Ann Thorac Surg 2006;81:2217-2225
© 2006 The Society of Thoracic Surgeons
Original article: Cardiovascular
Pravastatin Improves Remodeling and Cardiac Function After Myocardial Infarction by an Antiinflammatory Mechanism Rather than by the Induction of Angiogenesis
Tao-Sheng Li, MD
*
,
Masaya Takahashi, MD,
Ryo Suzuki, MD,
Toshiro Kobayashi, MD,
Hiroshi Ito, MD,
Akihito Mikamo, MD,
Kimikazu Hamano, MD
Division of Cardiovascular Surgery, Department of Medical Bioregulation, Yamaguchi University School of Medicine, Yamaguchi, Japan
Accepted for publication December 20, 2005.
* Address correspondence to Dr Li, Department of Medical Bioregulation, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan; (Email: litaoshe{at}yamaguchi-u.ac.jp).
 |
Abstract
|
|---|
BACKGROUND: Recent studies have reported that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (or statins) can improve angiogenesis. Using an acute infarction model, we examined the therapeutic merit of statins on angiogenesis, alone and in combination with cell-based therapy.
METHODS: Zucker fatty rats, a strain characterized by obesity, hyperglycemia, and hyperlipidemia, were used for this study. After ligating the left anterior descending artery, rats were given oral pravastatin 5 or 50 mg/kg per day, or an intramyocardial injection of a total 2 x 107 autologous bone marrow mononuclear cells, or a combination of both. Cardiac function was assessed by echocardiography before treatment, then 7, 14, and 28 days after treatment. Histologic estimation of microvessel density, lymphocyte infiltration, and collagen fiber accumulation in the infarcted myocardium was performed 28 days after treatment.
RESULTS: Cardiac function was improved, and collagen deposition was decreased significantly after either cell implantation or pravastatin administration alone, but no synergistic effect was seen by their combination. However, microvessel density in the infarcted myocardium was increased only by implantation of bone marrow mononuclear cells, and not by administration of pravastatin. Pravastatin resulted in significant decreases in the serum levels of interleukin 1ß and tumor necrosis factor-
, and also in the infiltration of CD45-positive cells, but not CD117-positive stem cells, in infarcted myocardium. Neither the number of circulating CD34-positive cells nor their endothelial differentiation potency was increased significantly 14 days after oral administration of pravastatin.
CONCLUSIONS: Pravastatin can improve cardiac function after myocardial infarction, but through an antiinflammatory mechanism, rather than by induction of therapeutic angiogenesis. No synergistic effect for inducing angiogenesis was found by the combination of pravastatin and implantation of bone marrow mononuclear cells.
|
Introduction
|
|---|
The implantation of bone marrow mononuclear (stem) cells into ischemic hearts has been found to induce therapeutic angiogenesis and improve cardiac function in experimental animal models [1–3]. Clinical trials have also shown the safety and feasibility of implanting autologous peripheral blood or bone marrow-derived cells for the treatment of ischemic heart disease [4–9]. Although the effectiveness of this new therapy has yet to be confirmed in double-blind randomized clinical trials, these clinical trials have reported the improvement of objective symptoms, regional blood flow, and cardiac function in some patients after treatment [4–9]. However, most ischemic heart diseases are complicated by hyperlipemia or diabetes, or both. The conditions of hyperlipemia and diabetes have been found to induce the dysfunction of endothelial cells, peripheral blood endothelial progenitor cells (EPCs), and bone marrow stem cells [10–13]. This suggests that the effectiveness of implanting autologous peripheral blood or bone marrow–derived cells for the treatment of ischemic heart disease might be impaired in patients with hyperlipemia or diabetes.
Beyond their cholesterol-lowering effect, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (or statins) have recently been found to improve angiogenesis in several experimental ischemic models and also in patients with ischemic diseases [14–19]. Although the precise mechanisms remain unclear, it is thought that the statins improve angiogenesis by activating the protein kinase Akt [14], mobilizing EPCs [13, 16], reducing senescence, and increasing the proliferation of EPCs, as well as by increasing endothelial function [17]. Thus, it would seem that a synergistic effect might be achieved by implanting autologous bone marrow–derived cells in combination with statin administration for the treatment of ischemic heart disease, especially in patients whose disease is complicated by hyperlipemia or diabetes.
