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发表于 2009-3-5 10:47 |只看该作者 |倒序浏览 |打印

a First Department of Pathology,

b Second Department of Internal Medicine,9 a# ]( B4 m- J' W, X3 `
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c Regeneration Research Center for Intractable Diseases, Kansai Medical University, Osaka, Japan;+ b# u3 N, t, r( Q- M+ t& X
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d Department of Biotechnology, Kyoto Institute of Technology, Kyoto, Japan;! W" R0 a0 ?2 C
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e Department of Internal Medicine II and Faculty of Medicine, University of Miyazaki, Miyazaki, Japan;, Q* k6 |8 Z( p% z3 r: Z- ^

f Faculty of Pharmaceutical Science, Okayama University, Okayama, Japan  Q# u3 x9 l, j- }6 M9 L3 Z0 [" e
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Key Words. Hepatocyte growth factor ? Doxorubicin-induced cardiomyopathy ? Ultrasound-mediated destruction of microbubbles ? Cardiac progenitor cell

Correspondence: Susumu Ikehara, M.D., Ph.D., First Department of Pathology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi City, Osaka 570-8506, Japan. Telephone: 81-6-6993-9429; Fax: 81-6-6994-8283; e-mail: ikehara@takii.kmu.ac.jp

ABSTRACT+ I+ S$ J6 l! [3 H
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Unlike ischemic cardiomyopathies, which are amenable to procedures like revascularization including therapeutic angiogenesis, nonischemic cardiomyopathies, once they have reached an end stage of drug refractoriness, can only be treated radically by heart transplantation . However, there are several problems in cardiac transplantation such as shortage of donors, rejection of transplanted hearts, and side effects of immunosuppressive therapies . Doxorubicin is used as a potent and broad-spectrum antineoplastic agent prescribed for the treatment of various cancers, including both solid tumors and leukemia. Unfortunately, despite its broad effectiveness, long-term therapy with doxorubicin is associated with a high incidence of a cumulative and irreversible dilated cardiomyopathy followed by congestive heart failure, which is often fatal to the patients . The morphology of the heart of the doxorubicin-induced cardiomyopathy is similar to dilated cardiomyopathy (DCM), in which progressive heart failure and sudden cardiac death from ventricular arrhythmia occur . Therefore, doxorubicin-induced cardiomyopathy is experimentally regarded as a model of DCM . However, the precise mechanism underlying the development of doxorubicin-induced cardiomyopathy remains unclear, although previous data indicate that doxorubicin induces cardiomyopathy through free radicals .- f. S, D/ s1 }' F8 u1 |
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Recent studies have shown that ultrasound-mediated destruction of microbubbles (UMDM) is a promising method for the delivery of bioactive agents to the heart  and that hepatocyte growth factor (HGF) has attractive effects on injured hearts such as antifibrosis, antiapoptosis, antioxidative stress, and angiogenesis . In this study, we demonstrate that the delivery of HGF into the doxorubicin-injured heart using a method of UMDM improves left ventricular (LV) contractile function.

MATERIALS AND METHODS
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rhHGF Delivered by UMDM Improves Cardiac Function
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At the baseline assessment (first examination), the mice in all groups showed significantly lower %FS than untreated mice (Table 1); mean LVDd in untreated mice showed less than 3.0 mm, whereas all groups of doxorubicin-injected mice showed more than 3.0 mm. %FS of untreated mice showed more than 50%, whereas mean %FS of mice treated with doxorubicin showed from 33%–37%.! i0 I7 ~5 O7 ]3 c
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Table 1. Baseline characteristics

