Abstract
OBJECTIVE:
After acute myocardial infarction, during the cardiac repair phase, periostin is released into the infarct and activates signaling pathways that are essential for the reparative process. However, the role of periostin in chronic cardiac remodeling after myocardial infarction remains to be elucidated. Therefore, the objective of this study was to investigate the relationship between tissue periostin and cardiac variables in the chronic cardiac remodeling induced by myocardial infarction.
METHODS:
Male Wistar rats were assigned to 2 groups: a simulated surgery group (SHAM; n = 8) and a myocardial infarction group (myocardial infarction; n = 13). After 3 months, morphological, functional and biochemical analyses were performed. The data are expressed as means±SD or medians (including the lower and upper quartiles).
RESULTS:
Myocardial infarctions induced increased left ventricular diastolic and systolic areas associated with a decreased fractional area change and a posterior wall shortening velocity. With regard to the extracellular matrix variables, the myocardial infarction group presented with higher values of periostin and types I and III collagen and higher interstitial collagen volume fractions and myocardial hydroxyproline concentrations. In addition, periostin was positively correlated with type III collagen levels (r = 0.673, p = 0.029) and diastolic (r = 0.678, p = 0.036) and systolic (r = 0.795, p = 0.006) left ventricular areas. Considering the relationship between periostin and the cardiac function variables, periostin was inversely correlated with both the fractional area change (r = -0.783, p = 0.008) and the posterior wall shortening velocity (r = -0.767, p = 0.012).
CONCLUSIONS:
Periostin might be a modulator of deleterious cardiac remodeling in the chronic phase after myocardial infarction in rats.
Fibrosis; Myocardial Infarction; Periostin
INTRODUCTION
Cardiac remodeling describes changes in the size, geometry, shape, composition and function of
the heart after cardiac injury. Importantly, chronic ventricular remodeling is now recognized as an
important pathological process that results in progressive ventricular dysfunction and the clinical
presentation of heart failure or death (11. Pfeffer JM, Finn PV, Zornoff LA, Pfeffer MA. Endothelin-A receptor antagonism
during acute myocardial infarction in rats. Cardiovasc Drugs Ther. 2000;14(6):579-87,
http://dx.doi.org/10.1023/A:1007890126061.
http://dx.doi.org/10.1023/A:100789012606...
2. Cohn JN, Ferrari R, Sharpe N. Cardiac Remodeling - concepts and clinical
implications: a consensus paper from an international forum on cardiac remodeling. J Am Coll
Cardiol. 2000;35(3):569-82, http://dx.doi.org/10.1016/S0735-1097(99)00630-0.
http://dx.doi.org/10.1016/S0735-1097(99)...
3. Swynghedaunw B. Molecular mechanisms of myocardial remodeling. Physiol Rev.
1999;79(1):215-62.-44. Zornoff LAM, Paiva SAR, Duarte DR, Spadaro J. Ventricular remodeling after
myocardial infarction: concepts and clinical implications. Arq Bras Cardiol.
2009;92(2):157-64.). Thus, it is critical to know the pathophysiological alterations
involved in these processes.
After myocardial infarction (MI), remodeling is a dynamic process that results from the
activation of molecular and cellular pathways involving both myocytes and extracellular matrix
components, including collagens, glycoproteins, proteoglycans, glycosaminoglycans and matricellular
proteins (55. Zamilpa R, Lindsey ML. Extracellular matrix turnover and signaling during cardiac
remodeling following MI: causes and consequences. J Mol Cell Cardiol. 2010;48(3):558-63,
http://dx.doi.org/10.1016/j.yjmcc.2009.06.012.
http://dx.doi.org/10.1016/j.yjmcc.2009.0...
,66. Dobaczewski M, Gonzalez-Quesada C, Frangogiannis NG. The extracellular matrix as
a modulator of the inflammatory and reparative response following myocardial infarction. J Mol
Cell Cardiol. 2010;48(3):504-11, http://dx.doi.org/10.1016/j.yjmcc.2009.07.015.
http://dx.doi.org/10.1016/j.yjmcc.2009.0...
).
Matricellular proteins are a family of structurally unrelated extracellular macromolecules that
play limited roles in tissue architecture but serve as links between cells and the extracellular
matrix. In general, matricellular proteins are minimally expressed in normal hearts but are
upregulated following cardiac injury (77. Frangogiannis NG. Matricellular proteins in cardiac adaptation and disease.
Physiol Rev. 2012;92(2):635-88, http://dx.doi.org/10.1152/physrev.00008.2011.
http://dx.doi.org/10.1152/physrev.00008....
).
One of the most important matricellular proteins is periostin, which plays a role in the
maturation and differentiation of fibroblasts in the developing neonatal heart (77. Frangogiannis NG. Matricellular proteins in cardiac adaptation and disease.