Using an acute infarction model in Zucker fatty rats, a strain characterized by diabetes and hyperlipidemia, we investigated the therapeutic merit of administering pravastatin alone to induce angiogenesis, and the possible synergistic effect achieved by the combined implantation of autologous bone marrow mononuclear cells.
|
Material and Methods
|
|---|
Animals
Male 25-week-old Zucker fatty (fa/fa) rats were used for these experiments (Charles River, Osaka, Japan), which were approved by the Institutional Animal Care and Use Committee of Yamaguchi University. The investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).
Collection and Cultivation of Bone Marrow Mononuclear Cells
Bone marrow cells were collected from the femurs and tibias of Zucker fatty rats, and bone marrow mononuclear cells (BM-MNCs) were isolated by density gradient centrifugation as described previously [2]. Cells were suspended with phosphate-buffered saline solution (PBS) at a density of 5 x 108 cells/mL for injection in the in vivo study.
To observe how the statins affect the secretion of cytokines from BM-MNCs, freshly collected BM-MNCs were suspended at a density of 3 x 106 cells/mL in RPMI 1640 medium supplemented with 15% fetal bovine serum, 100 U/mL penicillin, and 100 µg/mL streptomycin (Gibco, Grand Island, NY). The cells were seeded on 24-well plates and cultured at 37°C in a humidified environment with 5% CO2. After 3 days of culture with the addition of 10 or 100 µmol/L pravastatin, the concentration of interleukin-1ß (IL-1ß) and vascular endothelial growth factor (VEGF) in medium were measured with rat IL-1ß and a VEGF ELISA kit (R&D Systems, Minneapolis, MN), according to the manufacturer's instructions.
Myocardial Infarction Model and Experimental Protocol
A myocardial infarction model was established in rats as described previously [3]. After general anesthesia and tracheal intubation with an 18-gauge intravenous catheter, rats were artificially ventilated with room air (Harvard Apparatus Co, Inc) at 80 breaths/min. We performed a left thoracotomy through the fourth intercostal space and ligated the left anterior descending artery completely with 8-0 suture (Prolene; Ethicon, Somerville, NJ) under direct vision. The rats were then randomly divided into the following five groups: The PBS group (n = 8) rats were given an intramyocardial injection of 10 µL of PBS through a 31-gauge needle, at four points in the infarction area. The BMCI group (n = 10) rats were given an intramyocardial injection of 5 x 106 newly isolated BM-MNCs in 10 µL of PBS at four points in the infarction area. The PRAV group (n = 8) rats were given oral pravastatin daily at a dose of 5 mg/kg. The High PRAV group (n = 8) rats were given oral pravastatin daily at a dose of 50 mg/kg. The BMCI + PRAV group (n = 10) rats were given both the intramyocardial injection of BM-MNCs as described above and daily oral pravastatin at a dose of 5 mg/kg.
Echocardiography
Cardiac function was assessed by a single observer blinded to the treatment regimen before treatment, then 7, 14, and 28 days after treatment, by echocardiography using a 7.5-MHz annular array transducer [3]. After the induction of light general anesthesia, the hearts were imaged two-dimensionally in long-axis views at the level of the greatest left ventricular (LV) diameter. The systolic and diastolic LV areas were measured at the same time. This view was used to position the M-mode cursor perpendicular to the LV anterior and posterior walls. The LV end-diastolic diameters and LV end-systolic diameters were measured from M-mode recordings according to the leading-edge method. The LV fraction of shortening was calculated as the LV end-diastolic diameter minus the LV end-systolic diameter, then divided by the LV end-diastolic diameter x 100.
