Effects of Intramyocardial Administration of Slow-Release Basic Fibroblast Growth Factor on Angiogenesis and Ventricular Remodeling in a Rat Infarct Model

Abstract

oth coronary artery bypass grafting and percutaneous coronary intervention ameliorate angina pectoris, prevent myocardial infarction and improve the long-term survival of patients with atherosclerotic coronary artery disease. However, the nature of coronary arteries significantly impacts the quality of life. Standard therapies for myocardial revascularization are often limited because of diffuse lesions or small-caliber vessels. Angiogenic therapy to induce myocardial neovascularization is not dependent on vessel caliber and provides an alternative treatment alone or in combination with standard revascularization. Basic fibroblast growth factor (bFGF) is a potent angiogenic protein that induces endothelial and smooth muscle cell proliferation in vivo and elicits angiogenesis that includes the migration and proliferation of endothelial cells, vascular tube formation and linkage to the extant vascular network. 1 Intracoronary injections of bFGF reduce infarct size in a canine model of myocardial infarction and improve myocardial function in chronically ischemic porcine hearts. 2,3 We have previously shown that the intramyocardial administration of bFGF increased the number of capillaries and arterioles in the peri-infarct region, increased regional myocardial blood flow and consequently improved ven- Circulation Journal Vol.70, April 2006tricular function in a canine infarction model. 4 However, angiogenesis induced by growth factors has not been always successful. Despite high binding affinity for acidic polysaccharides such as heparin and heparan sulfate in the extracellular matrix, bFGF has a short biological half-life in tissues. 5 The sustained release of bFGF might help to enhance its angiogenic activity in vivo. 6,7 Gelatin is a nontoxic, biodegradable, natural polymer with low antigenicity and gelatin hydrogel is considered to be a preferable matrix for the sustained release of protein drugs, such as growth factors. 8,9 However, the effects of intramyocardial injections of slow-release bFGF on vascular growth, cardiomyocyte apoptosis and cardiac function have not been investigated in detail. The present study evaluates the ability of gelatin hydrogels to enhance the benefits of bFGF on neoangiogenesis, cardiomyocyte apoptosis, myocardial fibrosis, ventricular remodeling and cardiac function in a rat infarction model. Methods Preparation of bFGFHuman recombinant bFGF and gelatin hydrogels were provided by Kaken Pharmaceutical, Tokyo, Japan. Gelatin with an isoelectric point of 4.9 was prepared using alkaline treatment of bovine collagen with Ca(OH)2. To obtain gelatin hydrogels that incorporated bFGF, 0.7 ml of saline containing 350 g of bFGF was impregnated into freezedried hydrogels. The release of biologically active bFGF is sustained as a result of hydrogel degradation in vivo. Empty gelatin hydrogels free of bFGF were similarly prepared. Background Basic fibroblast growth factor (bFGF) stimulates neoangiogenesis. Incorporation into biodegradable gelatin hydrogels provides the sustained release of bFGF....

Angiotensin-Receptor Blockade Reduces Border Zone Myocardial Monocyte Chemoattractant Protein-1 Expression and Macrophage Infiltration in Post-Infarction Ventricular Remodeling

“…17 Recent studies demonstrated that the border zone myocardium might be a novel therapeutic target in the treatment of post-MI LV remodeling. 20,34 We demonstrated that MCP-1 expression and macrophage infiltration increased more prominently in the border zone myocardium compared with the noninfarcted myocardium of infarcted hearts. Immunohistochemistry demonstrated that MCP-1 expression was observed in the infiltrating macrophages in the infarcted and border zone regions.…”

Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration

“…These strategies have been used mainly for the delivery of VEGF [14,[29][30][31], FGF1 [19] and FGF2 [32,33]. Although hydrogels represent an appealing class of delivery vehicles, technical difficulties related to injection of the gelatin hydrogel into the thin ventricular wall of infarcted rat hearts have been reported [34]. Moreover, while liposomes have been shown to accumulate experimentally in areas of MI [30,35,36], their clinical application has been hindered because they are unstable and readily interact with high-density lipoproteins in blood.…”

Sustained-Release Erythropoietin Ameliorates Cardiac Function in Infarcted Rat - Heart Without Inducing Polycythemia

“…It is pertinent to comment on reasons why we used SR EPO sheets rather than gelatin hydrogel microspheres incorporating EPO. In our earlier studies, gelatin hydrogel microspheres [28][29][30][31] and sheets 6,7 were used as a carrier of SR bFGF. For the purpose of healing of devascularized sternum, we used gelatin sheets incorporating bFGF, for anatomical reasons, 6,7 but in the case of MI, we injected a solution of 100 l containing gelatin bFGF microspheres into several sites of the border zones of MI scar tissue.…”