Sustained release of basic fibroblast growth factor using gelatin hydrogel improved left ventricular function through the alteration of collagen subtype in a rat chronic myocardial infarction model
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Chronic myocardial infarction (CMI) tends to be resistant to treatments possibly due to extensive solid fibrotic scar, hypoxia mediated by poorly vascularized environment, and/or inflammation and apoptosis. Here we aimed to testify the therapeutic effects of sustained release of basic fibroblast growth factor (bFGF) using gelatin hydrogel (GH) in a rat chronic MI model and to elucidate the therapeutic mechanism including the alteration of extracellular matrix component.
CMI model rats are prepared by the permanent ligation of proximal left anterior descending coronary artery. After 4 weeks, GH sheets (GHSs) with bFGF (100 µg) (bFGF group) or with phosphate-buffered saline (Vehicle group) were implanted to the CMI models to evaluate the effect of bFGF–GHS on chronic scar tissue. Sham operation group was also prepared (n = 5 for each).
4 weeks after implantation, bFGF–GHS significantly improved cardiac contractile function (fractional shortening: 21.8 ± 1.1 vs 21.5 ± 1.3 vs 29.7 ± 1.8%; P < 0.001/fractional area change: 33.0 ± 1.4 vs 34.1 ± 2.3 vs 40.6 ± 1.8%; P < 0.001) (Sham vs Vehicle vs bFGF) accompanied with neovascularization. Immunohistochemical studies revealed that bFGF–GHS increased collagen III/I ratio indicating the alteration of solid scar tissue. Quantitative RT-PCR results showed a decrease of collagen I mRNA expression within border MI zone.
The implantation of bFGF–GHS altered the collagen subtype of the fibrotic scar more suitable for tissue repair. The treatment of sustained-release bFGF may be promising for ischemic heart disease through chronic pathology.
KeywordsBasic fibroblast growth factor Gelatin hydrogel Ischemic heart disease Drug delivery system Collagen
This work was supported by grants from Japan Agency for Medical Research and development (AMED) (to KM), and Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (to HM) (#25462137). We thank Shuichi Miyake (Kyoto Univ.) for the excellent technical support.
Compliance with ethical standards
Conflict of interest
The authors have declared that no conflict of interest exists.
- 3.Perin EC, Willerson JT, Pepine CJ, Henry TD, Ellis SG, Zhao DX, et al. Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA. 2012;307:1717–26.CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Takehara N, Tsutsumi Y, Tateishi K, Ogata T, Tanaka H, Ueyama T, et al. Controlled delivery of basic fibroblast growth factor promotes human cardiosphere-derived cell engraftment to enhance cardiac repair for chronic myocardial infarction. J Am Coll Cardiol. 2008;52:1858–65.CrossRefPubMedGoogle Scholar
- 20.Tambara K, Premaratne GU, Sakaguchi G, Kanemitsu N, Lin X, Nakajima H, et al. Administration of control-released hepatocyte growth factor enhances the efficacy of skeletal myoblast transplantation in rat infarcted hearts by greatly increasing both quantity and quality of the graft. Circulation. 2005;112:I129–34.PubMedGoogle Scholar
- 21.Kumagai M, Minakata K, Masumoto H, Yamamoto M, Yonezawa A, Ikeda T, et al. A therapeutic angiogenesis of sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogel sheets in a canine chronic myocardial infarction model. Heart Vessels (in press).Google Scholar
- 22.Masumoto H, Matsuo T, Yamamizu K, Uosaki H, Narazaki G, Katayama S, et al. Pluripotent stem cell-engineered cell sheets reassembled with defined cardiovascular populations ameliorate reduction in infarct heart function through cardiomyocyte-mediated neovascularization. Stem Cells. 2012;30:1196–205.CrossRefPubMedGoogle Scholar