A second examination using echocardiography was performed 4 weeks after doxorubicin injection (2 weeks after first examination). In group 1 (Dox), at the second examination, %FS decreased significantly and LVDd increased (Figs. 1, 2); changes in the means of %FS and LVDd from first examination to second examination were from 35% and 3.3 mm to 32% and 3.6 mm, respectively. Similarly to group 1 (Dox), at the second examination, we could not detect any functional improvement in group 2 (Dox, UMDM) or group 3 (Dox, IV-rhHGF) using echocardiography (Fig. 2).
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Figure 1. Doxorubicin induces the dilated cardiomyopathy. Mice were injected intraperitoneally with doxorubicin (20 mg/kg). After 2 weeks, the mice were examined by echocardiography to see whether doxorubicin had induced the cardiomyopathy. Representative data of the changes in left ventricle contractile functions (A) 2 weeks and (B) 4 weeks after doxorubicin injection in the same mouse are shown.
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Figure 2. Changes in %FS and LVDd after treatment with ultrasound-mediated destruction of microbubbles and/or recombinant human hepatocyte growth factor in doxorubicin-injected mice. Two weeks after doxorubicin injection (first examination), LV contractile functions of the mice were examined by echocardiography and the mice were divided into five groups. The mice in each group were treated as described in Materials and Methods. Two weeks after starting the treatment, LV contractile functions were examined again (second examination). %FS and LVDd before and after treatment in each group are shown. Abbreviations: %FS, percent fractional shortening; LVDd, left ventricle dimension at end-diastole; LV, left ventricle.

In contrast with these control groups, echocardiography revealed a significant improvement of LV-contractile function in groups 4 (Dox, IV-rhHGF UMDM) and 5 (Dox, three times ) at the second examination. In group 4 (Dox, IV-rhHGF UMDM), %FS significantly increased, whereas the LVDd remained unchanged (Fig. 2); the changes in means of %FS and LVDd from the first examination to the second examination were from 37% and 3.2 mm to 42% and 3.0 mm, respectively. In group 5 (Dox, three times ), %FS was significantly improved, and the LVDd showed a tendency to decrease (Figs. 2, 3); the changes in means of %FS and LVDd from the first examination to the second examination in group 5 were from 33% and 3.2 mm to 48% and 3.0 mm, respectively. Therefore, LV contractile function in group 4 (Dox, IV-rhHGF UMDM) were improved more than those in control groups (change in %FS: –7.2% ± 6.4% , –16.5% ± 22.9% , –10.2% ± 13.5% , and 15.4% ± 17.7% ). LV contractile functions in group 5 (Dox, three times ) was improved more than that in group 4 (Dox, IV-rhHGF UMDM) (percent change in %FS: 15.4% ± 17.7%  vs. 46.7% ± 19.8% ).

Figure 3. Focal delivery of rhHGF into the hearts by UMDM improves LV contractile functions in doxorubicin-injured hearts. Two weeks after doxorubicin injection, LV contractile functions of the mice were examined by echocardiography (first examination). The mice were then treated with (IV-rhHGF UMDM) in total three times every other day. Two weeks after starting the treatment, LV contractile functions were examined again (second examination). Two representative data of changes in LV contractile functions (A, B) before and (C, D) after treatment in the same mice are shown. Abbreviations: IV-rhHGF, intravenous injection of rhHGF; LV, left ventricle; rhHGF, recombinant human hepatocyte growth factor; UMDM, ultrasound-mediated destruction of microbubbles.
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rhHGF Delivered by UMDM Improves Morphology of Doxorubicin-Injured Heart

