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Ann Thorac Surg 2008;85:562-570. doi:10.1016/j.athoracsur.2007.06.002
© 2008 The Society of Thoracic Surgeons
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Right arrow Myocardial infarction

Original Articles: Cardiovascular

Therapeutic Effect of Midkine on Cardiac Remodeling in Infarcted Rat Hearts

Shinya Fukui, MDa, Satoru Kitagawa-Sakakida, MD, PhDb, Sin Kawamata, MD, PhDc, Goro Matsumiya, MD, PhDa, Naomasa Kawaguchi, PhDd, Nariaki Matsuura, MD, PhDd, Yoshiki Sawa, MD, PhDa,*

a Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
b Molecular Pharmacology, Osaka University Graduate School of Medicine, Osaka, Japan
c Foundation for Biomedical Research and Innovation, Kobe, Japan
d Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan

Accepted for publication June 1, 2007.

* Address correspondence to Dr Sawa, Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan (Email: yshksw{at}hotmail.com).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Midkine is expressed in the developing fetus and in adult organs stressed by ischemia, but its physiologic role in ischemic organs is poorly understood. Here we investigated the effect of midkine on cardiac remodeling after ischemia caused by myocardial infarction.

Methods: The expression pattern of the endogenous midkine gene in rat heart was evaluated by real-time polymerase chain reaction for 2 weeks after myocardial infarction. To investigate its effect, recombinant midkine was injected into hearts 2 weeks after myocardial infarction, and cardiac functions were monitored by echocardiography. Six weeks later, the hearts were removed, and the areas of infarcted and viable tissue and the extent of cardiomyocyte hypertrophy were determined histologically.

Results: The midkine gene was strongly upregulated in the infarcted myocardium, but this upregulation lasted less than 2 weeks. Cardiac remodeling was significantly and dose-dependently attenuated by midkine treatment. The midkine treatment also increased collagen accumulation and facilitated angiogenesis in the infarcted area, and the viable muscle area after myocardial infarction dose-dependently increased. Despite this increase of viable muscle area, the midkine-treated hearts showed significantly less cardiomyocyte hypertrophy than vehicle-treated hearts, suggesting midkine had prevented chronically ischemic cells from dying and dropping out by angiogenesis.

Conclusions: Our results indicate midkine can attenuate cardiac remodeling after myocardial infarction, and suggest midkine has therapeutic potential for subacute myocardial infarction.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Progress in the treatment of myocardial infarction (MI) has significantly reduced acute mortality from ischemic cardiomyopathy. As a result, however, a large number of patients suffer from chronic heart failure caused by the loss of the infarcted myocardium. Patients with postinfarction heart failure account for nearly half of the candidates for cardiac transplantation [1]. Currently, heart transplantation is the only curative procedure for end-stage heart failure. However, cardiac transplantation is limited by donor heart availability. Therefore, an important goal for treating MI is to protect the heart by preventing the cardiac remodeling induced by the loss of myocardium.

Several cytokines, including granulocyte colony-stimulating factor, hepatocyte growth factor, insulinlike growth factor-1, and leukemia inhibitory factor have beneficial effects on cardiac remodeling after myocardial infarction [2–6]. These cytokines mobilize bone-marrow–derived cells to the injured heart after MI and induce the regeneration of myocardium or prevent the activation of cell death in the viable myocardium after infarction, limiting the ventricular dilation and myocardial loading.

Midkine (MDK) is a developmentally regulated cytokine and is highly conserved from Drosophila to human. Midkine has been implicated in neural development, neurodegenerative diseases, and certain cancers. Midkine is expressed in the radial glial processes of the embryonic brain, along which neural stem cells migrate and differentiate [7, 8]. Midkine shows mitotic, antiapoptotic, and angiogenic activities, which are the basic property required for the regeneration of injured tissues, not only in developing neural tissues but also in the adult brain [7–9]. Furthermore, some reports suggest that MDK is expressed in and contribute to the repair of injured extraneural organs, including the liver and heart [10–13]. In addition, MDK stimulates collagen by enhancing the expression of transforming growth factor-β1 [14].