Physiol Rev. 2012;92(2):635-88, http://dx.doi.org/10.1152/physrev.00008.2011.
http://dx.doi.org/10.1152/physrev.00008....
). After acute MI, during the cardiac repair phase, periostin is
released into the infarct and activates signaling pathways that are essential for the reparative
process (88. Matsui Y, Morimoto J, Uede T. Role of matricellular proteins in cardiac tissue
remodeling after myocardial infarction. World J Biol Chem.
2010;1(5):69-80.
9. Kühn B, del Monte F, Hajjar RJ, Chang YS, Lebeche D, Arab S, et al.
Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat
Med. 2007;13(8):962-9, http://dx.doi.org/10.1038/nm1619.
http://dx.doi.org/10.1038/nm1619...
10. Shimazaki M, Nakamura K, Kii I, Kashima T, Amizuka N, Li M, et al. Periostin is
essential for cardiac healing after acute myocardial infarction. J Exp Med.
2008;205(2):295-303, http://dx.doi.org/10.1084/jem.20071297.
http://dx.doi.org/10.1084/jem.20071297...
-1111. Oka T, Xu J, Kaiser RA, Melendez J, Hambleton M, Sargent MA, et al. Genetic
manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular
remodeling. Circ Res. 101(3):313-21.).
However, the role of periostin in chronic cardiac remodeling after MI remains to be elucidated.
Therefore, the objective of this study was to investigate the relationship between periostin and
cardiac variables in the chronic cardiac remodeling induced by coronary occlusion in rats.
MATERIALS AND METHODS
All experiments and procedures were performed in accordance with the National Institute of Health's Guide for the Care and Use of Laboratory Animals and were approved by the Animal Ethics Committee of our institution.
Male Wistar rats that weighed 200-250 g were assigned to 2 groups. One group underwent simulated surgery without the induction of an MI (SHAM group; n = 8), and the other group was subjected to an MI (MI group; n = 13). Water and diet were supplied ad libitum. The rats were observed for 3 months, after which morphological, functional and biochemical analyses were performed.
Coronary artery ligation
When the animals achieved body weights of 200-250 g, an MI was induced as previously described (1212. Minicucci MF, Azevedo PS, Martinez PF, Lima AR, Bonomo C, Guizoni DM, et al. Critical infarct size to induce ventricular remodeling, cardiac dysfunction and heart failure in rats. Int J Cardiol. 2011;151(2):242-3.,1313. Duarte DR, Minicucci MF, Azevedo PS, Matsubara BB, Matsubara LS, Novelli EL, et al. The role of oxidative stress and lipid peroxidation in ventricular remodeling induced by tobacco smoke exposure after myocardial infarction. Clinics. 2009;64(7):691-7.). In brief, the rats were anesthetized with ketamine (70 mg/kg) and xylazine (1 mg/kg), and after a left thoracotomy, the heart was exteriorized. The left atrium was retracted to facilitate the ligation of the left coronary artery with 5-0 mononylon between the pulmonary outflow tract and the left atrium. The heart was then replaced in the thorax, and the lungs were inflated by positive pressure as the thoracotomy was closed. The rats were housed in a temperature-controlled room (24°C) with a 12-h light:dark cycle.
Echocardiographic analysis
After 3 months, all animals were weighed and evaluated by a transthoracic echocardiographic exam
(1414. Minicucci MF, Azevedo PS, Santos DF, Polegato BF, Santos PP, Okoshi K, et al.
Echocardiographic predictors of ventricular remodeling after acute myocardial infarction in rats.
Arq Bras Cardiol. 2011;97(6):502-6,
http://dx.doi.org/10.1590/S0066-782X2011005000117.
http://dx.doi.org/10.1590/S0066-782X2011...
,1515. Paiva SAR, Novo R, Matsubara BB, Matsubara LS, Azevedo PS, Minicucci MF, et al.
β-carotene attenuates the paradoxical effect of tobacco smoke on the mortality of rats after
experimental myocardial infarction. J Nutr. 2005;135(9):2109-13.). The same
observer made all measurements according to the leading-edge method recommended by the American
Society of Echocardiography/European Association of Echocardiography (1616. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al.
Recommendations for chamber quantification: a report from the American Society of
Echocardiography's guidelines and standards Committee and the chamber quantification writing
group, developed in conjunction with the European Association of Echocardiography, a branch of the
European Society of Cardiology. J Am Soc Echocardiogr. 2005;18(12):1440-63,
http://dx.doi.org/10.1016/j.echo.2005.10.005.
http://dx.doi.org/10.1016/j.echo.2005.10...
