Glycosylated CD147 reduces myocardial collagen cross‐linking in cardiac hypertrophy
Glycosylated CD147 reduces myocardial collagen cross‐linking in cardiac hypertrophy
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DOI：
10.1002/jcb.26713
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发表时间：
2018-06
影响因子：
4
通讯作者：
Ning-yu Ru;Long-Biao Cui;Bo Jiao;Lin Zhang;Shuai Jiang;Zhi-Bin Yu
中科院分区：
文献类型：
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作者：
Ning-yu Ru;Long-Biao Cui;Bo Jiao;Lin Zhang;Shuai Jiang;Zhi-Bin Yu
从慢性压力超负荷引起的心肌肥厚到心力衰竭的机制尚不清楚。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。本研究采用Goldblatt两肾一夹(2K1C)大鼠模型模拟AngⅡ诱导的高血压。2K1C大鼠血管紧张素Ⅱ水平升高，不仅导致左心室向心性肥厚和心肌纤维化，而且使CD147的表达和糖基化水平增加。超声心动图检测2K1C大鼠16周的左心室结构和功能有从心肌肥厚向心力衰竭转变的迹象。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)。GnT-V激动剂维甲酸进一步增加2K1C大鼠肥厚左室壁糖基化的CD147，并激活基质金属蛋白酶-2/-9(MMP2/9)。同时，2K1C大鼠肥厚的左心室内胶原交联度显著降低。反之，N-糖链生物合成抑制剂衣霉素可抑制2K1C大鼠心脏CD147的糖基化及基质金属蛋白酶-2和基质金属蛋白酶-9的活性，从而维持稳定的胶原交联。以上结果提示，Ang II使糖基化的CD147表达增加，从而激活了基质金属蛋白酶-2和基质金属蛋白酶-9。活化的基质金属蛋白酶降解了胶原，从而减少了胶原的交联。最后，在慢性压力超负荷下，由于失去了胶原交联物的限制，肥厚的左心室逐渐扩张。因此，代偿性左心室肥厚逐渐过渡到充血性心力衰竭。
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.