Here, we examined the expression of MDK in rat hearts after MI and tested whether MDK could have therapeutic effects on subacute MI heart through its stimulation of collagen expression and their angiogenic, antiapoptotic, and growth-promoting activities.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Animals and Surgical Procedures
Male Lewis rats were used at 8 weeks of age (weight, 220 to 250 g [Seac Yoshitomi, Fukuoka, Japan]). All animals received humane care under the Guidelines on Animal Experiments of Osaka University Graduate School of Medicine and the Japanese Animal Protection and Management Law. The rats were anesthetized with ketamine (90 mg/kg) and xylazine (10 mg/kg); and MI was produced by ligation of the left anterior descending coronary artery (LAD) under mechanical ventilation, as described [15]. Two weeks after the ligation, baseline cardiac functions were measured, and the infarcted rats were treated by injecting various doses of recombinant human MDK (R&D Systems, Minneapolis, Minnesota) into the border-zone myocardium at four sites. The injections were performed by reopening the left thorax of the animals under the same anesthesia. The cytokine was given in doses of 1, 5, or 25 µg in 200 µL collagen gel using a 30G needle, as previously described [16]; and the control rats received collagen gel alone (n = 10 for each subgroup). Collagen gel was used to avoid the loss of the protein when it was injected into the heart.

Time Course of MDK Gene Expression After MI
Infarcted and noninfarcted left ventricular (LV) myocardium from the LAD-ligated rats was removed 4, 7, 14, or 56 days after the ligation and immediately stored in RNAlater solution (QIAGEN, Hilden, Germany) until use (n = 5 for each time point). The infarcted border was included in the infarcted area. Native myocardium from 15 normal rats was also removed and used as reference samples. Total RNA was extracted with the RNeasy mini kit (QIAGEN), and the relative levels of transcripts from the MDK genes were measured by the real-time quantitative polymerase chain reaction technique using the ABI PRISM 7700 sequence detection system [17]. The nucleotide sequences for the forward primers, reverse primers, and TaqMan probes were as follows. Rat MDK: forward, CGG ATG GTC TCC TGG CAC; reverse, AGC AAG GAC TGC GGC ATG; and probe, GCC ACA CGC CCC CCA GCT. The average copy number of gene transcripts in each sample was normalized to GAPDH, and the fold induction was calculated using the formula: Fold induction = normalized value in a sample after MI divided by average of the normalized value from the 15 reference myocardium samples.

Echocardiographic Assessment of Cardiac Function
The LV functions of the treated rats were monitored by echocardiograph 2, 4, and 6 weeks after the injection and compared with echocardiographs taken before the injection (baseline). Cardiac ultrasonography was recorded with a SONOS 5500 (Agilent Technologies, Palo Alto, California) using a 12-MHz annular array transducer under slight anesthesia with diethyl ether. The hearts were imaged in short-axis two-dimensional views at the level of the papillary muscles, and the LV end-systolic area, LV end-diastolic area, and LV dimensions at end systole (LVDs) and end diastole (LVDd) were determined. The ejection fraction (EF) was calculated by Pombo’s method, as EF (%) = (LVDd3 - LVDs3) / LVDd3 x 100. Heart rate and blood pressure were continuously recorded during the measurements, with a Model MK-2000 blood pressure monitor (Muromachi Kikai, Tokyo, Japan) using the indirect tail cuff method.