). The end-systolic and end-diastolic cavity areas were calculated as the sum of
the areas from both the short- and long-axis views in diastole (SumD) and systole (SumS),
respectively. The fractional area change (FAC) was calculated from the composite cavity areas as
follows: FAC = (SumD-SumS)/SumD. Additionally, the left ventricular mass index (LVMI) was calculated
using the equation LVMI = {[(LVEDD+2*LVWT)3-(LVEDD)3
]*1.04}/BW. The transmitral diastolic flow velocities (E and A velocities) were obtained from
the apical four-chamber view. The E/A ratio, the isovolumetric relaxation time and the isovolumetric
relaxation time corrected by the heart rate (TRIV/RR0.5) were used as indices of the left
ventricular (LV) diastolic function.
In vitro left ventricular function analysis
One day after the echocardiographic study, the rats were anesthetized with thiopental sodium (50
mg/kg, i.p.) and were administered heparin (2000 UI, i.p.). The chest was subjected to a median
sternotomy under artificial ventilation. The entire heart was quickly removed from the chest and
transferred to a perfusion apparatus (model 830 Hugo Sachs Eletronick-Green-stasse). The ascending
aorta was isolated and cannulated for retrograde perfusion with filtered and oxygenated
Krebs-Henseleit solution, which was maintained at a constant temperature (37°C) and perfusion
pressure (75 mmHg). All hearts were paced at 200 to 250 beats/min. The procedures and measurements
were performed following a previously described method (1717. Azevedo PS, Minicucci MF, Chiuso-Minicucci F, Justulin LA Jr, Matsubara LS,
Matsubara BB, et al. Ventricular remodeling induced by tissue vitamin A deficiency in rats. Cell
Physiol Biochem. 2010;26(3):395-402, http://dx.doi.org/10.1159/000320563.
http://dx.doi.org/10.1159/000320563...
).
Morphometric analysis
Upon the completion of the functional analyses, the right and left ventricles (including the
interventricular septum) were dissected, separated and weighed. Transverse sections of the LV were
fixed in 10% buffered formalin and embedded in paraffin. Five-micron-thick sections were stained
with hematoxylin and eosin (HE) or the collagen-specific stain picrosirius red (Sirius red F3BA in
aqueous saturated picric acid). The myocyte cross-sectional area was determined for a minimum of 100
myocytes per HE-stained cross-section. Measurements were obtained from digital images (400×
magnification) that were collected with a video camera attached to a Leica microscope; the images
were analyzed with the Image-Pro Plus 3.0 software program (Media Cybernetics; Silver Spring, MD).
The myocyte cross-sectional area was measured with a digital pad, and the selected cells were
transversely cut in such a way that the nucleus was in the center of the myocyte (1818. Rafacho BP, Santos P, Assalin HB, Ardisson LP, Roscani MG, Polegato BF, et al.
Role of vitamin D in the cardiac remodeling induced by tobacco smoke exposure.
Int J Cardiol. 2012;155(3):472-3.). The interstitial collagen volume fraction was determined for
the entire cardiac section that was stained with picrosirius red by analyzing digital images that
were captured under polarized light (200× magnification). The cardiac tissue components were
identified according to the following staining patterns: red for collagen fibers, yellow for
myocytes and white for interstitial space. The collagen volume fraction was calculated as the sum of
all of the connective tissue areas divided by the sum of all of the connective tissue and myocyte
areas. On average, 35 microscopic fields per heart were analyzed with a 20× lens. Perivascular
collagen was excluded from this analysis (1919. Paiva SA, Zornoff LA, Okoshi MP, Okoshi K, Matsubara LS, Matsubara BB, et al.
Ventricular remodeling induced by retinoic acid supplementation in adult rats.
Am J Physiol Heart Circ Physiol. 2003;284(6):H2242-6.). The infarcted
and viable muscle lengths for both the endocardial and epicardial circumferences were determined
using planimetry. The infarct size was calculated by dividing the endocardial and epicardial
circumferences of the infarcted area by the total epicardial and endocardial ventricular
circumferences. The measurements on the midventricular slices (5-6 mm from the apex) were performed
under the assumption that the left midventricular slice had a close linear relationship with the sum
of the area measurements from all of the heart slices (2020. Zornoff LA, Paiva SA, Minicucci MF, Spadaro J. Experimental myocardium
infarction in rats: analysis of the model. Arq Bras Cardiol. 2009;93(4):434-40,
http://dx.doi.org/10.1590/S0066-782X2009001000018.
http://dx.doi.org/10.1590/S0066-782X2009...
).
Myocardial hydroxyproline concentration
The myocardial hydroxyproline concentration was used to estimate the extent of fibrosis.
