Blockade of MyD88 attenuates cardiac hypertrophy and decreases cardiac myocyte apoptosis in pressure overload-induced cardiac hypertrophy in vivo.
In this study, we evaluated whether blocking myeloid differentiation factor-88 (MyD88) could decrease cardiac myocyte apoptosis following pressure overload. Adenovirus expressing dominant negative MyD88 (Ad5-dnMyD88) or Ad5-green fluorescent protein (GFP) (Ad5-GFP) was transfected into rat hearts (n = 8/group) immediately followed by aortic banding for 3 wk. One group of rats (n = 8) was subjected to aortic banding for 3 wk without transfection. Sham surgical operation (n = 8) served as control. The ratios of heart weight to body weight (HW/BW) and heart weight to tibia length (HW/TL) were calculated. Cardiomyocyte size was examined by FITC-labeled wheat germ agglutinin staining of membranes. Cardiac myocyte apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and myocardial interstitial fibrosis was examined by Masson's Trichrome staining. Aortic banding significantly increased the HW/BW by 41.0% (0.44 +/- 0.013 vs. 0.31 +/- 0.008), HW/TL by 47.2% (42.7 +/- 1.30 vs. 29.0 +/- 0.69), cardiac myocyte size by 49.6%, and cardiac myocyte apoptosis by 11.5%, and myocardial fibrosis and decreased cardiac function compared with sham controls. Transfection of Ad5-dnMyD88 significantly reduced the HW/BW by 18.2% (0.36 +/- 0.006 vs. 0.44 +/- 0.013) and HW/TL by 22.3% (33.2 +/- 0.95 vs. 42.7 +/- 1.30) and decreased cardiomyocyte size by 56.8%, cardiac myocyte apoptosis by 76.2%, as well as fibrosis, and improved cardiac function compared with aortic-banded group. Our results suggest that MyD88 is an important component in the Toll-like receptor-4-mediated nuclear factor-kappaB activation pathway that contributes to the development of cardiac hypertrophy. Blockade of MyD88 significantly reduced cardiac hypertrophy, cardiac myocyte apoptosis, and improved cardiac function in vivo.
Ha
Tuanzhu
T
Department of Surgery, East Tennessee State University, Campus Box 70575, Johnson City, Tennessee 37614-0575, USA.
Hua
Fang
F
Li
Yuehua
Y
Ma
Jing
J
Gao
Xiang
X
Kelley
Jim
J
Zhao
Aiqiu
A
Haddad
Georges E
GE
Williams
David L
DL
Browder
I William
IW
Kao
Race L
RL
Li
Chuanfu
C
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency*; D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000175:diagnosis* / Q000209:etiology / Q000503:physiopathology*; D002478:Cells, Cultured; D006973:Hypertension / Q000150:complications* / Q000175:diagnosis / Q000503:physiopathology*; D008297:Male; D053594:Myeloid Differentiation Factor 88; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index
D048868:Adaptor Proteins, Signal Transducing; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88