Histologic Examinations
Six weeks after the injection, all the treated hearts were stopped at diastole by the infusion of a cold cardioplegia solution (24 mEq/L potassium in a 5% glucose solution) and removed. The hearts were then sectioned horizontally through the center of the infarcted area. All the samples were fixed with 10% buffered formalin and embedded in paraffin. Routine hematoxylin-eosin and Masson’s trichrome staining were performed, and picro-sirius red staining to analyze collagen accumulation or periodic acid-Schiff staining for cardiomyocyte hypertrophy was performed in specific treatment groups, as described [[18, 19]. Quantitative morphometric analysis for each sample was performed with MacScope software (Mitani, Tokyo, Japan). The collagen volume fraction in the infarcted and the noninfarcted area was calculated as the percentage of red-stained tissue in the sum of muscle area and connective tissue. The data were collected from 10 fields per section per animal at a magnification of x200. For the myocyte cell size, we randomly selected 10 fields from each ventricle, obtained images at a magnification of x400, and 5 myocytes were randomly chosen per field. The averaged results from the 10 hearts in each group are shown. In addition, deparaffinized 2-µm–thick sections of the hearts removed 6 weeks after injection were stained with an anti–von Willebrand factor antibody (A0082; Dako, Glostrup, Denmark) to assess the vascular density for each treatment group.

For the MDK staining shown in Figure 1B, the hearts were removed 1 week after the LAD ligation and stored at –80°C (n = 5). Frozen sections, 5-µm thick, were incubated with polyclonal goat anti-rat MDK serum (sc-1398; Santa Cruz Biotechnology, Santa Cruz, California) and visualized using an ABC kit (Vector Laboratories, Burlingame, California) 20].


Figure 1
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  		Fig 1. (A) Expression of midkine (MDK) mRNA in infarcted rat hearts. Open symbols represent the infarcted left ventricular myocardium, and closed symbols represent the noninfarcted myocardium of ligated left anterior descending artery (LAD) Lewis hearts. (B) Immunohistochemical staining for MDK protein showed MDK in the surviving cardiomyocytes of the border zone and infarcted area (arrowhead) but not in the noninfarcted area of the heart after myocardial infarction. Left, border-zone area in the hematoxylin-eosin–stained heart; middle, border-zone area in the anti-MDK–stained heart; right, noninfarcted area in the anti-MDK-stained heart.

 
Statistical Analysis
All data are expressed as the mean ± SE. The time-course data of cardiac functions were subjected to two-way repeated measurement multiple analyses of variance (ANOVA) using StatView 5.0 (Abacus Concepts, Berkeley, California), and an unpaired Student’s t test was used to verify the difference between the indicated groups. Other comparisons were performed by one-way ANOVA with Bonferroni’s post hoc test or an unpaired Student’s t test. All p values less than 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Expression of the MDK Gene After Myocardial Infarction
A low but detectable level of MDK mRNA was expressed in normal rat myocardium (MDK/GAPDH, 0.00083 ± 0.00008, n = 15), and an increased expression was induced after MI (Fig 1A). This expression peaked 7 days after LAD ligation and rapidly decreased by 14 days after the ligation. This strong induction was not observed in noninfarcted myocardium. The MDK mRNA level in the infarcted area increased roughly 18-fold, compared with the average of the normalized value from native Lewis rats. Immunohistochemical analysis revealed that the cells expressing MDK were the surviving cardiomyocytes in the border zone between the infarcted and noninfarcted tissue and in the infarcted areas, but not those in the noninfarcted areas (Fig 1B).

Left Ventricle Functional Analysis
Cardiac functions were monitored every other week under stable hemodynamic conditions (Table 1). The LV end-diastolic area, LV end-systolic area, EF, heart rate, and mean blood pressure at baseline were not significantly different among the treatment groups. In the gel-treated control group, both the LV end-diastolic area and LV end-systolic area gradually increased, and the difference from baseline reached significance at 6 weeks (Figs 2A, B, and Table 1). The EF of the gel-treated control hearts decreased continuously from 2 to 6 weeks after the treatment (Fig 2C and Table 1). In contrast, the change in the LV end-diastolic area and LV end-systolic area of hearts treated with 25 µg MDK were minimal and were significantly smaller than those observed for the gel-treated control hearts (Figs 2A and B). In addition, the EF of the MDK-treated hearts at 4 or 6 weeks was significantly better than that of the gel-treated control hearts (Fig 2C). This effect of inhibiting LV remodeling after MI was dependent on the dose of MDK injected (Fig 2D and Table 1).


