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1 Department of Internal Medicine, School of Medicine, State University of Campinas, 13081-970 Campinas, São Paulo; and 2 Department of Pathology, Triângulo Mineiro School of Medicine, 38025-440 Uberaba, Minas Gerais, Brazil
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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To investigate the effects of colchicine on left ventricular (LV) function and hypertrophy (LVH) of rats subjected to constriction of transverse aorta (TAoC), we evaluated SO (sham operated, vehicle; n = 25), SO-T (sham operated, colchicine 0.4 mg/kg body wt ip daily; n = 38), TAoC (vehicle; n = 37), and TAoC-T (TAoC, colchicine; n = 34) on the 2nd, 6th, and 15th day after surgery. Colchicine attenuated LVH of TAoC-T compared with TAoC rats, as evaluated by ratio between LV mass (LVM) and right ventricular mass, LV wall thickness, and average diameter of cardiac myocytes. Systolic gradient across TAoC (~45 mmHg), LV systolic pressure, LV end-diastolic pressure, and rate of LV pressure increase (+dP/dt) were comparable in TAoC-T and TAoC rats. However, the baseline and increases of LV systolic pressure-to-LVM and +dP/dt-to-LVM ratios induced by phenylephrine infusion were greater in TAoC-T and SO-T compared with SO rats. Baseline and increases of +dP/dt-to-LVM ratio were reduced in TAoC compared with SO rats. TAoC rats increased polymerized fraction of tubulin compared with SO, SO-T, and TAoC-T rats. Our results indicate that colchicine treatment reduced LVH to pressure overload but preserved LV function.
myocardium; microtubules; cytoskeleton
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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SEVERAL OBSERVATIONAL STUDIES in genetic models and humans demonstrated that cytoskeletal alterations occurring as primary or secondary events are associated with cardiomyopathies and that, in some circumstances, such defects contribute to heart failure (3, 9-13, 16, 22). The cardiac myocyte cytoskeleton is considered to include proteins, whose primary function is to link and anchor structural components inside the cell (17). The integrity of the cytoskeleton has been shown to be central to the transduction of mechanical stress and agonist-induced stimuli into biochemical events that propagate inside the cell (7).
Data from various sources (8, 18-20, 23-25) have implicated increased density of the cardiac myocyte microtubular network as a cause for contractile impairment in pressure-overload hypertrophy, in which the increased amount of microtubules acts as a viscous element, inhibiting sarcomere shortening. Accordingly, microtubule depolymerization after either colchicine or cold exposure has been shown to return the contractile function of hypertrophic myocardium and cardiac myocytes to normal (8, 19, 24). On the other hand, studies (14, 21) have indicated that the integrity of microtubules is important to the activation of key molecular mechanisms related to the initial hypertrophic growth induced by stretch and pressure overload. Exposure to colchicine reduced the increased expression of fetal contractile proteins and immediate early genes, as well as the increase of total cardiac RNA content in the myocardium of rats subjected to pressure overload. However, because, in such studies, the analyses were restricted to the initial molecular phenotypic changes in response to increased load, no conclusion could be drawn about the influence of microtubular integrity on cardiac mass and geometry during the hypertrophic growth. These previous observations led us to hypothesize that inhibition of tubulin polymerization by treatment with colchicine would interfere in the hypertrophic growth and simultaneously, by reducing the amount of polymerized tubulin and microtubular network, would improve the contractile function of overloaded myocardium and preserve left ventricular (LV) function.
Thus, in this study, we examined the effects of long-term treatment with colchicine on the LV hypertrophic growth and function of rats subjected to pressure overload caused by transverse aorta constriction. LV hypertrophic growth was assessed by comparing the ratio between LV (LVM) and right ventricular (RV) mass (RVM) in colchicine-treated and untreated rats that underwent transverse aortic constriction. LV geometry was determined from planimetric analysis of histological sections, and cardiac function was evaluated by measuring the LV pressures and the rate of increases of LV pressure (+dP/dt) at baseline and during hemodynamic stress caused by phenylephrine infusion.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. The experiments were performed on male Wistar rats (140-180 g) obtained from animal facilities of the State University of Campinas (Campinas, SP, Brazil). The rats were assigned to four groups: namely, SO (sham operated, treated with saline, 100 µl ip daily; n = 25), SO-T (SO treated with colchicine, 0.4 mg/kg body wt ip daily; beginning the day before the surgery; n = 38), TAoC (rats that underwent constriction of transverse aorta, treated with saline, 100 µl ip daily; n = 37), and TAoC-T (TAoC, treated with colchicine, 0.4 mg/kg body wt ip daily; beginning the day before the surgery; n = 34). All procedures followed the University's guidelines to use animals in experimental studies.