Histologic Analysis
All the rats were killed and the hearts were harvested 28 days after treatment. To measure the microvessel density in the infarcted myocardium, 5-µm-thick frozen sections were stained with anti-rat CD31 antibody (Pharmingen, San Diego, CA). The number of microvessels was counted under x200 magnification by a single observer blinded to the treatment regimen, and a total of 20 different fields on two independent slides from different cross sections were randomly selected for each sample. We calculated the mean number of microvessels per field in the infarcted myocardium for statistical analysis.
Azan staining was also done to determine the degree of collagen fiber accumulation in the infarcted region. Using the image analysis software, NIH IMAGE (National Institutes of Health, Research Service Branch, Bethesda, MD), the area of fibrosis was calculated as the area of stained fibrotic tissue divided by the total area of infracted region. Measurements were done on three separate sections of each heart, and the averages were used for statistical analysis.
To observe the infiltration of lymphocytes and hematopoietic stem cells in the infarcted region, the tissue sections were stained with fluorescein isothiocyanate–labeled antibodies against rat CD45 and CD117 (Caltag Laboratories). The infiltrated CD45 and CD117 cells were counted under fluorescence microscopy with x200 magnification by a single blinded observer. At least 20 fields were selected randomly, and the mean number of positive cells per field was used for statistical analysis.
Circulating CD34-Positive Cells and Endothelial Differentiation Assay
To observe the mobilizing effect on EPCs by pravastatin, 12 supplementary rats were randomly given daily oral saline solution (n = 4), 5 mg/kg pravastatin (n = 4), or 50 mg/kg pravastatin (n = 4). Before and 3, 7, and 14 days after treatment, peripheral blood mononuclear cells were isolated by density gradient centrifugation from each rat. We measured the CD34-positive cells quantitatively using a flow cytometry (FACScan, Becton Dickinson), as described previously [2].
To observe the endothelial differentiation, peripheral blood mononuclear cells were collected 14 days after the oral administration of saline solution or pravastatin. The cells were then suspended at a density of 3 x 106 cells/mL in RPMI 1640 medium as described above, with the addition of 50 ng/mL VEGF, 5 ng/mL basic fibroblast growth factor, and 5 ng/mL insulin-like growth factor-1. Cells were cultured on four-well chamber culture slides (Nalge Nunc International) coated with 0.1 mg/mL fibronectin. After 7 days of culture, they were fixed in 1% formaldehyde and blocked with 2% bovine serum albumin, then incubated with phycoerythrin-conjugated antibody against vascular endothelial-cadherin (Pharmingen). The positively stained cells were counted under fluorescence microscopy with x200 magnification by a single blinded observer, and the mean number of positive cells per field was used for statistical analysis.
Statistical Analysis
All data are expressed as mean ± standard deviation. Statistical significance was evaluated by analysis of variance, followed by Scheffe's procedure, using the StatView software (version 5.0). A value of p less than 0.05 was considered significant.
|
Results
|
|---|
Cytokines and Triglyceride
High concentration of pravastatin (100 µmol/L) significantly decreased the secretion of IL-1ß and VEGF from cultured BM-MNCs, whereas low normal concentration of pravastatin (10 µmol/L) significantly inhibited only the secretion of IL-1ß, not VEGF, from the BM-MNCs (Fig 1).
View larger version (26K):
[in this window]
[in a new window]
|
Fig 1. The effect of statins on the secretion of interleukin 1ß (IL-1ß) and vascular endothelial growth factor (VEGF) from bone marrow mononuclear cells after 3 days of cultivation. (A) Compared with the control, the interleukin 1ß concentration in the medium was significantly decreased by the addition of 10 or 100 µmol/L pravastatin. (B) Compared with the control, the vascular endothelial growth factor concentration in the medium was significantly decreased by the addition of 100 µmol/L, but not 10 µmol/L, pravastatin. All data are representative of six independent experiments by triplicate assessments.
|
|
We followed the changes in body weight, as well as in the serum triglyceride, IL-1ß, and tumor necrosis factor- (TNF-) levels after treatment in the rats (Table 1). The body weight dropped after infarction, but recovered completely within 28 days after treatment in all groups. Although the serum triglyceride level decreased very slightly after pravastatin administration, no significant difference was observed among the groups. However, the inflammatory cytokines, IL-1ß and TNF-, in the serum were significantly lower in the PRAV, High PRAV, and BMCI + PRAV groups than in the PBS and BMCI groups, 7 and 14 days after treatment.