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  		Table 1 Cardiac Functions of Infarcted Rat Hearts After Midkine (MDK) Injection
 

Figure 2
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  		Fig 2. Echocardiographic assessments of cardiac function after midkine (MDK) treatment. Changes in left ventricular (LV) end-diastolic area (A), LV end-systolic area (B), or ejection fraction (C) from baseline measurements for the groups treated with gel alone (open symbols) or with 25 µg recombinant MDK (closed symbols). Repeated measurement analysis of variance indicated that the two curves were significantly different (A, p < 0.01; B, p < 0.05; C, p < 0.01), and the comparisons at each time point also indicated significant differences (*p < 0.05; **p < 0.01 versus control [Cont.]). This attenuation of LV remodeling was dose dependent, as judged from the change in LV end-diastolic area 6 weeks after treatment (D) (*p < 0.05 versus control).

 
Histologic Basis for Attenuation of LV Remodeling
The gross appearance of hearts treated with gel alone or with 25 µg recombinant MDK is shown in Figure 3A. In the short-axis sections through the center of the MI, the infarct scar area, stained blue, was thinner and longer in the gel-treated control group (Figs 3B and C), but the total calculated MI area was not significantly affected by any dose of MDK injected (Fig 3D). On the other hand, the noninfarcted myocardium of the hearts that received 25 µg MDK appeared thick, and represented a significantly larger area than that of the gel-treated control hearts (Fig 3E). The increase in the noninfarcted area in the MDK-treated hearts was MDK-dose dependent.


Figure 3
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  		Fig 3. Morphometric analysis of infarcted rat hearts after midkine (MDK) treatment. Hearts treated with gel alone or with 25 µg MDK were stained with Masson’s trichrome, and two representative sections from each group are shown. (A) Left, gel-alone treated control; right, MDK treated. Note the smaller left ventricle cavity and thicker infarct scar and left ventricular muscle in the MDK-treated hearts. (B, C) The thickness and the length of the myocardial infarction (MI) area were thicker and shorter in the MDK-treated hearts. (D) The infarct scar area was not significantly affected by any dose of MDK injected. (E) The area of the noninfarcted muscle was dose-dependently increased by the injection of MDK. (Each group, n = 10.) (EF = ejection fraction; LVEDA = left ventricular end-diastolic area; W = weeks.)

 
Collagen Volume Fraction in Infarcted and Noninfarcted Area
Microscopic evaluation using picro-sirius red staining showed a significantly greater collagen volume fraction in the infarcted area of the MDK-treated hearts that was compatible with thicker infarcted scar (Fig 4). However, the collagen volume fraction in the noninfarcted myocardium of the MDK-treated hearts was significantly less than in the gel-treated control hearts (Fig 4). The collagen volume fraction in the noninfarcted area of gel-treated control hearts was homogenous, reflecting LV remodeling after MI (Fig 4).


Figure 4
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  		Fig 4. Assessment of the collagen volume fraction (CVF) in the gel-treated control and midkine (MDK)-treated hearts. Sections of heart were stained with picro-sirius red staining. Infarcted area in the MDK-treated hearts showed striking accumulation of collagen (A, upper left: gel-alone treated control; upper right: MDK-treated in the infarcted area). The gel-treated control hearts revealed homogeneous collagen volume fraction in their noninfarcted myocardium (A, lower left: gel-treated control; lower middle: MDK-treated in the noninfarcted area; lower right: age-matched normal rat hearts). (B) Left, the collagen volume fraction in the infarcted area was significantly greater in the MDK-treated hearts than in the gel-treated control hearts. Right, the collagen volume fraction in the MDK-treated hearts was significantly less in the noninfarcted area. (MI = myocardial infarction.)

 
Effect of MDK on Angiogenesis
We assessed the vascular density of hearts treated with gel alone or with 25 µg MDK (Fig 5A). Von Willebrand factor-positive vessels were prominent in the infarct scar and border-zone areas of the MDK-treated hearts. The vascular density was significantly greater in the MDK-treated hearts than in the gel-treated control ones (Fig 5B). The number of vessels in the noninfarcted area was relatively low, and it was not possible to reliably compare their numbers between the control and MDK-treated hearts.


