Published online before print February 5, 2007, doi: 10.1161/01.HYP.0000258703.36986.13
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(Hypertension. 2007;49:865.)
© 2007 American Heart Association, Inc.
Original Articles |
ß1 Integrins Modulate ß-Adrenergic Receptor–Stimulated Cardiac Myocyte Apoptosis and Myocardial Remodeling
From the Department of Physiology, James H. Quillen College of Medicine, James H. Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City.
Correspondence to Krishna Singh, Department of Physiology, James H. Quillen College of Medicine, East Tennessee State University, PO Box 70576, Johnson City, TN 37614. E-mail singhk{at}etsu.edu
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Abstract |
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Sympathetic nerve activity increases in the heart during cardiac failure. Here, we hypothesized that ß1 integrins play a protective role in chronic ß-adrenergic receptor–stimulated cardiac myocyte apoptosis and heart failure. L-isoproterenol (iso; 400 µg/kg per hour) was infused in a group of wild-type (WT) and ß1 integrin heterozygous knockout (hKO) mice. Left ventricular structural and functional remodeling was studied at 7 and 28 days of iso-infusion. Western blot analysis demonstrated reduced ß1 integrin levels in the myocardium of hKO-sham. Iso-infusion increased heart weight:body weight ratios in both groups. However, the increase was significantly higher in WT-iso. M-mode echocardiography indicated increased left ventricular end-diastolic diameter, percentage of fractional shortening, and ejection fraction in the WT-iso group. The percentage of fractional shortening and ejection fraction were significantly lower in hKO-iso versus hKO-sham and WT-iso. Peak left ventricular developed pressure and left ventricular end-diastolic pressure measured using Langendorff–perfusion analyses were significantly higher in the WT-iso group (P<0.05 versus WT-sham and hKO-Iso). The number of TUNEL-positive myocytes was significantly higher in hKO-iso hearts 7 and 28 days after iso-infusion. The increase in myocyte cross-sectional area and fibrosis was higher in the WT-iso group. Matrix metalloproteinase-9 protein levels were significantly higher in WT-iso, whereas matrix metalloproteinase-2 levels were increased in hKO-iso hearts. Iso-infusion increased phosphorylation of c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 in both groups. The increase in c-Jun N-terminal kinase phosphorylation was significantly higher in hKO-iso (P<0.001 versus WT-iso). Thus, ß1 integrins play a crucial role in ß-adrenergic receptor–stimulated myocardial remodeling with effects on cardiac myocyte hypertrophy, apoptosis, and left ventricular function.
Key Words: ß1 integrins • ß-adrenergic receptor • apoptosis • heart failure • MMPs • JNK
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Introduction |
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Sympathetic nerve activity increases in the heart during cardiac failure. Prolonged stimulation of the ß-adrenergic neurohormonal axis contributes to the progression of heart failure and mortality in animal models and human patients.1,2 Excessive ß-adrenergic receptor (ß-AR) stimulation induces cardiac myocyte apoptosis in vivo and in vitro and cardiac chamber remodeling associated with hypertrophy and/or fibrosis.3–7
Integrins, a family of 
ß-heterodimeric cell surface receptors, link the extracellular matrix (ECM) proteins and the intracellular cytoskeleton. Integrins are demonstrated to play an important role in the regulation of various genes related to cell growth, apoptosis, and hypertrophy.8 Cardiac myocytes predominantly express ß1 integrins.9 Recently, our laboratory has shown that stimulation of ß1 integrin signaling protects cardiac myocytes against ß-AR–stimulated apoptosis in vitro.10,11 ß-AR stimulation increases expression and activity of matrix metalloproteinase (MMP)-2 in cardiac myocytes.12 Evidence has been provided that MMP-2 may interfere with the survival signals induced by ß1 integrin.11 Using myocardial infarction (MI) as a model of myocardial remodeling, we have shown increased cardiac myocyte apoptosis in the myocardium of mice deficient in ß1 integrin.13
Here, we studied the role of ß1 integrins in cardiac myocyte apoptosis and myocardial remodeling after ß-AR stimulation using wild-type (WT) and ß1 integrin–deficient mice. We report that ß1 integrins play a crucial role in ß-AR–stimulated myocardial remodeling with effects on ventricular function, apoptosis, hypertrophy, and fibrosis. To gain an insight into the mechanism by which ß1 integrin affects ß-AR–stimulated myocardial remodeling, we measured protein levels of MMP-2 and MMP-9 and studied activation of extracellular signal regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK).