Cardiac Function
Echocardiography showed that the motion of the LV anterior wall was obviously better 28 days after the administration of pravastatin and the implantation of BM-MNCs in the PRAV, High PRAV, BMCI, and BMCI + PRAV groups compared with the PBS group (Fig 2A). Quantitative analysis showed that the LV percentage of fractional shortening was significantly higher in the BMCI and BMCI + PRAV groups than in the other groups 7 days after treatment (p < 0.01; Fig 2B). The percentage of fractional shortening was also significantly higher in the PRAV and High PRAV groups than in the PBS group. However, the percentage of fractional shortening did not differ significantly between the PRAV and High PRAV group, or between the BMCI and BMCI + PRAV groups.
View larger version (32K):
[in this window]
[in a new window]
|
Fig 2. Echocardiographic assessment of cardiac function. (A) Representative M-mode echocardiograms done 28 days after treatment in each group. (B) Quantitative analysis of the time course changes in cardiac function showed that the percentage fraction shortening (FS%) of the left ventricle (LV) recovered significantly better in the pravastatin (PRAV; 5 mg/kg) and high pravastatin (High PRAV; 50 mg/kg) groups than in the phosphate-buffered saline solution (PBS) group, and that the recovery was even better in the rats injected intramyocardially with bone marrow mononuclear cells (BMCI) and also receiving pravastatin (BMCI + PRAV).
|
|
Microvessel Density
After 28 days of treatment, the microvessel density, an index of neovascularization, was significantly higher in the BMCI and BMCI + PRAV groups than in the PRAV, High PRAV, and PBS groups (81.8 ± 11.0 in the BMCI group and 91.2 ± 12.2 in the BMCI + PRAV group, versus 69.7 ± 13.3 in the PRAV group, 53.3 ± 5.6 in the High PRAV group, and 58.0 ± 5.7 in the PBS group; p < 0.01). However, there was no significant difference in microvessel density among the PRAV, High PRAV, and PBS groups, although the microvessel density was lower in the High PRAV group than in the PRAV group (p = 0.065; Fig 3).
View larger version (49K):
[in this window]
[in a new window]
|
Fig 3. Microvessel density in the infarcted myocardium 28 days after treatment. (A) More microvessels were observed in the rats injected intramyocardially with bone marrow mononuclear cells (BMCI) and also receiving pravastatin (BMCI + PRAV) than in the other groups. (B) Quantitative analysis showed that the microvessel density was significantly higher in the BMCI and BMCI + PRAV groups than in the phosphate-buffered saline solution (PBS), pravastatin (PRAV; 5 mg/kg), and high pravastatin (High PRAV; 50 mg/kg) groups, but it did not differ among the PBS, PRAV, and High PRAV groups. Inversely, the microvessel density showed a lower trend in the High PRAV group than in the PBS group (p = 0.065).
|
|
Collagen Deposition
There was much less collagen deposition in the infarcted myocardium in the PRAV, High PRAV, BMCI, and BMCI + PRAV groups than in the PBS group (Fig 4A). Quantitative analysis showed that the percentage of fibrotic area was significantly lower in the PRAV, High PRAV, BMCI, and BMCI + PRAV groups than in the PBS groups 28 days after treatment (Fig 4B). Although the percentage of fibrotic area was lower in the BMCI and BMCI + PRAV groups than in the PRAV and High PRAV groups, there was no significant difference among the four groups.