Figure 5
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  		Fig 5. Assessment of vascular density in the gel-treated control and midkine (MDK)-treated hearts. (A) Sections of heart were stained with an antibody to von Willebrand factor, and most of the positive vessels were observed in the infarct scar area or the border zone of the MDK-treated hearts (upper: low magnification; lower: high magnification). (B) The vascular density in the MDK-treated hearts was more than twice that in the gel-treated control hearts. Arrowheads indicate von Willebrand factor-positive vessels.

 
Cardiomyocytes Less Hypertrophic in MDK-Treated Hearts Than in Controls
To clarify the cellular basis for the increase in the noninfarcted area in the MDK-treated hearts, the cardiac myocyte remodeling was assessed using periodic acid-Schiff staining (Fig 6A). Cardiomyocytes in the gel-treated control group had a significantly greater diameter (Fig 6B), length (Fig 6C), and cell size (Fig 6D), reflecting volume and pressure overloads after the MI, than those in the MDK-treated hearts.


Figure 6
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  		Fig 6. Assessment of cardiac myocyte remodeling in the gel-treated control and midkine (MDK)-treated hearts. (A) Hearts treated with gel alone or 25 µg MDK were periodic acid-Schiff stained. Age-matched normal Lewis hearts were stained for comparison. The cardiomyocyte width (B), length (C), and cell size (D) were measured. The cardiomyocytes of the MDK-treated hearts were significantly less hypertrophic than those of the gel-treated control hearts, although the cells were still significantly hypertrophic compared with the normal cardiomyocytes.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
In this study, we found that the level of MDK transcripts rapidly increased in the adult rat myocardium after infarction. The expression level was high but transient, peaking at 1 week and recovering to near-normal levels as early as 2 weeks after the infarction, when LV remodeling started to progress. The injection of MDK 2 weeks after the MI significantly attenuated the subsequent LV remodeling and myocardial fibrosis. The wall of the infarcted area was thicker and the collagen accumulation in the infarcted area was greater in the MDK-treated hearts than in the controls. Vascular density in the infarcted and border areas was greater in the MDK-treated hearts than in the controls. The area of the noninfarcted myocardium was greater, but there was less cardiomyocyte hypertrophy in the MDK-treated hearts than in the controls.

Previous studies reported that MDK expression is induced in stressed adult organs such as the ischemic heart and kidney [12, 13, 21]. Our findings clarified the time course of the increased expression level of MDK in a rat model of MI. Although the increased expression was transient, the selective expression of MDK by the surviving cardiomyocytes suggested it might be an incomplete rescue signal from hearts suffering ischemic damage. Furthermore, MDK has been recently reported to play a protective role against cardiac ischemia and reperfusion injury through prevention of apoptosis [13]. Therefore, we began investigating the role of MDK by injecting it into infarcted hearts 2 weeks after the MI, when LV remodeling started to progress.

Cardiac remodeling after MI, which is clinically defined by changes in the LV size, shape, and function, appears to be compensatory initially, but has generally adverse effects and is linked to the progression of heart failure. Histologically, cardiomyocyte hypertrophy and interstitial fibrosis are usually observed in the remodeled heart, and a larger LV cavity correlates with a poorer prognosis for patients with coronary artery disease [22–24]. Thus, it is now widely believed that cardiac remodeling is an important therapeutic target in patients with MI.

Because three dependent factors, that is, infarct size, infarct healing, and ventricular wall stresses, are known to influence the process of ventricular enlargement [22], we investigated histological changes in the hearts treated with MDK. In our study, the wall thickness and the collagen volume fraction of the infarcted area were thicker and greater in the MDK-treated hearts, although the infarct size was not affected by MDK. For infarct healing and ventricular wall stress, the amount of collagen accumulation in the infarcted area is important in LV function after MI [25]. A thickened and strong wall could overcome ventricular wall tension. A previous study showed that granulocyte colony-stimulating factor administration after MI attenuates postinfarct ventricular expansion, in association with increased transforming growth factor-β1 and collagen expression in the infarcted area [18]. Midkine was also reported to enhance the migration of inflammatory cells upon ischemic injury, upregulate the expression of transforming growth factor-β1, and stimulate collagen production [14, 21]. In our study, the improved cardiac function and prevention of LV enlargement may have been the consequences of an altered inflammatory reaction affecting collagen within the infarct zone.