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Methods |
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Vertebrate Animals
All of the experiments were performed in accordance with the protocols approved by the Institutional Animal Care and Use Committee. Heterozygous knockout mice for ß1 integrins (hKO) and WT mice, purchased from Jackson Research Laboratory, were of 129xblack Swiss hybrid background. Genotyping was performed by PCR. We used hKO mice because ß1 integrin homozygous mice die because of inner cell mass failure and peri-implantation lethality.14
Isoproterenol Infusion
Isoproterenol (iso; 400 µg kg–1 h–1) was infused in age-matched (4-month) mice.15
Echocardiographic Studies
In vivo heart function and chamber dimensions were assessed using a Toshiba Aplio 80 Imaging System as described.16
Langendorff Preparation
Langendorff perfusion analysis was carried out as described.17
Morphometric Studies
After Langendorff studies, the intra-left ventricular (LV) balloon was filled to a diastolic pressure of 5 mm Hg, and the hearts were arrested in diastole with KCl (30 mmol/L) followed by perfusion fixation with 10% buffered formalin.
TUNEL Staining
The staining to detect apoptosis was carried out as per the manufacturer’s instructions (cell death detection assay kit, Roche).
Western Blot Analysis
Lysates from LV tissues were prepared in ice-cold radioimmunoprecipitation assay buffer and analyzed as described.18
Statistical Analyses
Data are represented as mean±SE. Data were analyzed using Student t tests or 1-way ANOVA and a posthoc Tukey’s test. P <0.05 were considered to be significant.
An extended Methods section for iso-infusion, echocardiography, Langendorff preparation, morphometric studies, TUNEL staining, and Western blot analysis is provided in a data supplement available online at http://hyper.ahajournals.org.
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Results |
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ß-AR Stimulation and Levels of ß1 Integrins
Western blot analysis indicated reduced levels of ß1 integrins in the myocardium of the hKO-sham group when compared with WT-sham (P<0.05 versus WT-sham; n=5; Figure 1). Iso-infusion (7 days) did not significantly change the levels of ß1 integrins in WT or hKO groups. Interestingly, appearance of a ß1 integrin immunoreactive band with apparent molecular weight of
55 kDa was observed in both iso-infused groups. The intensity of this 55-kDa fragment was significantly lower in hKO-iso group (P<0.01 versus WT-iso and sham; n=5; Figure 1). Because monoclonal antibodies raised against the extracellular domain of ß1 integrin are used for Western blot analysis, the observed 55-kDa band most likely represents the previously identified extracellular domain of ß1 integrin.19
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P<0.05 vs WT) and fragmented ß1 integrin (*P<0.05 vs WT-iso; #P<0.001 vs sham) normalized to actin.
Morphometric Studies
There was no significant change in body weight 28 days after iso-infusion. The heart weight/body weight ratios were increased in both the iso-groups 28 days after iso-infusion. However, the increase in the heart weight/body weight ratio was significantly higher in the WT-iso group (P<0.05 versus WT-sham and hKO-iso; Table 1). Iso-infusion (7 and 28 days) increased the myocyte cross-sectional area in both groups, which was significantly higher in WT-iso when compared with hKO-iso (Table 1).
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Echocardiographic Parameters
At baseline, there was no difference in LV end-systolic dimension, LV end-diastolic dimension, septal wall thicknesses, percentage of fractional shortening (%FS), and ejection fraction (%) between the WT and hKO groups. A time course change in echocardiographic parameters 7, 14, and 28 days after iso-infusion is depicted in Table S1. Iso-infusion (28 days) increased heart rate in both groups with no significant difference between the 2 iso-groups (Table 2). LV end-diastolic dimension was significantly increased in the WT-iso group but not in hKO-iso group. LV septal wall thicknesses were increased in both iso-groups with no significant difference between the 2 iso-groups. Percentage of FS and ejection fraction (%) were significantly increased in the WT-iso group when compared with WT-sham. In contrast, %FS and ejection fraction (%) were significantly lower in hKO when compared with the hKO-sham and WT-iso groups.
