Early combined treatment with sildenafil and adipose-derived mesenchymal stem cells preserves heart function in rat dilated cardiomyopathy.
BACKGROUND
We investigated whether early combined autologous adipose-derived mesenchymal stem cell (ADMSC) and sildenafil therapy offers an additive benefit in preserving heart function in rat dilated cardiomyopathy (DCM).


METHODS
Adult Lewis rats (n = 8 per group) were divided into group 1 (normal control), group 2 (saline-treated DCM rats), group 3 [2.0 × 106 ADMSC implanted into left ventricular (LV) myocardium of DCM rats], group 4 (DCM rats with sildenafil 30 mg/kg/day, orally), and group 5 (DCM rats with combined ADMSC-sildenafil). Treatment was started 1 week after DCM induction and the rats were sacrificed on day 90.


RESULTS
The results showed that mitochondrial protein expressions of connexin43 and cytochrome-C were lowest in group 2, and lower in groups 3 and 4 than in group 5 (p < 0.002). Conversely, oxidative index was highest in group 2, and also higher in groups 3 and 4 than in group 5 (p < 0.0003). The mRNA expressions of interleukin (IL)-10, Gro/IL-8, endothelial nitric oxide synthase, and Bcl-2 were lowest in group 2, and lower in groups 3 and 4 compared with group 5 (p < 0.0001). The mRNA expressions of matrix metalloproteinase-9, Bax, caspase 3, and stromal-cell derived factor-1α were highest in group 2, and higher in groups 3 and 4 than in group 5 (p < 0.0004). Apoptosis and fibrosis in LV myocardium were most prominent in group 2 and higher in groups 3 and 4 than in group 5, whereas angiogenesis and LV ejection fraction were lowest in group 2 and lower in groups 3 and 4 than in group 5 (p < 0.003).


CONCLUSIONS
Early combined ADMSC/sildenafil is superior to either treatment alone in preserving LV function.
Lin
Yu-Chun
YC
Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Leu
Steve
S
Sun
Cheuk-Kwan
CK
Yen
Chia-Hung
CH
Kao
Ying-Hsien
YH
Chang
Li-Teh
LT
Tsai
Tzu-Hsien
TH
Chua
Sarah
S
Fu
Morgan
M
Ko
Sheung-Fat
SF
Wu
Chiung-Jen
CJ
Lee
Fan-Yen
FY
Yip
Hon-Kan
HK
D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000503:physiopathology / Q000628:therapy*; D018031:Connexin 43 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D009929:Organ Size; D018384:Oxidative Stress; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage*; D011687:Purines / Q000008:administration & dosage; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage*; D014463:Ultrasonography
D018031:Connexin 43; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D045304:Cytochromes c; D000068677:Sildenafil Citrate