Aortic constriction procedure. After anesthesia (ketamine 100 mg/kg and diazepam 6 mg/kg ip), the rats were placed on a temperature-controlled surgical table. The thoracic cavity was opened at the second left intercostal space, and a silver clip (500 µm ID) was positioned in the transverse aorta just before the origin of the left common carotid artery. The thoracic cavity was closed, and the rats were maintained in a preheated chamber until they recovered from anesthesia. Sham operation was similarly performed, except that the silver clip was implanted in the thymus mass.
Experimental design and hemodynamic monitoring.
After the recovery of anesthesia, the rats were moved to individual
cages, where they were maintained for periods of 2, 6, or 15 days after
surgery. During these periods, the rats were treated daily with single
shots of saline or colchicine. At the end of each period, the rats were
anesthetized, and a short (3-cm-long) heat-stretched PE-50 (external
diameter ~200 µm) cannula was inserted into the right common
carotid artery and advanced into the LV for pressure measurements. A
Tygon polyvinyl-tipped cannula was positioned in the lower abdominal
aorta throughout the right femoral artery for the measurement of
arterial pressure downstream to aortic constriction. After hemodynamic
stability, baseline ventricular and aortic pressures were continuously
monitored for 20 min. At the end of this period, all rats underwent a
phenylephrine dose-response protocol (10-76
µg · kg
1 · min1),
with each dose infused for 3 min. The pressure signals were sampled at 300 Hz each, digitized, and processed with WINDAQ-PRO data-acquisition software (DATAQ Instruments, Akron, OH).
Morphological studies. After the baseline hemodynamic monitoring, the rats were euthanized with an intravenous injection of 500 µl of 2% lidocaine, which induced a diastolic cardiac arrest. The hearts were excised for mass determination. The LV was then transversely sectioned in three pieces, which were immersed in phosphate-buffered formalin fixative (pH 7.2). These specimens were thin sectioned (5 µm) for planimetric measurements of LV and morphometric study of cardiac myocytes by light microscopy. The LV wall thickness (LVWT) and cavity diameter (LVD) of formalin-fixed sections were analyzed by planimetric measurement. Transverse sections taken from midventricle were stained with hematoxylin and eosin. The sections were digitized directly from the slides with a commercial scanner and analyzed with NIH Image analyzer software (http://rsb.info.nih.gov/nih-image/). The same sections were used for the analysis of average diameter and the number of nuclei of cardiac myocytes per myocardial section. The diameter of isolated cardiac myocytes was measured in fibers sectioned longitudinally at the level of their nuclei.
Western blotting of free and polymerized tubulin.
The Western blot analysis of tubulin was performed as described
previously (8). Briefly, a sample of LV myocardial tissue (250 mg) was homogenized in microtubule stabilizing buffer (50% glycerol, 5% DMSO, 10 mmol/l NaH2PO4, 0.5 mmol/l EGTA, 0.5 mmol/l MgSO4) and centrifuged at 100,000 g at 25°C for 10 min. The supernatants were saved as the
free tubulin fractions, and the pellets were resuspended at 0°C in
microtubule depolymerizing buffer (0.25 mol/l sucrose, 10 mmol/l
NaH2PO4, 0.5 mmol/l MgSO4). After
1 h at 0°C, they were centrifuged at 100,000 g at
4°C for 15 min, and the supernatants were saved as polymerized
tubulin fractions. Equal proportions of the free and polymerized
samples were loaded onto an 8-16% gradient SDS-PAGE, transferred
to a nitrocellulose membrane, and probed with a monoclonal antibody
against 
-tubulin (Zymed). Quantification of Western blots (NIH Image
analyzer software) was obtained by the integrated optical density
increase over background density in a rectangular region of interest.
Within a given experiment, the mean signal value in the control group
was defined as 100, and the signal density for colchicine-treated rats
was calculated as a percentage of the mean value obtained from SO rats
within the same blot.
Statistical analysis. The results are presented as means ± SE. Differences between means were tested by one-way ANOVA for repeated measures and Bonferroni's multiple-range test. A P < 0.05 was considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Heart mass and hemodynamics.