View larger version (51K):
[in this window]
[in a new window]
|
Fig 4. Azan staining of a cross section through the infarcted myocardium 28 days after treatment. (A) There was obviously less fibrotic tissue in the infarcted myocardium in the rats injected intramyocardially with bone marrow mononuclear cells (BMCI) and also receiving pravastatin (BMCI + PRAV), and also in the pravastatin (PRAV; 5 mg/kg) and high pravastatin (High PRAV; 50 mg/kg) groups than in the phosphate-buffered saline solution (PBS) group. (B) Compared with the PBS group, quantitative analysis showed that the fibrotic area was significantly lower in the BMCI and BMCI + PRAV groups, and also in the PRAV and High PRAV groups.
|
|
Lymphocytes and Hematopoietic Stem Cells in the Infarcted Myocardium
Immunostaining analysis showed fewer CD45-positive cells in the PRAV and High PRAV groups (Fig 5A), and quantitative analysis confirmed that the number of CD45-positive cells was significantly lower in the PRAV and High PRAV groups than in the PBS group 28 days after treatment (p < 0.01; Fig 5B). However, the number of CD117-positive stem cells did not differ significantly among the PBS, PRAV, and High PRAV groups 28 days after treatment (Fig 5A and B). The significantly greater number of CD117-positive cells in the BMCI and BMCI + PRAV groups should be related to the fact that we also counted the CD117-positive hematopoietic stem cells within the implanted BM-MNCs.
View larger version (69K):
[in this window]
[in a new window]
|
Fig 5. The infiltration of CD45-positive lymphocytes and CD117-positive hematopoietic stem cells in the infarcted myocardium 28 days after treatment. (A) A representative image of immunostaining with fluorescein isothiocyanate–labeled antibodies against CD45 and CD117 in each group. (B) Quantitative analysis showed that there were significantly fewer CD45-positive cells, but not CD117-positive cells, in the pravastatin (PRAV; 5 mg/kg) and high pravastatin (High PRAV; 50 mg/kg) groups than in the phosphate-buffered saline solution (PBS) group. The increase in CD117-positive cells in the rats injected intramyocardially with bone marrow mononuclear cells (BMCI) and also receiving pravastatin (BMCI + PRAV) was calculated from the count of implanted CD117-positive hematopoietic stem cells in the bone marrow–derived mononuclear cells.
|
|
Circulating Endothelial Progenitor Cells and Their Endothelial Differentiation Potency
We monitored the changes in circulating EPCs by measuring the CD34-positive cells in peripheral blood. Compared with baseline, the number of CD34-positive cells did not increase significantly 3, 7, or 14 days after the administration of 5 or 50 mg/kg pravastatin (Fig 6A). Similarly, the in vitro assessment of endothelial differentiation potency also showed that the number of VE-cadherin–positive cells in peripheral blood mononuclear cells from rats given PBS, 5 mg/kg pravastatin, or 50 mg/kg pravastatin for 14 days did not change significantly after 7 days of cultivation (Fig 6B).
View larger version (48K):
[in this window]
[in a new window]
|
Fig 6. The mobilization effect of endothelial progenitor cells by pravastatin. (A) Compared with the baseline, the number of circulating CD34-positive cells in peripheral blood did not change significantly after the administration of 5 or 50 mg/kg pravastatin. (B) In vitro assessment of the endothelial differentiation potency of peripheral blood mononuclear cells. After 7 days of cultivation, the number of vascular endothelial-cadherin–positive cells in the mononuclear cells did not differ significantly among the rats given 14 days of continuous daily oral 5 mg/kg pravastatin, 50 mg/kg pravastatin, or phosphate-buffered saline solution (PBS) only. Data are representative of four independent experiments by triplicate assessments.
|
|
|
Comment
|
|---|
In this study, we found that significant improvement in cardiac function was achieved either by the daily administration of normal or high-dose pravastatin, or by the intramyocardial implantation of autologous BM-MNCs. Furthermore, in accordance with the findings of our previous studies [2, 3], the implantation of autologous BM-MNCs resulted in a significant increase in microvessels after infarction, by inducing therapeutic angiogenesis, which is considered to improve cardiac function. However, the microvessel density in infarcted myocardium was not increased by the administration of pravastatin at normal or high doses, although both doses resulted in improved cardiac function after infarction.
