).


Figure 2
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  		Fig. 2 Colchicine, β1-integrin blocking antibody and mechanical stretch-induced hypertrophonic response of NRVMs. (A) Incorporation of 3H-leucine measured over the final 4 h of the 12 and 24 h periods of persistent centrifugal mechanical stretch. (B) Mean ANP release. Data was calculated from 5 wells in each group. *p<0.05 vs. non-stretch.

 
The amount of ANP in the non-stretch media after 24 h incubation was 1.88±0.54 pmol/105cells. Stimulation of ANP release was observed at 12 and 24 h with mechanical stretch. Maximal ANP release in the stretch groups was 1.2-fold (at 12 h) and 2.0-fold (at 24 h) vs. the non-stretch group. The effect of stretch on ANP secretion was partially blocked by treatment with colchicine (4 µmol/ml) and β1-integrin blocking antibody (10 µg/ml). (Fig. 2B) These results suggest that integrins, integrin β1 in particular, and microtubules are at least in part responsible for mechanical stress-induced hypertrophy in NRVMs.

3.3. Effect of anti-integrin β1 antibody on polymerization and disorder of microtubules in hypertrophic cardiomyocytes
We have previously demonstrated that mechanical stress stimulated polymerization of microtubules, can be inhibited by colchicine [4]. To clarify whether integrin signaling was required for stretch induced polymerization of microtubules after mechanical stretch, NRVMs were pre-incubated with anti-integrin-β1-blocking antibody (10 µg/ml) to inhibit integrin signaling. Surprisingly, anti-integrin β1 blocking antibody had similar effects to colchicine (4 µmol/ml) and partly inhibited the mechanical stretch-induced increase in polymerization of microtubules.

The pixel intensity and distribution of the microtubule image was estimated using laser scanning confocal images of immunofluorescence labeled NRVMs with an antibody to β-tubulin. In the non-stretched group, the pixel intensity of the microtubule image was less than 300 (arbitrary units) and the pixel distribution was even (Fig. 3A). After being stretched for 12 h and 24 h, the maximum pixel intensity of the microtubule image was increased and the pixel distribution was uneven. At 12 h the pixel intensity was more than 1400 (arbitrary units) (Fig. 3B). At 24 h, it had increased significantly to more than 1600 (arbitrary units) and the structure of the microtubules was collapsed. Moreover, a strong reflection of fluorescence could be seen in some cells, which took on a "piebald" appearance with light and shade contrast (Fig. 3C). After pre-incubating with anti-integrin-β1-blocking antibody (10 µg/mL), the pixel intensity of the microtubule image decreased to less than 1000 (arbitrary units) at12 h and around 500 (arbitrary units) at 24 h (Fig. 3D and E) and the pixel distribution was even. This was similar to the effect observed after pre-treating with colchicine [around 800 (arbitrary units) at 12 h; less than 600 (arbitrary units) at 24 h] (Fig. 3F, G).


Figure 3
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  		Fig. 3 Anti-integrin β1 antibody suppressed stretch-induced over polymerization and disorder of microtubules in hypertrophic NRVMs. A. Non-stretch group; B, C. Stretched for 12 and 24 h; D, E. Cardiomyocytes pre-incubated with anti-integrin-β1-blocking antibody (10 µg/ml) at 12 and 24 h; F, G. Cardiomyocytes pretreated with colchicine at 12 and 24 h.

 
3.4. Effects of integrin-microtubule pathway on the secretion of angiotensin II
The increase in angiotensin II levels caused by stretch of cardiac myocytes, led to an increase in protein synthesis rate and total cellular protein. The increase in Ang II in the stretch groups was inhibited by anti-integrin-β1-blocking antibody and colchicine. The concentration of Ang II was increased in the stretch groups at 24 h (65.12±2.62, p<0.05, compared to the non-stretch). There was no significant difference in the levels of Ang II in the non-stretch groups [(22.64±1.46) at 12 h; (50.75±1.41) at 24 h], the anti-integrin β1 antibody groups [(26.03±3.97) at 12 h; (50.16±2.83) at 24 h] and the colchicine groups [(31.35±1.73) at 12 h; (52.04±3.14) at 24 h], (p>0.05). (Fig. 4) There was a tendency for Ang II to increase with the increased duration of culture time. But the ratio of the increase at the two time points indicated no difference between the three groups (p>0.05). This suggested that the increase in secretion was not related to the duration of culture but was directly proportional to the duration of stretch.


Figure 4
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  		Fig. 4 Colchicine and β1-integrin blocking antibody inhibited mechanical stretch-induced increase in angiotensin II levels in culture medium. *p<0.05 vs. non-stretch.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
In this study, mechanical stretch increased 3H-leucine incorporation into cardiomyocytes, ANP release and Ang II levels. Anti-integrin β1 antibody effectively inhibited these increases in 3H-leucine incorporation and Ang II, a similar effect was seen for colchicine. These results suggest that integrins, integrin β1 in particular, and microtubules are at least in part responsible for mechanical stress-induced hypertrophy in NRVMs.

Integrins, as the main receptors that connect the cytoskeleton to the extracellular matrix (ECM), have an intimate relationship with force. Integrins were initially considered solely as molecules necessary for adhesive interactions between cells and the ECM. In this experiment, the mAb against integrin β1 subunit, common to receptors for both laminin and fibronectin, participate in both agents binding [25-27]. Recently, integrins have also been identified as mechano-transduction molecules in cardiac cells converting mechanical signals to biochemical ones [18,19]. As shown most dramatically in gene deletion experiments, normal integrin function has been found to be essential for these processes in cardiac myocytes and the intact heart [16,17]. In our preliminary studies and others, β1-integrin protein levels were up-regulated in the hemodynamically loaded rat heart, which suggested that integrins might transmit mechanically initiated signals from the extracellular matrix and cause hypertrophic signaling events. But, the details of this mechanical signaling pathway are unknown.

We have previously found that mechanical stress stimulates cardiomyocyte hypertrophy with polymerization of microtubules, and that this effect could be inhibited by colchicine [4]. These results suggested that microtubules were involved in the early hypertrophic responses of the myocardium. It was also possible that polymerization and depolymerization of the microtubule played a role in the transduction of mechanical signals in cells. In this study, β1-integrin blocking antibody was also shown to inhibit the polymerization of microtubules induced by mechanical stress, which suggests that integrins could adjust the polymerization and depolymerization of microtubules [20].

Microtubules are one of main cytoskeletal components, together with actin and intermediate filaments. The microtubule network is dynamic, composed by self-association of P and β-tubulin dimers [21]. According to changes in physical condition, microtubules are normally in a dynamic state, with individual tubulin molecules constantly entering and leaving the microtubules [22]. This process is adjusted and controlled by microtubule associated proteins (MAPs). Phosphorylated MAPs are able to attach to microtubules and increase their stability [23]. In this process, the availability of MAPs is related not only to the amount of MAPs, but also to activation and phosphorylation (unpublished observations). Colchicine competitively inhibits the binding of monomers of tubulin and polymerization of microtubules. However, the suppression of polymerization of microtubules by β1-integrin blocking antibody may be related to activation of focal adhesion kinase (FAK) and cascade reaction. It is known that changes in the activation state or clustering of integrins are necessary for modulation of FAK phosphorylation [24]. So it is likely that β1-integrin causes increased polymerization of microtubules by activation of FAK, which induces phosphorylation of MAPs.

In conclusion, our data fully support a role for integrins and microtubules in cardiac myocyte hypertrophic signaling. Additional studies are necessary and are currently ongoing in our laboratory to define the β1-integrin signaling pathways more specifically.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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