Hydroxyproline (HOP) was measured in the tissues (the septum of the LV and the mid-ventricular slice
of the RV) according to the method described previously (2121. Zornoff LAM, Matsubara BB, Matsubara LS, Paiva SAR, Spadaro J. Early rather than
delayed administration of lisinopril protects the heart after myocardial infarction in rats. Basic
Res Cardiol. 2000;95(3):208-14, http://dx.doi.org/10.1007/s003950050183.
http://dx.doi.org/10.1007/s003950050183...
).
Briefly, the tissues were dried for 4 h using a Speedvac Concentrator SC 100 that was attached to a
refrigerated condensation trap (RVT 100) and vacuum pump (VP 100, Savant Instruments, Inc.,
Farmingdale, NY). The dry weights of the tissues were determined, and the samples were hydrolyzed
overnight at 110°C with 6 N HCl (1 ml/10 mg dry tissue). A 50-μl aliquot of the hydrolysate
was transferred to an Eppendorf tube and dried in the Speedvac Concentrator. Deionized water (1 ml)
was added, and the sample was transferred to a tube with a Teflon screw cap. Potassium borate buffer
(1 ml, pH 8.7) was added to maintain a constant pH, and the sample was oxidized with 0.3 ml of
chloramine T solution at room temperature for exactly 20 min. The oxidative process was stopped by
adding 1 ml of 3.6 mol/l sodium thiosulfate and mixing thoroughly for 10 s. The solution was
saturated with 1.5 g of KCl. The tubes were capped and heated in boiling water for 20 min. After
cooling to room temperature, the aqueous layer was extracted with 2.5 ml of toluene. Next, 1 ml of
toluene extract was transferred to a 12×75 mm test tube. Then, 0.4 ml of Ehrlich's
reagent was added to allow the color to develop for 30 min. The absorbances were read at 565 nm
against a reagent blank. Deionized water and 20 μg/ml HOP were used as the blank and standard,
respectively (2222. Matsubara LS, Matsubara BB, Okoshi MP, Cicogna AC, Janicki JS. Alterations in
myocardial collagen content affect rat papillary muscle function. Am J Physiol Heart Circ
Physiol. 2000;279(4):H1534-9.).
Western blot analysis
LV samples were extracted using Tris-Triton buffer (10 mM Tris pH 7.4, 100 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 10% glycerol, 0.1% SDS, 0.5% deoxycholate, 1 nM EDTA, 1 mM EGTA, a 1 mM mixture of protease inhibitors, 1 mM sodium orthovanadate, 1 mM sodium fluoride and 1% leupeptin, aprotinin and pepstatin) to detect collagen I, collagen III and periostin. The samples were then centrifuged at 12,000 rpm at 4°C for 20 min, and the supernatant was collected. The supernatant protein content was quantified using the Bradford method. The samples were separated on a 10% SDS-polyacrylamide gel, and the separated proteins were transferred to a nitrocellulose membrane. The membrane was blocked with 5% nonfat dry milk in Tris-buffered saline containing Tris 1 M pH 8.0, NaCl 5 M and Tween-20 at room temperature for 2 h. The membrane was then incubated with the following primary antibodies: anti-collagen III, mouse monoclonal IgG1 (Abcam, Inc., Canada, ab 6310); anti-collagen I A1, rabbit polyclonal IgG (Santa Cruz Biotechnology, Inc., Europe, sc 8784R); and anti-periostin, goat polyclonal IgG (Santa Cruz Biotechnology, Inc., Europe, sc 49480). The membrane was washed with TBS and Tween-20 and was then incubated with secondary peroxidase-conjugated antibodies. A Super Signal® West Pico Chemiluminescent Substrate (Pierce Protein Research Products, Rockford, USA) was used to detect the bound antibodies. GAPDH (GAPDH [6C5], mouse monoclonal IgG1, Santa Cruz Biotechnology, Inc., Europe, sc 32233) was used for western blot normalization of collagen I, III and periostin.
Statistical analysis
The data are expressed as means±SD or medians (including the lower and upper quartiles). The Kolmogorov-Smirnov test was used to test for the normally distributed data. Comparisons between groups were performed using Student's t test for parameters with normal distributions. Otherwise, comparisons between groups were performed using the Mann-Whitney U test. Correlations between continuous variables were performed with the Spearman's test. The χ2 test or Fisher Exact test was used to compare categorical variables. The data analyses were performed with SigmaStat for Windows v2.03 (SPSS Inc., Chicago, IL). The significance level was set at 5%.
RESULTS
The mean infarct size was 33.2±13.4%, and the rats in the SHAM group weighed more 3 months after surgery. The echocardiographic data are listed in Table 1. The animals in the MI group had higher values of left cardiac chambers corrected by body weight, higher LVMIs and lower relative wall thicknesses (RWTs) compared with the SHAM group. In addition, there were no differences in the diastolic function variables; however, systolic function was worse in the MI group.
