Chen Guo-Ping, Zhang Xiao-Qin, Wu Tao, Han Jie, Ye Dan
Department of Endocrinology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
Department of Respirology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China.
Mol Med Rep. 2017 May;15(5):3153-3160. doi: 10.3892/mmr.2017.6360. Epub 2017 Mar 23.
The proliferation of vascular smooth muscle cells (VSMCs) is one of the main features of atherosclerosis accelerated by hyperglycemia. Our previous studies found that farnesyl pyrophosphate synthase (FPPS, EC 2.5.1.10), an essential enzyme in the mevalonate pathway, was upregulated in aorta media from diabetic mice along with the process of atherosclerosis. However, the exact role of FPPS in high glucose‑induced proliferation of VSMCs is largely unclear. In our study, we found that alendronate (an FPPS inhibitor) attenuated diabetic accelerated atherosclerosis in vivo and suppressed high glucose‑induced VSMCs proliferation in vitro. Moreover, in aorta from streptozotocin (STZ)‑induced diabetic mice, 16‑week treatment of alendronate decreased the activation of small GTPase (Ras, RhoA, and Rac1), but had no effect on the expression of cystathionine γ‑lyase (CSE), the pivotal H2S‑producing enzyme. Meanwhile, in VSMCs cultured in high glucose‑containing media, alendronate remarkably decreased total CoQ content, increased the H2S level, depressed small GTPases (Ras, RhoA, and Rac1) activation, but yet had no effect on expression of CSE. In conclusion, FPPS inhibition by alendronate attenuated the high glucose‑induced proliferation of VSMCs both in vivo and in vitro, probably though depressing H2S metabolism and suppressing small GTPases (Ras, RhoA, and Rac1) activation.
血管平滑肌细胞（VSMCs）的增殖是高血糖加速动脉粥样硬化的主要特征之一。我们之前的研究发现，法尼基焦磷酸合酶（FPPS，EC 2.5.1.10）是甲羟戊酸途径中的一种关键酶，在糖尿病小鼠的主动脉中膜中随着动脉粥样硬化进程而上调。然而，FPPS在高糖诱导的VSMCs增殖中的确切作用仍不清楚。在我们的研究中，我们发现阿仑膦酸钠（一种FPPS抑制剂）在体内减轻了糖尿病加速的动脉粥样硬化，并在体外抑制了高糖诱导的VSMCs增殖。此外，在链脲佐菌素（STZ）诱导的糖尿病小鼠的主动脉中，16周的阿仑膦酸钠治疗降低了小GTP酶（Ras、RhoA和Rac1）的激活，但对关键的硫化氢产生酶胱硫醚γ-裂解酶（CSE）的表达没有影响。同时，在含高糖培养基中培养的VSMCs中，阿仑膦酸钠显著降低了总辅酶Q含量，提高了硫化氢水平，抑制了小GTP酶（Ras、RhoA和Rac1）的激活，但对CSE的表达没有影响。总之，阿仑膦酸钠抑制FPPS在体内和体外均减轻了高糖诱导的VSMCs增殖，可能是通过抑制硫化氢代谢和抑制小GTP酶（Ras、RhoA和Rac1）的激活来实现的。
