Reduced cardiac hypertrophy in toll-like receptor 4-deficient mice following pressure overload.
OBJECTIVE
We have previously demonstrated that nuclear factor kappa B (NFkappaB) activation is needed for the development of cardiac hypertrophy in vivo. NFkappaB is a downstream transcription factor in the Toll-like receptor (TLR)-mediated signaling pathway; therefore, we investigated a role of TLR4 in cardiac hypertrophy in vivo.


METHODS
TLR4-deficient mice (C.C3H-Tlr4(lps-d), n = 6), wild-type (WT) genetic background mice (BALB/c, n = 6), TLR4-deleted strain (C57BL/10ScCr, n = 8), and WT controls (C57BL/10ScSn, n = 8) were subjected to aortic banding for 2 weeks. Age-matched surgically operated mice served as controls. In a separate experiment, rapamycin (2 mg/kg, daily) was administered to TLR4-deficient mice and WT mice immediately following aortic banding. The ratio of heart weight/body weight (HW/BW) was calculated, and cardiac myocyte size was examined by FITC-labeled wheat germ agglutinin staining of membranes. NFkappaB binding activity and the levels of phospho-p70S6K in the myocardium were also examined.


RESULTS
Aortic banding significantly increased the ratio of HW/BW by 33.9% (0.601 +/- 0.026 vs. 0.449 +/- 0.004) and cell size by 68.4% in WT mice and by 10.00% (0.543 +/- 0.011 vs. 0.495 +/- 0.005) and by 11.8% in TLR4-deficient mice, respectively, compared with respective sham controls. NFkappaB binding activity and phospho-p70S6K levels were increased by 182.6% and 115.2% in aortic-banded WT mice and by 78.0% and 162.0% in aortic-banded TLR4-deficient mice compared with respective sham controls. In rapamycin-treated aortic-banded mice, the ratio of HW/BW was increased by 18.0% in WT mice and by 3.5% in TLR4-deficient mice compared with respective sham controls.


CONCLUSIONS
Our results demonstrate that TLR4 is a novel receptor contributing to the development of cardiac hypertrophy in vivo and that both the TLR4-mediated pathway and PI3K/Akt/mTOR signaling are involved in the development of cardiac hypertrophy in vivo.
Ha
Tuanzhu
T
Department of Surgery, East Tennessee State University, Johnson City, 37614-0575, USA.
Li
Yuehua
Y
Hua
Fang
F
Ma
Jinag
J
Gao
Xiang
X
Kelley
Jim
J
Zhao
Aiqiu
A
Haddad
Georges E
GE
Williams
David L
DL
William Browder
I
I
Kao
Race L
RL
Li
Chuanfu
C
D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009203:Myocardial Infarction; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000627:therapeutic use; D051197:Toll-Like Receptor 4 / Q000172:deficiency*
D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus