Copyright © 2005, European Society of Cardiology
Reduced cardiac hypertrophy in toll-like receptor 4-deficient mice following pressure overload
aDepartment of Surgery, East Tennessee State University, Campus Box 70575, Johnson City, TN 37614-0575, USA
bAnimal Model Research Center, Nanjing University, 210093, China
cDepartment of Internal Medicine, East Tennessee State University, Johnson City, TN 37614, USA
dDepartment of Physiology and Biophysics, Howard University, Washington DC 20059, USA
* Corresponding author. Department of Surgery, East Tennessee State University, Campus Box 70575, Johnson City, TN 37614-0575, USA. Tel.: +1 423 439 6349; fax: +1 423 439 6259. Email address: Li{at}MAIL.ETSU.EDU
Objective: We have previously demonstrated that nuclear factor kappa B (NF
B) activation is needed for the development of cardiac hypertrophy in vivo. NFB 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-Tlr4lps-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. NFB 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. NFB 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.
Conclusion: 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.
KEYWORDS Toll-like receptor; Cardiac hypertrophy; Signaling pathways; Nuclear factor KappaB (NFB); PI3K/Akt signaling pathway
Time for primary review 30 days
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