To confirm the improvement of the morphology of the hearts in group 5, we macroscopically examined doxorubicin-injured hearts 2 weeks after the repetitive treatments of (IV-rhHGF UMDM). As shown in Figure 4, the heart in group 1 showed a thin LV wall compared with the untreated heart, whereas the heart in group 5 showed a thicker LV wall than that in group 1, being a similar morphology to that of a normal heart. Thus, we confirmed that doxorubicin induces cardiomyopathy and that rhHGF delivered by UMDM improves morphology and function of the doxorubicin-injured heart.
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Figure 4. Morphological improvement of the heart treated with (IV-rhHGF UMDM). Mice in which cardiomyopathy was induced by doxorubicin were treated with (IV-rhHGF UMDM) in total three times every other day. The specimens were stained with hematoxylin and eosin staining. (A, B): Heart of an untreated mouse and the heart of only doxorubicin-treated mouse (group 1), respectively. (C, group 5): Two weeks after starting the treatment, the mice were euthanized and the heart examined for morphological changes. Abbreviations: IV-rhHGF, intravenous injection of recombinant human hepatocyte growth factor; UMDM, ultrasound-mediated destruction of microbubbles.
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rhHGF Induces Proliferations of Cardiomyocytes, |7 p' ]1 k- |" J1 m' T0 s% Q$ C
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Ahmet et al.  have reported that HGF has cardioprotective effects, such as antifibrosis and antiapoptosis, in the canine model of tachycardia-induced cardiomyopathy. However, HGF was initially found to be a potent mitogen of hepatocytes, and we have also reported that HGF has effects on the proliferation of hematopoietic cells . To clarify the mechanisms underlying the improvement of LV contractile function, we examined whether treatment with (IV-rhHGF UMDM) can augment the proliferation of cardiomyocytes. For evaluation of the proliferating activity of cardiomyocytes, we examined the incorporation of BrdU into the cardiomyocytes in groups 1 and 5. We stained the specimens using anti-BrdU Ab, anti-desmin Ab, and 4,6-diamidino-2-phenylindole (DAPI) and have concluded that cardiomyocytes can proliferate because they are positive for desmin and BrdU is incorporated into the nuclei. We confirmed that they are cardiomyocytes based on their morphology and positivity for desmin; DAPI was used to confirm the localization of BrdU because BrdU was incorporated into the nuclei. As shown in Figure 5, many BrdU  cardiomyocytes were found in the heart in group 5 but very few BrdU-positive cardiomyocytes were found in the heart in group 1.& H2 y# R. V3 R( S- e2 c

Figure 5. (IV-rhHGF UMDM) accelerates the proliferation of myocardium. Mice in groups 1 and 5 were also prepared for the examination of in vivo proliferation assay of cardiomyocytes. Two weeks after induction of cardiomyopathy by doxorubicin, the mice were intraperitoneally injected with BrdU, as described in Materials and Methods. At the same time, treatment with (IV-rhHGF UMDM) in total of three times every other day was started in group 5. Two weeks after starting BrdU injection, the mice were euthanized and incorporation of BrdU into the heart was analyzed. (A, B): Incorporation of BrdU into the heart in groups 1 and 5, respectively. Arrows: BrdU  cardiomyocytes (C): Means and SDs of percent BrdU-positive cells in the cardiomyocytes in groups 1 and 5. Abbreviations: BrdU, bromodeoxyuridine; IV-rhHGF, intravenous injection of recombinant human hepatocyte growth factor; UMDM, ultrasound-mediated destruction of microbubbles.! s! H* q  u' ]
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Cardiac Progenitor Cells Can Respond to rhHGF

It has been reported that the progenitor cells of cardiomyocytes exist in the heart . If this is so, the progenitor cells should respond to rhHGF, resulting in proliferating and differentiating into mature cardiomyocytes. First, we examined the expression of c-Met, a receptor for HGF in Sca-1  cardiac cells. We confirmed the existence of Sca-1  cells in the heart; the cells were small and oval-shaped but neither fibroblastic nor cardiomyocytic in shape, as previously reported (Figs. 6A, 6B) . The cells did not express CD45, suggesting that they were not contaminated by hematopoietic stem/progenitor cells, although they expressed c-Met (Fig. 6B). To confirm the expression of c-Met in the Sca-1  cardiac progenitor cells, we performed RT-PCR. As shown in Figure 6C, the heart shows low expression of c-Met, whereas Sca-1  cardiac progenitor cells clearly express c-Met. Next, we examined whether Sca-1  cardiac progenitor cells can proliferate in response to rhHGF. As shown in Figure 6D, thymidine uptake of Sca-1  cardiac progenitor cells increased under the cultured condition with rhHGF compared with the condition without rhHGF, suggesting that Sca-1  cardiac progenitor cells express c-Met and proliferate in response to HGF. These results suggest that Sca-1  cardiac progenitor cells proliferate and differentiate into mature cardiomyocytes in response to rhHGF and contribute to improve cardiac contractile function.