The in vitro LV function data revealed worse systolic (+ dP/dt max: SHAM: 4375±843, MI: 2675±813 mmHg/s; p = 0.012) and diastolic functions (- dP/dt max: SHAM: 2125 [1969-2500], MI: 1750.0 [1219-1750] mmHg/s; p = 0.008) in the MI group (Table 2).
The morphological data are listed in Table 3. The BW-corrected right ventricular weight (RVW) was elevated in the MI group. This result, which suggests cardiac hypertrophy, was in agreement with the higher values of the myocyte cross-sectional area (MCA) (SHAM: 305.7±53.1, MI: 492.6±65.3 μm2; p<0.001) observed in the MI group. In addition, the interstitial collagen volume fraction (SHAM: 1.85±0.70, MI: 4.02±0.61%; p<0.001) and HOP concentration (SHAM: 3.32±0.75, MI: 5.48±0.73 μg/mg; p = 0.002) were higher in the MI group.
Periostin (SHAM: 0.0009 [0.0007-0.0015], MI: 0.156 [0.111-0.234); p = 0.016] and collagen types I (SHAM: 1.90±1.07, MI: 4.14±0.82; p = 0.009) and III (SHAM: 1.01 [0.91-1.13], MI: 9.26 [6.61-10.73]; p = 0.016) were higher in the MI group than in the SHAM group (Table 4).
The periostin level was positively correlated with the type III collagen level (r = 0.673, p = 0.029) but not with the type I collagen level (r = 0.370, p = 0.275). Taking into account the relationship between periostin and the cardiac function variables, periostin was inversely correlated with FAC (r = -0.783, p = 0.008) and PWSV (r = -0.767, p = 0.012). Considering the association between periostin and the morphological variables, periostin was positively correlated with both the diastolic (r = 0.678, p = 0.036) and systolic (r = 0.795, p = 0.006) LV areas.
DISCUSSION
The objective of this study was to analyze the contribution of periostin in the chronic cardiac remodeling induced by MI. The expression of cardiac periostin increased 3 months after infarction. In addition, there were strong associations among periostin and cardiac fibrosis, ventricular enlargement and cardiac systolic dysfunction. Therefore, our data suggest that periostin might play a pathophysiological role in the detrimental chronic remodeling process following coronary occlusion in rats.
Extracellular matrix components play a critical role in the cardiac remodeling process. The most
dramatic changes in the cardiac extracellular matrix occur in the scenario of acute MI. Indeed, in
the early period, abundant inflammatory leukocytes infiltrate the infarcted area and phagocytose
dead cells and matrix debris. Then, the regression of inflammatory signals is noted, and fibroblasts
produce large amounts of extracellular matrix proteins, including collagen types I and III. Finally,
a mature scar is formed. Thus, alterations in the inflammatory, proliferative and maturation phases
may result in fatal complications after MI. For instance, slower healing, which results in an
infarcted area more susceptible to deformations, might provoke infarct expansion, aneurysm
formation, arrhythmia and cardiac rupture after infarction (11. Pfeffer JM, Finn PV, Zornoff LA, Pfeffer MA. Endothelin-A receptor antagonism
during acute myocardial infarction in rats. Cardiovasc Drugs Ther. 2000;14(6):579-87,
http://dx.doi.org/10.1023/A:1007890126061.
http://dx.doi.org/10.1023/A:100789012606...
,44. Zornoff LAM, Paiva SAR, Duarte DR, Spadaro J. Ventricular remodeling after
myocardial infarction: concepts and clinical implications. Arq Bras Cardiol.
2009;92(2):157-64.). Importantly, the composition of the
extracellular matrix plays a key role during all of the phases of infarct healing (77. Frangogiannis NG. Matricellular proteins in cardiac adaptation and disease.
Physiol Rev. 2012;92(2):635-88, http://dx.doi.org/10.1152/physrev.00008.2011.
http://dx.doi.org/10.1152/physrev.00008....
).
It is accepted that periostin is a critical modulator of collagen deposition, fibrosis and scar
mechanics (2323. Snider P, Standley KN, Wang J, Azhar M, Doestschman T, Conway SJ. Origen of
cardiac fibroblasts and the role of periostin. Circ Res. 2009;105(10):934-47,
http://dx.doi.org/10.1161/CIRCRESAHA.109.201400.
http://dx.doi.org/10.1161/CIRCRESAHA.109...
). Periostin expression by cardiac fibroblasts
is high during early neonatal life and subsequently declines to barely detectable levels in adult
life (2424. Norris RA, Moreno-Rodrigues R, Hoffman S, Markwald RR. The many facets of the
matricellular protein peristin during cardiac development, remodeling, and pathophysiology.
J Cell Commun Signal. 2009;3(3-4):275-86,
http://dx.doi.org/10.1007/s12079-009-0063-5.
http://dx.doi.org/10.1007/s12079-009-006...
