Article

Transplantation of cardiotrophin-1-expressing myoblasts to the left ventricular wall alleviates the transition from compensatory hypertrophy to congestive heart failure in Dahl salt-sensitive hypertensive rats

Kobe University, Kōbe, Hyōgo, Japan
Journal of the American College of Cardiology (Impact Factor: 15.34). 07/2004; 43(12):2337-47. DOI: 10.1016/j.jacc.2004.02.048
Source: PubMed

ABSTRACT We investigated whether autologous transplantation of skeletal myoblasts (MB) transferred with cardiotrophin-1 (CT-1) gene could retard the transition to heart failure (HF) in Dahl salt-sensitive (DS) hypertensive rats.
Although MB is a therapeutic candidate for chronic HF, little is known about the efficiency of this strategy when applied in nonischemic HF. Cardiotrophin-1 has potent hypertrophic and survival effects on cardiac myocytes. We hypothesized that transplantation of CT-1-expressing myoblasts could provide cardioprotective effects against ventricular remodeling in DS hypertensive rats.
The DS rats were fed a high salt diet for 6 weeks and developed left ventricular (LV) hypertrophy at 11 weeks. At this stage, animals underwent MB to the myocardium with skeletal myoblasts transferred with CT-1 gene using retrovirus (transplantation of CT-1-expressing myoblasts [MB + CT], n = 31) or myoblasts alone (MB, n = 31). The sham group rats were injected with phosphate-buffered saline (n = 24).
At 17 weeks, MB and MB + CT groups showed a significant alleviation of LV dilation and contractile dysfunction compared with the sham group. The degree of alleviation was significantly greater in the MB + CT group than the MB group (LV end-diastolic dimension: sham 7.06 +/- 0.14 mm, MB 6.51 +/- 0.16 mm, MB + CT 6.24 +/- 0.07 mm; fractional shortening: sham 32.1 +/- 1.4%, MB 38.5 +/- 1.5%, MB + CT 43.2 +/- 0.8%). Histological examination revealed that the myocyte size was 20% larger in the MB + CT group at 17 weeks than in the age-matched sham group. Upregulation of renin-angiotensin and endothelin systems during the transition to HF was attenuated by myoblast transplantation, and this effect was enhanced in the MB + CT group.
Transplantation of skeletal myoblasts combined with CT-1-gene transfer could be a useful therapeutic strategy for HF.

0 Bookmarks
 · 
143 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Silica-based hybrid mesostructured materials (MCM-41 type) containing surfactant- embedded Methylene Blue have been prepared and characterized by several techniques, including UV-Vis spectroscopy and cyclic voltammetry, and compared to other systems containing the same dye molecule. The micellar phase of the hybrid material was found to be permeable to protons, which may be of interest for potential applications in chemical and biological sensing devices.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Reactive oxygen species (ROS) is deeply involved in the process of ventricular remodeling after myocardial infarction (MI). Under oxidative stress, endothelial nitric oxide synthase (eNOS) can be converted to a ROS generator, because a relative lack of tetrahydrobiopterin (BH4), an essential cofactor for NO synthesis, leads to eNOS uncoupling. The uncoupled eNOS generates superoxide rather than NO. The possible role of ROS generated by eNOS in ventricular remodeling after MI was investigated. Methods and Results Rats were treated with oral BH4 supplementation starting at 3 days before coronary artery ligation. At 4 weeks after MI, there was augmented superoxide production in association with reduced BH4/dihydrobiopterin (BH2) ratio and eNOS dimer/monomer protein ratio in the heart. Treatment with BH4 increased BH4/BH2 ratio and eNOS dimer/monomer ratio, and decreased superoxide production. In BH4-treated MI rats, left ventricular size was smaller, thickness of the non-infarcted posterior wall was thinner, and cardiac function wits preserved compared with the control MI rats. Conclusions The present study suggested that ventricular remodeling process after MI leads to BH4 oxidation and resulted in uncoupled eNOS-derived superoxide generation, which further augmented the remodeling process and deteriorated cardiac function.
    Circulation Journal 09/2008; 72(9):1512-1519. DOI:10.1253/circj.CJ-08-0072 · 3.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The incidence of human autologous transplanted skeletal myoblast (SkM) cell death in ischemic myocardium was higher in the first few days after cell therapy. We proposed that human SkM treated by human stromal cell-derived factor (SDF-1α) protein or tranfected by SDF-1α, precondition them against oxidative or anoxic injury. The purification of human SkM (80∼90%) culture was assessed for desmin and CXCR4 expression using immunostaining and flow cytometry respectively. Cells were transfected to overexpress SDF-1α or treated with rSDF-1α (10∼200 ng/ml, 1∼4 h) were either exposed to anoxia or treated with 100μM H2O2 for different time periods (1∼6 h anoxia) (1∼3 h H2O2). Optimized conditions for transfection of SDF-1α gene into human SkM were achieved, using FuGene(TM)6/phSDF-1α(3:2 v/w, 4 h transfection) with 125μ M ZnCl2 (p< 0.001), up to 7 days post-transfection as compared with transfected SkM without ZnCl2 and non-transfected control cells. Transfection efficiency was assessed by immunostaining, ELISA, western blots and PCR. LDH analysis showed significant decrease in release of LDH after exposure to 6 h anoxia or 100μ M H2O2 for 2 h as compared with the normal un-treated or un-transfected SkM (p< 0.001). In western blots assay, SDF-1α over-expressing human SkM or treated with rSDF-1α induced marked expression of total Akt (1.2-fold) and phospho-Akt (2.7-fold), Bcl2 (1.6-fold) and VEGF (5.8-fold) after exposure to 6 h anoxia as compared with human SkM controls. The preconditioning of donor transplanted human SkM with SDF-1α increased cell survival and promoted cytoprotective effect against oxidative or anoxic injury that may be an innovative approach for clinical application.
    06/2011; 4(1):50-60. DOI:10.15283/ijsc.2011.4.1.50

Full-text (2 Sources)

Download
44 Downloads
Available from
May 26, 2014