Figure 6. Sca-1  cardiac progenitor cells express c-Met and proliferate in response to HGF. Frozen sections of the heart of the mouse were stained with fluorescein isothiocyanate–labeled anti–Sca-1 mAb, Cy5.5-labeled anti-CD45 mAb, and Alexa555-labeled anti–c-Met Ab, followed by observation with a confocal microscope. (A): Low-power view of the merged photograph. (B): High-power view of the Sca-1  cardiac progenitor cells. (C): mRNA expression of c-Met in Sca-1  cardiac progenitor cells using reverse transcription–polymerase chain reaction. (D): Proliferation responses in Sca-1  cardiac progenitor cells in response to recombinant human HGF. Abbreviations: HGF, hepatocyte growth factor; mAb, monoclonal antibody.; C/ u1 z# G( L# k9 L* D  y1 w
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Bone Marrow Cells Do Not Contribute to This Functional Improvement

It has been reported that bone marrow cells (BMCs) can differentiate into cardiomyocytes . Therefore, we examined whether repetitive treatment with (IV-rhHGF UMDM) induced the differentiation from BMCs into cardiomyocytes in the doxorubicin-injured heart. Two weeks after doxorubicin injection to  mice, the mice were treated with repetitive (IV-rhHGF UMDM). Two weeks after the treatment, we confirmed the improvement in LV contractile function (data not shown), and we prepared frozen sections from the heart and stained these with anti-desmin Ab, followed by staining with rhodamine-conjugated anti-goat Ab. The specimens were observed using a confocal microscope. We could not find any cells expressing both EGFP and desmin (data not shown). It has been reported that mobilized BMCs can differentiate into cardiomyocytes . Recently, we have also reported that immature progenitor cells are mobilized into the peripheral blood from the bone marrow in G-CSF–treated and/or M-CSF–treated mice . Therefore, we performed repetitive treatment with (IV-rhHGF UMDM) after administration of G-CSF plus M-CSF for 5 consecutive days in the  mice. However, we could not find any cells expressing both EGFP and desmin in the heart of the mice (data not shown). These results suggest that BMCs or bone marrow–derived cells cannot differentiate into cardiomyocytes in our system.3 k2 l! S  v. d" o

DISCUSSION

We thank Y. Tokuyama, M. Murakami-Shinkawa, and S. Miura for their expert technical assistance and Hilary Eastwick-Field and K. Ando for their help in the preparation of the manuscript. This work was supported by a grant from Haiteku Research Center of the Ministry of Education, a grant from the Millennium program of the Ministry of Education, Culture, Sports, Science and Technology, a grant from the Science Frontier program of the Ministry of Education, Culture, Sports, Science and Technology, a grant from The 21st Century Center of Excellence (COE) program of the Ministry of Education, Culture, Sports, Science and Technology, a grant from Otsuka Pharmaceutical Company, Ltd., grant-in-aid for scientific research (B) 11470062, grants-in-aid for scientific research on priority areas (A)10181225 and (A)11162221, Health and Labour Sciences research grants (Research on Human Genome, Tissue Engineering Food Biotechnology), a grant from the Department of Transplantation for Regeneration Therapy (sponsored by Otsuka Pharmaceutical Company, Ltd.), a grant from Molecular Medical Science Institute, Otsuka Pharmaceutical Co., Ltd., and a grant from Japan Immunoresearch Laboratories Co., Ltd. (JIMRO).! j9 D' Q8 a1 ]) G- G7 B( r3 R
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DISCLOSURES
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The authors indicate no potential conflicts of interest.
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