). However, periostin is upregulated in the injured
heart and plays a critical role in the regulation of inflammatory, reparative and fibrotic pathways
(2424. Norris RA, Moreno-Rodrigues R, Hoffman S, Markwald RR. The many facets of the
matricellular protein peristin during cardiac development, remodeling, and pathophysiology.
J Cell Commun Signal. 2009;3(3-4):275-86,
http://dx.doi.org/10.1007/s12079-009-0063-5.
http://dx.doi.org/10.1007/s12079-009-006...
). Thus, knowledge of the effects of periostin on cardiac
remodeling after MI is pivotal.
The role of periostin during the infarct-healing phase has been studied. In mice,
immunohistochemical analysis 1 week after MI revealed a massive accumulation of periostin within the
scar. In addition, periostin-null mice had significantly increased mortality during the first 10
days after MI, which was associated with a 2-fold greater rate of ventricular rupture compared with
the controls (1111. Oka T, Xu J, Kaiser RA, Melendez J, Hambleton M, Sargent MA, et al. Genetic
manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular
remodeling. Circ Res. 101(3):313-21.). Another study on periostin-null mice found
that, after acute MI, cardiac healing was impaired, resulting in a cardiac rupture as a consequence
of reduced myocardial stiffness caused by impaired collagen formation (1010. Shimazaki M, Nakamura K, Kii I, Kashima T, Amizuka N, Li M, et al. Periostin is
essential for cardiac healing after acute myocardial infarction. J Exp Med.
2008;205(2):295-303, http://dx.doi.org/10.1084/jem.20071297.
http://dx.doi.org/10.1084/jem.20071297...
). Therefore, the data strongly suggest that periostin is essential for cardiac
healing after acute MI by promoting myofibroblast migration and activation.
In contrast to the function of periostin during the infarct-healing phase, the role of periostin
during the chronic phase following an MI is less clear. Indeed, as mentioned previously, shortly
after coronary occlusion, periostin-null mice presented with greater ventricular ruptures. However,
periostin-null mice surviving the acute phase had significantly reduced fibrosis in the
non-infarcted area, which was associated with the attenuation of the ventricular systolic
dysfunction 8 weeks after the infarct (1111. Oka T, Xu J, Kaiser RA, Melendez J, Hambleton M, Sargent MA, et al. Genetic
manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular
remodeling. Circ Res. 101(3):313-21.). In another study,
Kuhn et al. administered Gelfoam patches loaded with periostin in rats subjected to coronary
occlusion. Between 1 and 12 weeks, the shortening and ejection fractions in coronary occlusion rats
increased significantly in comparison to the control animals. In addition, at 1 week after MI, the
treatment and control groups had the same LV dimensions. However, at 12 weeks, the end-diastolic
dimension was smaller in the periostin-treated rats, suggesting improved ventricular remodeling in
those rats (99. Kühn B, del Monte F, Hajjar RJ, Chang YS, Lebeche D, Arab S, et al.
Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat
Med. 2007;13(8):962-9, http://dx.doi.org/10.1038/nm1619.
http://dx.doi.org/10.1038/nm1619...
). Therefore, considering the conflicting
results, the role of periostin in chronic cardiac remodeling after MI remains to be elucidated.
In our study, the infarcted rats presented with increased LV dimensions. LV enlargement can occur
soon after MI as a result of infarct expansion, which increases the surface of the infarcted area by
the stretching and thinning of the damaged region. As a result of post-infarction expansion,
parietal tension is significantly increased, inducing the process of eccentric hypertrophy.
Therefore, regardless of its complexity, after myocardial infarction, the remodeling process is
frequently used as a synonym for ventricular dilation (11. Pfeffer JM, Finn PV, Zornoff LA, Pfeffer MA. Endothelin-A receptor antagonism
during acute myocardial infarction in rats. Cardiovasc Drugs Ther. 2000;14(6):579-87,
http://dx.doi.org/10.1023/A:1007890126061.
http://dx.doi.org/10.1023/A:100789012606...
2. Cohn JN, Ferrari R, Sharpe N. Cardiac Remodeling - concepts and clinical
implications: a consensus paper from an international forum on cardiac remodeling. J Am Coll
Cardiol. 2000;35(3):569-82, http://dx.doi.org/10.1016/S0735-1097(99)00630-0.
http://dx.doi.org/10.1016/S0735-1097(99)...
3. Swynghedaunw B. Molecular mechanisms of myocardial remodeling. Physiol Rev.
1999;79(1):215-62.-44. Zornoff LAM, Paiva SAR, Duarte DR, Spadaro J. Ventricular remodeling after
myocardial infarction: concepts and clinical implications. Arq Bras Cardiol.