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LV Pressure–Volume Relationships
Langendorff perfusion analysis indicated no differences in the LV-developed pressure– and LV end-diastolic pressure–volume relationship between the 2 sham groups (Figure 2). Iso-infusion (28 days) significantly increased LV-developed pressures, measured over a range of volumes, in the WT-iso (P<0.01 versus WT-sham; Figure 2A) but not in the hKO-iso group. LV-developed pressures at 
20 µL volumes were significantly higher in the WT-iso versus the WT-sham and hKO-iso groups (P<0.05). The maximal LV-developed pressure was significantly higher in the WT-iso group (WT-iso, 88.1±2.3; hKO-Iso, 65.47±2.8 mm Hg; P<0.05). The LV end-diastolic pressure–volume curve exhibited a significant rightward shift in the WT-iso group at volumes 30 µL (P<0.01 versus WT-sham; P<0.05 versus hKO-Iso; Figure 2B), indicating LV dilation.
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Apoptosis and Fibrosis
Iso-infusion (7 days) increased the number of TUNEL-positive myocytes in both of the groups (Figure 3A). However, the percentage of apoptotic myocytes was significantly higher in the hKO group (P<0.001 versus WT-iso; Figure 3B). The percentage of apoptotic myocytes remained higher in hKO-iso (percentage of apoptosis; WT-sham, 0.01±0.002; WT-iso, 0.31±0.01; [P<0.001 versus sham] hKO-sham, 0.01±0.001; hKO-iso, 1.68±0.08; P<0.001 versus WT-iso) 28 days after iso-infusion.
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Quantitative analysis of trichrome-stained sections indicated increased fibrosis in both iso-infused groups (7 and 28 days). However, the increase in fibrosis was significantly higher in the WT-iso as compared with the hKO-iso group (P<0.001 versus WT-sham; P<0.01 hKO-iso; Table 1).
Expression of MMP-2 and MMP-9
Iso-infusion (7 days) increased MMP-2 protein levels in both groups (Figure 4A). However, the increase in MMP-2 was significantly higher in the hKO-iso group (P<0.05 versus sham; P<0.01 versus WT-iso; n=4 to 5; Figure 4A) and remained higher in hKO-iso as compared with WT-iso (P<0.05 versus WT-iso; n=3 to 4; Figure 4B) 28 days after iso-infusion. Iso-infusion (7 days) increased MMP-9 protein levels only in the WT-iso (Figure 4A) but not in the hKO-iso group (P<0.01 versus WT-sham; P<0.01 versus hKO-iso; n=4 to 5). In fact, MMP-9 protein levels were significantly lower in hKO-iso as compared with hKO-sham (P<0.05 versus hKO-sham). MMP-9 protein levels were increased to a similar extent in both groups 28 days after iso-infusion (Figure 4B).
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Activation of ERK1/2 and JNK
To investigate intracellular signaling pathways, we measured the activation of mitogen-activated protein kinases (ERK1/2 and JNK).20 Phosphorylation of ERK1/2 was increased to a similar extent in both groups 7 days after iso-infusion (Figure 5A). However, phosphorylation of ERK1/2 was significantly higher in hKO-iso as compared with the WT-iso and sham groups (P<0.001 versus hKO-sham; P<0.05 WT-iso; Figure 5B) 28 days after iso-infusion. Iso-infusion (7 days) increased JNK phosphorylation in both groups. However, the increase was significantly higher in the hKO-iso group (P<0.001 versus hKO-sham; P<0.05 versus WT-iso; n=4; Figure 5A). JNK phosphorylation remained higher in hKO-iso as compared with the hKO-sham and WT-iso groups (P<0.05 versus hKO-sham; P<0.05 versus WT-iso; n=4 to 5; Figure 5B) 28 days after iso-infusion.