Another possible explanation for the attenuation of LV remodeling is that angiogenesis in the border area might prevent cardiomyocytes at risk of ischemia from dropping out as we previously observed an angiogenic effect of hepatocyte growth factor in the same infarcted rat model [26, 27]. After MI, the infarcted area is gradually extended owing to the subsequent death of cardiomyocytes in the border area, and expands by abnormal wall tension. Myocardial ischemia plays a critical role in cardiomyocyte death in the border area after MI and greatly affects LV remodeling. Therefore, we injected MDK, which has angiogenic activity, into border zone to induce angiogenesis. In previous reports, MDK was found to have an angiogenic role in the increased proliferation of endothelial cells, an effect that is increased by interleukin-8 in vitro [28, 29]. We observed shorter MI regions and greater angiogenesis in the border and infarcted areas of the MDK-treated hearts compared with controls. These data suggest that MDK facilitated angiogenesis, increased perfusion, and prevented the chronically ischemic cells at the border zone from dropping out.

Other effects of MDK were an increased area of viable noninfarcted muscle and LV wall thickening, which typically occur as the overloaded heart tries to normalize wall stress. The development of myocardial fibrosis in the noninfarcted area, which is associated with remodeling after MI, was also inhibited in the MDK-treated hearts, further supporting the idea that the injection of MDK could have beneficial effects on hearts with subacute MI.

In previous studies [3–6], insulinlike growth factor-1, hepatocyte growth factor, and granulocyte colony-stimulating factor were shown to prevent the ventricular remodeling of hearts with experimental MI. All these factors normalized the wall stress of the infarcted hearts by thickening the LV myocardial wall, although they caused the cardiomyocytes to hypertrophy. In our study, the noninfarcted myocardium in the MDK-treated hearts was enlarged, but the cardiomyocytes were significantly less hypertrophic than those in the gel-treated control hearts. This result may suggest that the number of cardiomyocytes was greater in the MDK-treated hearts than in the gel-treated hearts, considering the reported anti-apoptotic and growth-promoting actions of MDK [30–32]. It is possible that MDK somehow affects the turnover of cardiomyocytes after MI, and studies to directly evaluate the effect of MDK on cardiomyocytes are now under way.

This study has the following limitations. The route and timing of the MDK administration need to be fully tested to determine the best way to treat MI with MDK. For example, continuous intravenous administration would be easier or safer than direct injection into the myocardium. In addition, it is reasonable to speculate that a more dramatic effect might be seen if MDK were given sooner after the MI, for example, before the completion of cardiomyocyte death. Moreover, not only the cellular mechanism discussed above but also the molecular mechanisms for the effects of MDK remain to be clarified.

In conclusion, despite these limitations, this study indicates that MDK may play angiogenic and collagen-stimulative roles in the subacute MI rat heart. Our findings suggest that MDK plays a crucial role in LV remodeling in patients with subacute MI, although further studies are necessary to determine any deleterious consequences of its use.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
The authors thank Masako Yokoyama, Dr Atsuhiro Saito, and Dr Tsuyoshi Takahashi for their excellent technical assistance. This work was supported by a Grant-in-Aid from the Japanese Ministry of Education, Science, and Culture (18390376).


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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 Am. J. Physiol. Heart Circ. Physiol.Home page
H. Takenaka, M. Horiba, H. Ishiguro, A. Sumida, M. Hojo, A. Usui, T. Akita, S. Sakuma, Y. Ueda, I. Kodama, et al.
Midkine prevents ventricular remodeling and improves long-term survival after myocardial infarction
Am J Physiol Heart Circ Physiol, February 1, 2009; 296(2): H462 - H469.
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