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.
OBJECTIVE
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.


BACKGROUND
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
Transplantation of skeletal myoblasts combined with CT-1-gene transfer could be a useful therapeutic strategy for HF.
Toh
Ryuji
R
Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Kawashima
Seinosuke
S
Kawai
Miki
M
Sakoda
Tsuyoshi
T
Ueyama
Tomomi
T
Satomi-Kobayashi
Seimi
S
Hirayama
Sonoko
S
Yokoyama
Mitsuhiro
M
D000818:Animals; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017690:Cell Transplantation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D003971:Diastole / Q000187:drug effects; D004195:Disease Models, Animal; D004452:Echocardiography; D015716:Electrocardiography, Ambulatory; D018014:Gene Transfer Techniques; D006333:Heart Failure / Q000503:physiopathology / Q000628:therapy*; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D008955:Models, Cardiovascular; D032448:Myoblasts, Skeletal / Q000637:transplantation*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D018377:Neurotransmitter Agents / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D015854:Up-Regulation / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
D015415:Biomarkers; D016207:Cytokines; D018377:Neurotransmitter Agents; C092073:cardiotrophin 1