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Discussion |
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Previously, we have provided evidence that ß1 integrins play a protective role in ß-AR–stimulated apoptosis in adult rat cardiac myocytes.10 The important finding of the present study is that ß1 integrins play a crucial role in ß-AR–stimulated myocardial remodeling with effects on cardiac myocyte hypertrophy, apoptosis, and LV fibrosis and function. ß-AR stimulation increased cardiac hypertrophy, apoptosis, and fibrosis in both WT and ß1 integrin-deficient mice. However, the increase in fibrosis and hypertrophy was higher in the WT-iso group, whereas the increase in the number of cardiac myocyte apoptosis was higher in the hKO-iso group. Activation of JNK and MMP-2 protein levels was higher in the hKO-iso group 7 and 28 days after iso-infusion, whereas MMP-9 protein levels were higher in the WT-iso group 7 days after iso-infusion.
Cardiac myocytes predominantly express ß1 integrins.9 The expression of ß1 integrins increases in the heart post-MI.13 In the present study, we did not observe an increase in intact ß1 integrin protein levels 7 days after iso-infusion. This is consistent with our previous finding, where ß-AR stimulation failed to increase the expression of ß1 integrins in adult rat cardiac myocytes.10 The monoclonal antibody against ß1 integrin recognized a 55-kDa fragment in both iso-infused hearts. Levels of a 55kDa ß1 integrin fragment (extracellular domain) are shown to be increased in the heart during cardiac hypertrophy and heart failure.19 Using adenoviruses expressing a chimeric receptor consisting of the cytoplasmic tail domain of ß1A and the extracellular/transmembrane domain of the interleukin-2 receptor (TAC-ß1), we provided evidence that expression of the cytoplasmic domain of ß1 integrin induces apoptosis in adult rat ventricular myocytes.18 Shedding of ß1 integrin is proposed as a mechanism of cellular adaptation during cardiac hypertrophy.19 The increased ß1 integrin fragmentation in the WT heart versus the ß1 integrin-deficient heart may relate to adaptation to hypertrophy 7 days after iso-infusion.
ß1 integrins participate in the hypertrophic response of cardiac myocytes.21,22 Ventricular hypertrophy is an important compensatory mechanism that allows the heart to maintain its output. Chronic ß-AR stimulation is shown to increase heart rate and LV systolic function.23–25 Heart weight/body weight ratio (7 days) and myocyte cross-sectional area (7 and 28 days), indicators of hypertrophy, were higher in WT-iso versus hKO-iso. ß-AR stimulation increased heart rates to a similar extent in both iso-infused groups. Our observations of decreased cardiac function in ß1 integrin-deficient mice are consistent with the previous findings, where cardiac myocyte-specific excision of ß1 integrins led to depressed LV basal and dobutamine-stimulated contractility and relaxation as compared with the control group.26 It is interesting to note that ß-AR stimulation increased LV end-diastolic dimension only in the WT group, indicating increased LV dilatation in the WT-iso group. It is possible that the increased compensatory hypertrophic response in WT-iso mice may contribute to higher contractility of the myocardium over and above the inhibitory effects of LV dilatation. The functional data obtained using chronic ß-AR stimulation are distinctive from those obtained from MI as a model of myocardial remodeling.13 MI was associated with significantly increased LV end-systolic dimension and LV end-diastolic dimension with decreased %FS in ß1 integrin-deficient mice versus WT mice. Chronic ß-AR stimulation decreased %FS in ß1 integrin-deficient mice with no effect on LV end-diastolic dimension and LV end-systolic dimension. The reasons for the distinct findings may include fundamental differences between the 2 models. MI is suggested to induce an amalgam of patterns in which stretched and dilated infarcted tissue increases left-ventricular volume with a combined volume and pressure load on noninfarcted areas.27 Circulating levels of norepinepinephrine are shown to be increased in the rat post-MI.28 Treatment of rats using metoprolol, a ß1-AR–selective antagonist, is shown to partially reverse the remodeling process post-MI.29 However, angiotensin-converting enzyme inhibition remains the mainstay of clinical therapy, with new impressive data for the addition of aldosterone blockade and ß-AR blockade.27 It is also possible that ß1 integrin-deficient mice may exhibit increased LV end-diastolic dimension and LV end-systolic dimension if the observation time is extended beyond 1 month.
