Effect of Toll-like Receptor 4 on Cardiac Hypertrophy in Hypertension

为了探讨Toll样受体4(TLR4)在血管紧张素II(Ang II)或去甲肾上腺素(NE)诱导的压力超负荷后心肌肥大和功能中的作用。将TLR4基因敲除的小鼠和野生型(WT)遗传背景小鼠(BALB/c)随机分为两组，分别植入血管紧张素II(AT II)或去甲肾上腺素(NE)渗透压微泵2周。血管紧张素II和去甲肾上腺素均使四组大鼠的收缩压显著升高(p&lt；0.05)，而在整个实验过程中，四组大鼠的血压和心率无显著差异。与Ang II诱导的压力超负荷WT小鼠相比，Ang II诱导的压力超负荷TLR4基因敲除小鼠的射血分数(EF)和短轴缩短率(%FS)均显著增加(p&lt；0.05)，且左心室收缩末期内径(LVESd，p&lt；0.05)明显减小。相反，与去甲肾上腺素诱导的压力超负荷WT小鼠相比，去甲肾上腺素诱导的压力超负荷TLR4基因敲除小鼠的LVESd较小，EF和%FS增加，但这些指标均未达到统计学意义。四组间左室舒张末期内径、室间隔、左室舒张期壁厚度和心脏重量无差异。与Ang II诱导的压力超负荷WT小鼠相比，Ang II诱导的压力超负荷TLR4基因敲除小鼠血管周围胶原体积分数(p&lt；0.05)和管腔比(p&lt；0.05)均显著增加。这些结果提示，TLR4可能参与了Ang II诱导的心脏收缩功能障碍的发生，但不影响心肌肥厚。

We investigated the role of Toll-like receptor 4 (TLR4) in cardiac hypertrophy and function following angiotensin II (Ang II) or norepinephrine (NE) -induced pressure overload in mice in vivo.TLR4-knocked out mice, and wild-type (WT) genetic background mice (BALB/c) were randomized into two groups and implanted osmotic minipumps of Angiotensin II (AT II) or Norepinephrine (NE) for 2 weeks. Both Ang II and NE induced a significant increase in systolic blood pressures among the four groups (p<0.05), while blood pressures and heart rates were not significantly different among the four groups throughout the experiments. Compared with Ang II -induced pressure overload WT mice, Ang II-induced pressure overload TLR4-knockout mice showed a significant increase in both ejection fraction (EF) and % fractional shortening (%FS) (p<0.05), and also demonstrated a smaller left ventricular end-systolic dimension (LVESd, p<0.05). In contrast, compared with NE-induced pressure overload WT mice, NE-induced pressure overload TLR4-knockout mice showed smaller LVESd and an increase in EF and %FS; these indices, however, did not reach statistical significance. Left ventricular end-diastolic dimension, interventricular septum, left ventricular diastolic wall thickness, and heart weight did not differ among the four groups. Compared with Ang II-induced pressure overload WT mice, Ang II-induced pressure overload TLR4-knockout mice showed a significant increase in both perivascular collagen volume fraction (p<0.05), and wall-to-lumen ratio (p<0.05). These results suggest that TLR4 may be involved in the development of Ang II-induced cardiac systolic dysfunction without affecting cardiac hypertrophy.