TAoC and SO rats showed similar body weight gain along the period that
followed the surgery (Table 1).
Colchicine treatment retarded the body weight gain of both TAoC-T and
SO-T rats. These rats lost weight from the beginning of colchicine
treatment up to the 6th day after the surgery. After this period, both
groups of rats recovered their body weight gain. Changes of
LVM and RVM of SO and SO-T rats paralleled the
changes of body weight that occurred along the experimental period
(Table 1). The ratio between LVM and body weight increased
in TAoC and TAoC-T compared with SO and SO-T rats, respectively.
However, because this index of LV hypertrophy is influenced by
differences in body weight, we analyzed the ratio of LVM to
RVM (LVM/RVM), which remained
stable in SO and SO-T rats over the experimental period. In TAoC, it increased significantly along the experimental period, compared with
that in SO rats (Table 1). In addition, by the 6th and 15th day after
aortic constriction, LVM/RVM values of TAoC
rats were higher than the values of TAoC-T rats. Because the
LVM/RVM index was not influenced by changes in
body weight, this ratio was used to estimate the hypertrophic growth
induced by pressure overload. By the 15th postoperative day,
LVM/RVM was increased by 30% in TAoC and 15%
in TAoC-T rats, compared with SO and SO-T rats, respectively. Thus we
estimated that colchicine treatment reduced the load-induced LV
hypertrophic growth by ~50%.
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LV geometry and histology.
TAoC rats showed a progressive increase in LVWT (Fig.
3A). LVWT of TAoC
rats increased by 33 and 72% at the 6th and 15th day, respectively,
compared with values of the 2nd postoperative day. No significant
change was observed in LVWT of SO, SO-T, and TAoC-T rats
along the experimental period. However, LVWT values of SO-T and TAoC-T rats were lower than LVWT values of SO rats on
the 6th and 15th day after surgery.
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Effects of colchicine on tubulin.
To be sure that colchicine treatment effectively affected tubulin
polymerization in our hands, and also to assess the effect of pressure
overload on microtubules, groups of rats were prepared for Western blot
analysis with anti--tubulin antibody to determine the amount of free
and polymerized fractions of tubulin in the myocardial homogenates.
Figure 4 shows a representative example and average values of Western blots corresponding to polymerized and
free tubulin of myocardial homogenates from the various groups of rats
of this study. Most of the tubulin detected in the myocardial homogenates of SO, SO-T, TAoC, and TAoC-T rats was in the free fraction. TAoC rats showed a consistent increase in the polymerized fraction of tubulin, compared with the other groups of rats. Otherwise, TAoC-T rats showed values of polymerized slightly lower than the levels
of SO rats.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Pressure overload induces LV hypertrophy that is a compensatory response to increased wall stress. This has been considered a central principle by which cardiac function is maintained within normal ranges in chronically overloaded hearts. Accordingly, suppression of myocardial hypertrophy is expected to cause heart failure. We have shown in the present study that treatment with colchicine greatly attenuated the LV hypertrophic growth and remodeling induced by sustained pressure overload, but there was no detectable impairment of LV function at baseline or during the increased systolic stress induced by phenylephrine infusion. These results indicate that treatment with colchicine allowed the LV to adapt to pressure overload, even in the absence of LV hypertrophy.
Colchicine treatment and hypertrophic growth. The attenuation of hypertrophic growth in TaoC-T rats was demonstrated by the analysis of indexes such as LVM/RVM, LVWT/LVD, and the average diameter of cardiac myocytes. Our data showed that the values of these indexes consistently increased in TAoC, whereas TAoC-T had values comparable to those of SO rats. Curiously, treatment with colchicine produced a dramatic effect on myocyte diameter, which showed no change in TAoC-T rats along the experimental period, despite the fact that these rats showed some increase in LVM. The explanation for this is not apparent from our present results but could be related to survival of a greater number of myocytes in TAoC-T compared with TAoC rats. Our data showing a reduced number of cardiac myocyte nuclei per myocardial area in TAoC rats compared with TAoC-T and SO rats accord with this idea. It is well documented that pressure overload is associated with loss of cardiac myocytes by necrosis and apoptosis (1). Thus one could speculate that colchicine treatment, despite its effect on myocyte hypertrophic growth, might prevent the myocyte loss induced by pressure overload.