Cardiac myocyte apoptosis is suggested to play a crucial role in the pathogenesis of heart failure. Reduction in cardiac myocyte apoptosis by caspase inhibition improved LV function and survival in pregnant Gq mice.30 On the other hand, activation of MMP, specifically MMP-2, is suggested to decrease cardiac tissue tensile strength and cause systolic and diastolic dysfunction.31,32 Cardiac-specific expression of MMP-2 induces the development of cardiac contractile dysfunction in the absence of superimposed injury.33 Targeted deletion of MMP-2 attenuates early rupture and improves %FS in mice post-MI.34 MMP-2 is also shown to be associated with increased cardiac myocyte apoptosis after ß-AR stimulation.12 Here, we observed increased cardiac myocyte apoptosis and levels of MMP-2 in the myocardium of ß1 integrin-deficient mice as compared with WT 7 and 28 days after iso-infusion. Collectively, these data suggest that increased cardiac myocyte apoptosis and/or expression of MMP-2, at least in part, may play a role in decreased LV function in ß1 integrin-deficient mice. Previously, we have provided evidence that MMP-2 interferes with the survival signals of ß1 integrin and activates the JNK-dependent mitochondrial death pathway leading to apoptosis.11 Activation of JNK is suggested to play a proapoptotic role in ß-AR–stimulated apoptosis.35 Iso-infusion (3 mg/kg per day) for 6 hours to 7 days is shown to activate JNK, not ERK1/2, in rat hearts.24 We observed a greater increase in JNK activation in ß1 integrin-deficient mice after iso-infusion. Taken together, these studies suggest that increased MMP-2 expression and activity may induce cardiac myocyte apoptosis in ß1 integrin-deficient mice via the involvement of the JNK-dependent mitochondrial pathway.
Chronic sympathetic stimulation is shown to induce growth of interstitial tissue in the heart leading to fibrosis.7 MMPs play an important role in the remodeling of ECM.36 Of these, expression of MMP-2 is of particular interest, because MMP-2 degrades ECM substrates including type IV collagen, laminin, elastin, and interstitial fibrillar collagen.37–39 The data presented here suggest that deficiency of ß1 integrin may increase MMP-2 expression and activity leading to decreased interstitial fibrosis. Recently, lack of MMP-2 is shown to be associated with decreased myocardial fibrosis and hypertrophy in response to chronic pressure overload.40 The reasons for these contrasting findings are not yet clear. Deposition of interstitial fibrosis may represent a complex function of both collagen synthesis and deposition. It is interesting to note that 1 integrin-null mice exhibit increased expression of MMP-7 and MMP-9.41
Perspectives
The data presented here suggest that ß1 integrins play a crucial role in chronic ß-AR–stimulated LV dysfunction with effects on cardiac myocyte apoptosis, hypertrophy, and fibrosis. It is interesting to note that deficiency of ß1 integrins is associated with decreased systolic function and increased cardiac myocyte apoptosis. On the other hand, hypertrophic response, fibrosis, and LV dilation were significantly lower in ß1 integrin-deficient mice. These data suggest that ß1 integrin may play a beneficial role in the preservation of systolic function, whereas a decrease in ß1 integrins may be beneficial for cardiac diastolic function. The structural changes in myocardial ECM are considered to play an important role in the modulation of myocardial function and in the progression to heart failure. Analysis of components of ECM, including laminin, collagen type I and IV, fibronectin, and so forth, may provide insights into the regulation of heart function by ß1 integrins. Furthermore, chronic stimulation of ß1-AR subtype induces hypertrophy and apoptosis, whereas stimulation of ß2-AR promotes cell survival. Elucidation of processes that can shift the balance from apoptosis to cell survival during chronic ß-adrenergic stimulation may have important clinical implications.
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Acknowledgments |
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Sources of Funding
This work is supported by National Institutes of Health grant HL-071519 (K.S.), a merit review grant from the Department of Veterans Affairs (K.S.), and a postdoctoral fellowship from the American Heart Association, Southeast Affiliate 0525338B (P.K.).
Disclosures
None.
Received October 9, 2006; first decision October 29, 2006; accepted January 14, 2007.
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