Conversely, the high dose of pravastatin tended to decrease the microvessel density, indicating an inhibitory effect on angiogenesis. This suggests that the improvement in cardiac function achieved by pravastatin is not attributable to a mechanism of inducing angiogenesis. As daily administration of 40 mg/kg pravastatin in mice produces a plasma concentration of clinical range [20], the high-dose pravastatin (50 mg/kg) in this study should be expected to yield a slightly higher plasma concentration than that in patients administered vastly lower doses. We cannot deny that the increased regional perfusion generated by pravastatin improves cardiac function to some extent, because statins increase blood flow through the preexisting coronary collateral vessels by directly increasing endothelial nitric oxide production [21], and hyperglycemia reduces coronary collateral blood flow through a nitric oxide–mediated mechanism [22]. However, we did not measure the regional perfusion of the infarcted myocardium.
Previous studies have found that statins improve angiogenesis [14–19] but have no effect on coronary collateral flow in patients with coronary artery disease [23]. Conversely, in accordance with our findings, it has been found that statins inhibit the proliferation and migration of various cells [24–26], and that they decrease the production of VEGF and inhibit inflammation-induced angiogenesis, especially when given at a high dose [22–29]. More recently investigation has further demonstrated that high-dose statins not only increase antiangiogenic factor of endostatin and decrease VEGF, but also improve endothelial dysfunction in a chronic myocardial ischemic model of swine [30]. There are several possible reasons for these conflicting results: one is that statins have a dose-dependent biphasic effect on angiogenesis [28, 29], and another is that the angiogenic effect of statins may depend on the difference of animal model, the phase (acute versus chronic) and degree of ischemia (severe versus mild), the existence or not of diabetes and hyperlipidemia, and other regional and systemic conditions.
Contrary to recent reports [14–17], we did not observe an increase in the number of circulating CD34-positive cells, or their endothelial differentiation potency, until 2 weeks after the continuous daily administration of pravastatin at both normal and high doses. Although the exact reason for these conflicting data is unclear, it may be related to the differences in the species and statins used in our study and in previous experiments [14–17]. As we monitored the circulating CD34-positive cells in nonischemic rats, our study sought to identify whether the circulating CD34-positive cells could be increased by either bone marrow cell implantation or pravastatin administration in these myocardial ischemia rats.
Our histologic assessment showed that the collagen deposition in infarcted myocardium was decreased by oral pravastatin, the implantation of BM-MNCs, and their combination, which demonstrates improved LV remodeling after infarction. Therefore, the functional benefit by pravastatin treatment was considered to relate to an improvement in LV remodeling, rather than to increased regional perfusion by inducing angiogenesis. Our data showed that the administration of pravastatin significantly decreased the systemic levels of inflammatory cytokines, including IL-1ß and TNF-, but not VEGF (data not shown). In the same way, we found that the CD45-positive cells in the infarcted myocardium were also decreased significantly by pravastatin administration, but that the CD117-positive stem cells did not change significantly. This difference between CD45-positive and CD117-positive cells may be explained by the different mechanisms and factors for regulating the chemotaxis of lymphocytes and hematopoietic stem cells. Although we did not measure the inflammatory cytokines in infarcted myocardium, the decrease in systemic IL-1ß and TNF- and in local lymphocyte infiltration supported the antiinflammatory effect of pravastatin after infarction. Many other recent investigations have reported the antiinflammatory effect of statins [31, 32]. Otherwise, our data showed that pravastatin did not decrease the serum level of triglyceride, indicating the improvement of cardiac function by pravastatin was not related to their cholesterol-lowering effect.
