Abstract
To explore the impact of myocardial injection of mesenchymal stem cells (MSCs) and specific recombinant human VEGF165 (hVEGF165) plasmid on collagen remodelling in rats with furazolidone induced dilated cardiomyopathy (DCM). DCM was induced by furazolidone (0.3 mg/bodyweight (g)/day per gavage for 8 weeks). Rats were then divided into four groups: (i) PBS group (n = 18): rats received equal volume myocardial PBS injection; (ii) MSCs group (n = 17): 100 μl culture medium containing 105 MSCs were injected into four sites of left ventricular free wall (25 μl per site); (iii) GENE group (n = 18): pCMVen-MLC2v-EGFP-VEGF165 plasmid [5 × 109 pfu (0.2 ml)] were injected into four sites of left ventricular free wall (0.05 ml per site)] and (iv) MSCs+GENE group (n = 17): rats received both myocardial MSCs and pCMVen-MLC2v-EGFP-VEGF165 plasmid injections. After 4 weeks, cardiac function was evaluated by echocardiography. Myocardial mRNA expressions of type I, type III collagen and transforming growth factor (TGF)-β1 were detected by RT-PCR. The protein expression of hVEGF165 was determined by Western blot. Myocardial protein expression of hVEGF165 was demonstrated in GENE and MSCs+GENE groups. Cardiac function was improved in MSCs, GENE and MSCs+GENE groups. Collagen volume fraction was significantly reduced and myocardial TGF-β1 mRNA expression significantly down-regulated in both GENE and MSCs+GENE groups, collagen type I/III ratio reduction was more significant in MSCs+GENE group than in MSCs or GENE group. Myocardial MSCs and hVEGF165 plasmid injection improves cardiac function possibly through down-regulating myocardial TGF-β1 expression and reducing the type I/III collagen ratio in this DCM rat model.
Highlights
Dilated cardiomyopathy (DCM), a progressive disease of heart muscle, is a common cause of heart failure and the most frequent cause of heart transplantation [1, 2]
Collagen volume fraction was significantly reduced in mesenchymal stem cells (MSCs) and GENE group and further reduced in MSCs plus GENE group compared to PBS group at the end of study (Fig. 3A: Massion staining and Fig. 3B: Sirius red staining). von Willebrand factor staining showed a tendency for increased vWF expression in MSCs and GENE group and which was significantly up-regulated in MSCs+GENE group compared to PBS group (Fig. 4)
(2) Observed beneficial effects by MSCs and hVEGF165 were linked with reduced CVF and down-regulated myocardial expression of transforming growth factor (TGF)-b1, collagen I and collagen I/III ratio and higher expression of vWF and Matrix metalloproteinase (MMP)-9
Summary
Dilated cardiomyopathy (DCM), a progressive disease of heart muscle, is a common cause of heart failure and the most frequent cause of heart transplantation [1, 2]. VEGF neutralization attenuated erythropoietin-induced proliferation of myocardial endothelial cells and reduced myocardial incorporation of endothelial progenitor cells in rats with alkaline phosphatase-labelled bone marrow cells, suggesting VEGF is crucial for improving cardiac function in heart failure animals [9]. Formiga et al demonstrated that VEGF165 administered as continuous release in border zone of a rat model of ischaemia-reperfusion promoted angiogenesis (small caliber caveolin-1 positive vessels), arteriogenesis (a-SMA, a-Smooth muscle actin positive vessels) and attenuated myocardial remodelling [10]. Despite the promising experimental results indicating the beneficial effects of locally administrated MSCs and VEGF in various animal models, conflicting results were reported and it was shown that overexpressing VEGF by Semliki Forest virus failed to induce cardiac angiogenesis and rather impaired systolic function in the mRen transgenic rat heart failure model [11]. Most studies demonstrated beneficial effects of VEGF treatment in both cerebral and myocardial ischaemia model, viral (especially the Semliki Forest virus) mediated overexpressing of VEGF might face viral-related negative effects
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