Masuda Masashi, Miyazaki-Anzai Shinobu, Keenan Audrey L, Okamura Kayo, Kendrick Jessica, Chonchol Michel, Offermanns Stefan, Ntambi James M, Kuro-O Makoto, Miyazaki Makoto
J Clin Invest. 2015 Oct 26;125(12):4544-58. doi: 10.1172/JCI82871.
Recent evidence indicates that saturated fatty acid-induced (SFA-induced) lipotoxicity contributes to the pathogenesis of cardiovascular and metabolic diseases; however, the molecular mechanisms that underlie SFA-induced lipotoxicity remain unclear. Here, we have shown that repression of stearoyl-CoA desaturase (SCD) enzymes, which regulate the intracellular balance of SFAs and unsaturated FAs, and the subsequent accumulation of SFAs in vascular smooth muscle cells (VSMCs), are characteristic events in the development of vascular calcification. We evaluated whether SMC-specific inhibition of SCD and the resulting SFA accumulation plays a causative role in the pathogenesis of vascular calcification and generated mice with SMC-specific deletion of both Scd1 and Scd2. Mice lacking both SCD1 and SCD2 in SMCs displayed severe vascular calcification with increased ER stress. Moreover, we employed shRNA library screening and radiolabeling approaches, as well as in vitro and in vivo lipidomic analysis, and determined that fully saturated phosphatidic acids such as 1,2-distearoyl-PA (18:0/18:0-PA) mediate SFA-induced lipotoxicity and vascular calcification. Together, these results identify a key lipogenic pathway in SMCs that mediates vascular calcification.
最近的证据表明，饱和脂肪酸诱导的（SFA诱导的）脂毒性促成了心血管和代谢疾病的发病机制；然而，SFA诱导脂毒性的分子机制仍不清楚。在这里，我们已经表明，硬脂酰辅酶A去饱和酶（SCD）酶的抑制调节了饱和脂肪酸和不饱和脂肪酸的细胞内平衡，随后饱和脂肪酸在血管平滑肌细胞（VSMC）中的积累是血管钙化发展过程中的特征性事件。我们评估了SMC特异性抑制SCD以及由此产生的SFA积累是否在血管钙化的发病机制中起因果作用，并生成了SMC特异性缺失Scd1和Scd2的小鼠。SMC中同时缺乏SCD1和SCD2的小鼠表现出严重的血管钙化，内质网应激增加。此外，我们采用了shRNA文库筛选和放射性标记方法，以及体外和体内脂质组学分析，并确定完全饱和的磷脂酸，如1,2-二硬脂酰-PA（18:0/18:0-PA）介导SFA诱导的脂毒性和血管钙化。总之，这些结果确定了SMC中一条介导血管钙化的关键脂肪生成途径。
