Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China.
School of Medical Psychology, Fourth Military Medical University, Xi'an, China.
J Cell Biochem. 2018 Nov;119(10):8022-8034. doi: 10.1002/jcb.26713. Epub 2018 Jun 20.
The mechanism of transition from chronic pressure overload-induced cardiac hypertrophy to heart failure is still unclear. Angiotensin II (Ang II) may be an important factor that mediates the transition in the end-stage of cardiac hypertrophy. In the present study, Goldblatt two-kidney one-clip (2K1C) rat model was used to simulate Ang II-induced hypertension. The elevated Ang II not only induced the concentric hypertrophy of left ventricle and cardiac fibrosis, but also increased the expression and glycosylation of CD147 in 2K1C rats. The left ventricular structure and function detected by echocardiogram showed a sign of the transition from cardiac hypertrophy to heart failure in 16 weeks of 2K1C rats. Ang II can activate N-acetylglucosamine transferase V (GnT-V), a key enzyme for CD147 glycosylation. Retinoic acid, an agonist of GnT-V, further increased glycosylated CD147, and activated matrix metalloproteinase-2/-9 (MMP-2 and MMP-9) in the hypertrophied left ventricle of 2K1C rat. Meanwhile, collagen cross-linking in the hypertrophied left ventricle significantly reduced in 2K1C rats. On the contrary, tunicamycin, an inhibitor of N-glycan biosynthesis, inhibited glycosylation of CD147 and activity of MMP-2 and MMP-9, and then maintained a stable of collagen cross-linking in the 2K1C rat hearts. The above results suggested that Ang II increased glycosylated CD147 which activated MMP-2 and MMP-9. Collagens were degraded by the activated MMPs and then reduced collagen cross-linking. Finally, the hypertrophied left ventricle was progressively dilated in chronic pressure overload due to losing the limitation of collagen cross-linking. Therefore, the compensated hypertrophy of left ventricle gradually transited to congestive heart failure.
慢性压力超负荷诱导的心肌肥厚向心力衰竭转变的机制尚不清楚。血管紧张素 II（Ang II）可能是介导心肌肥厚终末期转变的重要因素。在本研究中，采用 Goldblatt 双肾一夹（2K1C）大鼠模型模拟 Ang II 诱导的高血压。升高的 Ang II 不仅诱导左心室向心性肥厚和心肌纤维化，还增加了 2K1C 大鼠中 CD147 的表达和糖基化。超声心动图检测到的左心室结构和功能显示，2K1C 大鼠在 16 周时已从心肌肥厚向心力衰竭过渡。Ang II 可激活 CD147 糖基化的关键酶 N-乙酰氨基葡萄糖转移酶 V（GnT-V）。视黄酸是 GnT-V 的激动剂，进一步增加了糖基化的 CD147，并激活了 2K1C 大鼠肥厚左心室中的基质金属蛋白酶 2/-9（MMP-2 和 MMP-9）。同时，2K1C 大鼠肥厚左心室中的胶原交联显著减少。相反，N-聚糖生物合成抑制剂衣霉素抑制了 CD147 的糖基化和 MMP-2 和 MMP-9 的活性，从而维持了 2K1C 大鼠心脏中胶原交联的稳定。上述结果表明，Ang II 增加了糖基化的 CD147，激活了 MMP-2 和 MMP-9。激活的 MMP 降解胶原，从而减少胶原交联。最后，由于胶原交联的限制丧失，慢性压力超负荷引起的肥厚左心室逐渐扩张。因此，左心室代偿性肥厚逐渐过渡为充血性心力衰竭。