2009;92(2):157-64.). Consequently, our data indicated that
myocardial infarction induced remodeling. It is well accepted that collagen accumulation in
non-infarcted areas is a crucial component of remodeling (55. Zamilpa R, Lindsey ML. Extracellular matrix turnover and signaling during cardiac
remodeling following MI: causes and consequences. J Mol Cell Cardiol. 2010;48(3):558-63,
http://dx.doi.org/10.1016/j.yjmcc.2009.06.012.
http://dx.doi.org/10.1016/j.yjmcc.2009.0...
,66. Dobaczewski M, Gonzalez-Quesada C, Frangogiannis NG. The extracellular matrix as
a modulator of the inflammatory and reparative response following myocardial infarction. J Mol
Cell Cardiol. 2010;48(3):504-11, http://dx.doi.org/10.1016/j.yjmcc.2009.07.015.
http://dx.doi.org/10.1016/j.yjmcc.2009.0...
). In accordance with this concept, LV dilation
was associated with fibrosis and was accessed using biochemical, histological and molecular methods.
Importantly, we found a correlation among periostin and collagen variables, indicating that
periostin might also be a relevant determinant of cardiac fibrosis in the chronic phase after
MI.
Although the relationship between periostin and collagen is indisputable, the association between
periostin and hypertrophy is less apparent. In a model of pressure overload, periostin-null mice
experienced decreased hypertrophy after 8 weeks compared with the control mice (1111. Oka T, Xu J, Kaiser RA, Melendez J, Hambleton M, Sargent MA, et al. Genetic
manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular
remodeling. Circ Res. 101(3):313-21.). However, in another study, periostin did not induce
hypertrophy of differentiated cardiomyocytes (99. Kühn B, del Monte F, Hajjar RJ, Chang YS, Lebeche D, Arab S, et al.
Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat
Med. 2007;13(8):962-9, http://dx.doi.org/10.1038/nm1619.
http://dx.doi.org/10.1038/nm1619...
). In our
study, there was a strong correlation between the periostin level and the LV dimension associated
with an inverse correlation between periostin and cardiac systolic function, suggesting that
periostin can modulate the chronic remodeling process after MI.
In conclusion, our results suggest that periostin might be a modulator of deleterious cardiac remodeling in the chronic phase after MI in rats.
REFERENCES
-
1Pfeffer JM, Finn PV, Zornoff LA, Pfeffer MA. Endothelin-A receptor antagonism during acute myocardial infarction in rats. Cardiovasc Drugs Ther. 2000;14(6):579-87, http://dx.doi.org/10.1023/A:1007890126061.
» http://dx.doi.org/10.1023/A:1007890126061 -
2Cohn JN, Ferrari R, Sharpe N. Cardiac Remodeling - concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J Am Coll Cardiol. 2000;35(3):569-82, http://dx.doi.org/10.1016/S0735-1097(99)00630-0.
» http://dx.doi.org/10.1016/S0735-1097(99)00630-0 -
3Swynghedaunw B. Molecular mechanisms of myocardial remodeling. Physiol Rev. 1999;79(1):215-62.
-
4Zornoff LAM, Paiva SAR, Duarte DR, Spadaro J. Ventricular remodeling after myocardial infarction: concepts and clinical implications. Arq Bras Cardiol. 2009;92(2):157-64.
-
5Zamilpa R, Lindsey ML. Extracellular matrix turnover and signaling during cardiac remodeling following MI: causes and consequences. J Mol Cell Cardiol. 2010;48(3):558-63, http://dx.doi.org/10.1016/j.yjmcc.2009.06.012.
» http://dx.doi.org/10.1016/j.yjmcc.2009.06.012 -
6Dobaczewski M, Gonzalez-Quesada C, Frangogiannis NG. The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction. J Mol Cell Cardiol. 2010;48(3):504-11, http://dx.doi.org/10.1016/j.yjmcc.2009.07.015.
» http://dx.doi.org/10.1016/j.yjmcc.2009.07.015 -
7Frangogiannis NG. Matricellular proteins in cardiac adaptation and disease. Physiol Rev. 2012;92(2):635-88, http://dx.doi.org/10.1152/physrev.00008.2011.
» http://dx.doi.org/10.1152/physrev.00008.2011 -
8Matsui Y, Morimoto J, Uede T. Role of matricellular proteins in cardiac tissue remodeling after myocardial infarction. World J Biol Chem. 2010;1(5):69-80.
-
9Kühn B, del Monte F, Hajjar RJ, Chang YS, Lebeche D, Arab S, et al. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat Med. 2007;13(8):962-9, http://dx.doi.org/10.1038/nm1619.