Because colchicine is a highly specific inhibitor of tubulin polymerization, it is plausible to think that the effect of colchicine treatment on LV hypertrophic growth is somehow related to this effect. Accordingly, we have shown that, in addition to reducing the LV hypertrophic growth, treatment with colchicine abrogated the increases in the amount of polymerized tubulin in overloaded myocardium. The fact that colchicine treatment did not affect specifically the LV growth or the amount of polymerized tubulin of SO-T compared with SO rats corroborates this hypothesis. Moreover, our results agree with previous observations (21) indicating that colchicine treatment abolished the expression of the early molecular markers of LV hypertrophy as well as the increased microtubule polymerization in overloaded myocardium. However, the mechanisms that relate the colchicine-induced reduction in the excessive polymerized microtubule to the inhibition of load-induced hypertrophy are still unclear and were not explored in the present study.Colchicine treatment and cardiac function. In this study, we also showed that colchicine treatment did not compromised the LV function, despite its effect on LV hypertrophic growth of rats subjected to sustained pressure overload. Indeed, colchicine treatment was shown to be accompanied by a better contractile performance of LV per unit of myocardial mass in TAoC-T compared with TAoC rats, either at baseline or in response to increased systolic stress induced by phenylephrine infusion. Thus the enhanced contractile performance would explain the preservation of cardiac function of TAoC-T rats, despite the lack of LV hypertrophy. This generally agrees with the results of studies performed in distinct animal models of hemodynamic overload (2, 4), supporting the concept that the LV, in the absence of a clear compensatory hypertrophy, can successfully adapt to chronic overload by enhancing myocardial contractility.
Studies in various experimental models have demonstrated that microtubule depolymerization ameliorates contractile dysfunction in cardiac myocytes (15, 19, 20, 24) and papillary muscles (25) from overloaded myocardium, suggesting that the excess of polymerized microtubules may exert negative inotropic effects by restraining the deformation of cardiac myocytes. Accordingly, this might explain the depression in contractile performance per unit mass of TAoC compared with SO rats, as well as the better contractile performance of TAoC-T rats observed in the present study. However, it is intriguing that colchicine treatment not only preserved but also improved contractile performance per unit of LVM of TAoC-T and SO-T rats. Although the explanation for these results are not apparent from our present data, the lack of detectable reduction in the amount of polymerized microtubules in the myocardium of TAoC-T and SO-T compared with SO rats would indicate that this effect may not be dependent exclusively on the disruption of myocardial microtubule network. Alternatively, colchicine treatment might directly influence the myocardial contractile performance. Accordingly, previous studies have shown that colchicine enhances the contractile performance by activating the excitation-contraction coupling, regulation of second messengers, and calcium signaling (5, 6). In summary, we have shown that colchicine treatment markedly attenuated the development of LV hypertrophy induced by pressure overload in rats, but preserved the LV function at baseline as well as at superimposed systolic stress induced by phenylephrine infusion. Furthermore, treatment with colchicine abolished the increased amount of polymerized tubulin in overloaded myocardium. These results suggest that modulation of microtubule assembly in the overloaded myocardium may, therefore, inhibit the load-induced hypertrophic growth and contribute to the preservation of the LV function, even in the presence of sustained overload.| |
ACKNOWLEDGEMENTS |
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This study was sponsored by grants from Fundação de Amparo a Pesquisa do Estado de São Paolo (Proc. 00/03542-9) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (Proc. 521098/97-1).
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FOOTNOTES |
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Address for reprint requests and other correspondence: K. G. Franchini, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Cidade Universitária "Zefferino Vaz," 13081-970 Campinas, SP, Brazil (E-mail: franchin{at}obelix.unicamp.br).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published December 13, 2002;10.1152/japplphysiol.00744.2002
Received 12 August 2002; accepted in final form 10 December 2002.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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) in LV peak systolic pressure (LVSP;
A), LV end-diastolic pressure (LVEDP; B), and
rate of increases of LV pressure (+dP/dt; C)
induced by infusion of increasing doses of PHE are shown in rats on the
15th day after surgery for aortic constriction or sham operation. SO,
sham operated; SO-T, SO treated with colchicine; TAoC, transverse aorta
constriction; TAoC-T, TAoC treated with colchicine. § TAoC vs. SO,
TAoC-T vs. SO-T: P < 0.05.
TAoC-T vs. TAoC, # SO-T vs. SO,
* TAoC-T vs. SO: P < 0.05.