We were unable to find any synergistic effect of the combination therapy of pravastatin and the implantation of BM-MNCs on either the induction of therapeutic angiogenesis or improvement of cardiac function, although it did result in slightly better improvement of cardiac function than that achieved by the implantation of BM-MNCs alone. Our in vitro investigation showed that statins can inhibit the secretion of IL-1ß and VEGF from BM-MNCs. As it is well known that some inflammatory cytokines produced from BM-MNCs, including IL-1ß, contribute to the induction of angiogenesis, we speculate that statins might partly attenuate the angiogenic potency induced by the implantation of BM-MNCs. This seems to contradict the fact that slightly better cardiac function was observed in the BMCI + PRAV group than the BMCI group. However, the antiinflammatory effect of statins should protect the ischemic myocardium against further damage to inflammatory cytokines, such as TNF-. Similarly, the slightly higher microvessel density in the BMCI + PRAV group than the BMCI group was contradicted with the fact that statins may attenuate angiogenesis induced by BM-MNCs. This might be explained by the improvement effect of statin to hyperlipemia-related and diabetes-related endothelial cell dysfunction [30], or by other unknown pleiotropic effects. Considering the opposite action between bone marrow cell implantation (some inflammatory cytokines play a role for inducing angiogenesis) and statin therapy (antiinflammatory effects), it is not surprising that no synergistic effects were observed by their combination. If we can find a new approach to induce angiogenesis purely through an inflammatory-independent pathway, then a synergistic effect could be expected by combination with statin therapy. Unfortunately, all of the well-known established methods for inducing therapeutic angiogenesis, including VEGF and basic fibroblast growth factor delivery, is partly through an inflammatory response mechanism.
In summary, we found that the administration of pravastatin improved cardiac function after myocardial infarction, but its combination with cell-based therapeutic angiogenesis induced by the implantation of BM-MNCs had no synergistic effect. Our data suggest that statins improve remodeling and cardiac function after myocardial infarction through an antiinflammatory mechanism rather than by inducing therapeutic angiogenesis.
|
Acknowledgments
|
|---|
This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture (16659372, 16591259, and 16390397). We thank Mako Ohshima for her excellent technical assistance.
|
References
|
|---|
- Kocher AA, Schuster MD, Szabolcs MJ, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function Nat Med 2001;7:430-436.[Medline]
- Li TS, Hamano K, Nishida M, et al. CD117+ stem cells play a key role in therapeutic angiogenesis induced by bone marrow cell implantation Am J Physiol Heart Circ Physiol 2003;285:H931-H937.[Abstract/Free Full Text]
- Nishida M, Li TS, Hirata K, Yano M, Matsuzaki M, Hamano K. Improvement of cardiac function by bone marrow cell implantation in a rat hypoperfusion heart model Ann Thorac Surg 2003;75:768-773.[Abstract/Free Full Text]
- Hamano K, Nishida M, Hirata K, et al. Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart diseaseclinical trial and preliminary results. Jpn Circ J 2001;65:845-847.[Medline]
- Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans Circulation 2002;106:1913-1918.[Abstract/Free Full Text]
- Assmus B, Schachinger V, Teupe C, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI) Circulation 2002;106:3009-3017.[Abstract/Free Full Text]
- Fuchs S, Satler LF, Kornowski R, et al. Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery diseasea feasibility study. J Am Coll Cardiol 2003;41:1721-1724.[Abstract/Free Full Text]
- Perin EC, Dohmann HF, Borojevic R, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure Circulation 2003;107:2294-2302.[Abstract/Free Full Text]
- Stamm C, Westphal B, Kleine HD, et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration Lancet 2003;361:45-46.[Medline]
- Heeschen C, Lehmann R, Honold J, et al. Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease Circulation 2004;109:1615-1622.[Abstract/Free Full Text]
- Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk N Engl J Med 2003;348:593-600.[Abstract/Free Full Text]
- Vasa M, Fichtlscherer S, Aicher A, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease Circ Res 2001;89:E1-E7.[Medline]
- Tepper OM, Galiano RD, Capla JM, et al. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures Circulation 2002;106:2781-2786.[Abstract/Free Full Text]
- Kureishi Y, Luo Z, Shiojima I, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals Nat Med 2000;6:1004-1010.[Medline]
- Vasa M, Fichtlscherer S, Adler K, et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease Circulation 2001;103:2885-2890.[Abstract/Free Full Text]
- Llevadot J, Murasawa S, Kureishi Y, et al. HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells J Clin Invest 2001;108:399-405.[Medline]
- Assmus B, Urbich C, Aicher A, et al. HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes Circ Res 2003;92:1049-1055.[Abstract/Free Full Text]
- Landmesser U, Engberding N, Bahlmann FH, et al. Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase Circulation 2004;110:1933-1939.[Abstract/Free Full Text]
- Pourati I, Kimmelstiel C, Rand W, Karas RH. Statin use is associated with enhanced collateralization of severely diseased coronary arteries Am Heart J 2003;146:876-881.[Medline]
- Johnson J, Carson K, Williams H, et al. Plaque rupture after short periods of fat feeding in the apolipoprotein E-knockout mousemodel characterization and effects of pravastatin treatment. Circulation 2005;111:1422-1430.[Abstract/Free Full Text]
- Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA Reductase inhibitors Circulation 1998;97:1129-1135.[Abstract/Free Full Text]
- Kersten JR, Toller WG, Tessmer JP, Pagel PS, Warltier DC. Hyperglycemia reduces coronary collateral blood flow through a nitric oxide-mediated mechanism Am J Physiol 2001;281:H2097-H2104.
- Zbinden S, Brunner N, Wustmann K, Billinger M, Meier B, Seiler C. Effect of statin treatment on coronary collateral flow in patients with coronary artery disease Heart 2004;90:448-449.[Free Full Text]
- Vincent L, Chen W, Hong L, et al. Inhibition of endothelial cell migration by cerivastatin, an HMG-CoA reductase inhibitorcontribution to its anti-angiogenic effect. FEBS Lett 2001;495:159-166.[Medline]
- Vincent L, Soria C, Mirshahi F, et al. Cerivastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, inhibits endothelial cell proliferation induced by angiogenic factors in vitro and angiogenesis in in vivo models Arterioscler Thromb Vasc Biol 2002;22:623-629.[Abstract/Free Full Text]
- Horiguchi A, Sumitomo M, Asakuma J, Asano T, Asano T, Hayakawa M. 3-Hydroxy-3-methylglutaryl-coenzyme a reductase inhibitor, fluvastatin, as a novel agent for prophylaxis of renal cancer metastasis Clin Cancer Res 2004;10:8648-8655.[Abstract/Free Full Text]
- Alber HF, Dulak J, Frick M, et al. Atorvastatin decreases vascular endothelial growth factor in patients with coronary artery disease J Am Coll Cardiol 2002;39:1951-1955.[Abstract/Free Full Text]
- Weis M, Heeschen C, Glassford AJ, Cooke JP. Statins have biphasic effects on angiogenesis Circulation 2002;105:739-745.[Abstract/Free Full Text]
- Frick M, Dulak J, Cisowski J, et al. Statins differentially regulate vascular endothelial growth factor synthesis in endothelial and vascular smooth muscle cells Atherosclerosis 2003;170:229-236.[Medline]
- Boodhwani M, Nakai Y, Voisine P, Sellke FW. High-dose atorvastatin improves hypercholesterolemic endothelial dysfunction without improving collateral-dependent myocardial perfusionrole of endostatin and vascular endothelial growth factor (abstract). Circulation 2005;112(Suppl 2):II-376.
- Dichtl W, Dulak J, Frick M, et al. HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells Arterioscler Thromb Vasc Biol 2003;23:58-63.[Abstract/Free Full Text]
- Han KH, Ryu J, Hong KH, et al. HMG-CoA reductase inhibition reduces monocyte CC chemokine receptor 2 expression and monocyte chemoattractant protein-1-mediated monocyte recruitment in vivo Circulation 2005;111:1439-1447.[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
J. Feng and F. W. Sellke
Invited commentary
Ann. Thorac. Surg.,
June 1, 2006;
81(6):
2225 - 2226.
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