» http://dx.doi.org/10.1038/nm1619 -
10Shimazaki M, Nakamura K, Kii I, Kashima T, Amizuka N, Li M, et al. Periostin is essential for cardiac healing after acute myocardial infarction. J Exp Med. 2008;205(2):295-303, http://dx.doi.org/10.1084/jem.20071297.
» http://dx.doi.org/10.1084/jem.20071297 -
11Oka T, Xu J, Kaiser RA, Melendez J, Hambleton M, Sargent MA, et al. Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling. Circ Res. 101(3):313-21.
-
12Minicucci MF, Azevedo PS, Martinez PF, Lima AR, Bonomo C, Guizoni DM, et al. Critical infarct size to induce ventricular remodeling, cardiac dysfunction and heart failure in rats. Int J Cardiol. 2011;151(2):242-3.
-
13Duarte DR, Minicucci MF, Azevedo PS, Matsubara BB, Matsubara LS, Novelli EL, et al. The role of oxidative stress and lipid peroxidation in ventricular remodeling induced by tobacco smoke exposure after myocardial infarction. Clinics. 2009;64(7):691-7.
-
14Minicucci MF, Azevedo PS, Santos DF, Polegato BF, Santos PP, Okoshi K, et al. Echocardiographic predictors of ventricular remodeling after acute myocardial infarction in rats. Arq Bras Cardiol. 2011;97(6):502-6, http://dx.doi.org/10.1590/S0066-782X2011005000117.
» http://dx.doi.org/10.1590/S0066-782X2011005000117 -
15Paiva SAR, Novo R, Matsubara BB, Matsubara LS, Azevedo PS, Minicucci MF, et al. β-carotene attenuates the paradoxical effect of tobacco smoke on the mortality of rats after experimental myocardial infarction. J Nutr. 2005;135(9):2109-13.
-
16Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography's guidelines and standards Committee and the chamber quantification writing group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18(12):1440-63, http://dx.doi.org/10.1016/j.echo.2005.10.005.
» http://dx.doi.org/10.1016/j.echo.2005.10.005 -
17Azevedo PS, Minicucci MF, Chiuso-Minicucci F, Justulin LA Jr, Matsubara LS, Matsubara BB, et al. Ventricular remodeling induced by tissue vitamin A deficiency in rats. Cell Physiol Biochem. 2010;26(3):395-402, http://dx.doi.org/10.1159/000320563.
» http://dx.doi.org/10.1159/000320563 -
18Rafacho BP, Santos P, Assalin HB, Ardisson LP, Roscani MG, Polegato BF, et al. Role of vitamin D in the cardiac remodeling induced by tobacco smoke exposure. Int J Cardiol. 2012;155(3):472-3.
-
19Paiva SA, Zornoff LA, Okoshi MP, Okoshi K, Matsubara LS, Matsubara BB, et al. Ventricular remodeling induced by retinoic acid supplementation in adult rats. Am J Physiol Heart Circ Physiol. 2003;284(6):H2242-6.
-
20Zornoff LA, Paiva SA, Minicucci MF, Spadaro J. Experimental myocardium infarction in rats: analysis of the model. Arq Bras Cardiol. 2009;93(4):434-40, http://dx.doi.org/10.1590/S0066-782X2009001000018.
» http://dx.doi.org/10.1590/S0066-782X2009001000018 -
21Zornoff LAM, Matsubara BB, Matsubara LS, Paiva SAR, Spadaro J. Early rather than delayed administration of lisinopril protects the heart after myocardial infarction in rats. Basic Res Cardiol. 2000;95(3):208-14, http://dx.doi.org/10.1007/s003950050183.
» http://dx.doi.org/10.1007/s003950050183 -
22Matsubara LS, Matsubara BB, Okoshi MP, Cicogna AC, Janicki JS. Alterations in myocardial collagen content affect rat papillary muscle function. Am J Physiol Heart Circ Physiol. 2000;279(4):H1534-9.
-
23Snider P, Standley KN, Wang J, Azhar M, Doestschman T, Conway SJ. Origen of cardiac fibroblasts and the role of periostin. Circ Res. 2009;105(10):934-47, http://dx.doi.org/10.1161/CIRCRESAHA.109.201400.
» http://dx.doi.org/10.1161/CIRCRESAHA.109.201400 -
24Norris RA, Moreno-Rodrigues R, Hoffman S, Markwald RR. The many facets of the matricellular protein peristin during cardiac development, remodeling, and pathophysiology. J Cell Commun Signal. 2009;3(3-4):275-86, http://dx.doi.org/10.1007/s12079-009-0063-5.
» http://dx.doi.org/10.1007/s12079-009-0063-5
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No potential conflict of interest was reported.
Publication Dates
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Publication in this collection
Oct 2013
History
-
Received
26 Mar 2013 -
Reviewed
28 Apr 2013 -
Accepted
16 May 2013