Ahn Sun Young, Choi Yon-Sik, Koo Hyun-Jung, Jeong Jae Hoon, Park Wook Ha, Kim Minseok, Piao Ying, Pak Youngmi Kim
Age-Related and Brain Diseases Research Center, Department of Nanopharmaceutical and Life Sciences, Department of Physiology, Kyung Hee University College of Medicine, Dongdaemoon-Gu Hoegi-Dong #1, Seoul 130-701, Korea.
Biochim Biophys Acta. 2010 Mar;1800(3):275-81. doi: 10.1016/j.bbagen.2009.09.005. Epub 2009 Sep 23.
Atherosclerosis is one of the major complications of diabetes, which may result from insulin resistance via mitochondrial dysfunction. Although a strong association between insulin resistance and cardiovascular disease has been suggested, it is not clear yet whether stress-inducing factors damage mitochondria and insulin signaling pathway in cardiovascular tissues.
We investigated whether stress-induced mitochondrial dysfunction might alter the insulin/Akt signaling pathway in A10 rat vascular smooth muscle cells (VSMC).
The treatment of oxidized low density lipoprotein (oxLDL) decreased ATP contents, mitochondrial respiration activity, mRNA expressions of OXPHOS subunits and IRS-1/2 and insulin-mediated phosphorylations of Akt and AMP-activated protein kinase (AMPK). Similarly, dideoxycytidine (ddC), the mtDNA replication inhibitor, or rotenone, OXPHOS complex I inhibitor, inhibited the insulin-mediated pAkt while increased pAMPK regardless of insulin. Reciprocally, an inhibitor of Akt, triciribine (TCN), decreased cellular ATP contents. Overexpression of Akt dominant positive reversed the oxLDL- or ddC-mediated ATP decrease but AMPK activator did not. Akt activation also normalized the aberrant VSMC migration induced by ddC.
Defective insulin signaling and mitochondrial function may collectively contribute to developing cardiovascular disease.
Akt may be a possible therapeutic target for treating insulin resistance-associated atherosclerosis.
动脉粥样硬化是糖尿病的主要并发症之一，可能由胰岛素抵抗通过线粒体功能障碍引起。尽管胰岛素抵抗与心血管疾病之间存在密切关联，但应激诱导因素是否会损害心血管组织中的线粒体和胰岛素信号通路尚不清楚。
我们研究了应激诱导的线粒体功能障碍是否会改变A10大鼠血管平滑肌细胞（VSMC）中的胰岛素/Akt信号通路。
氧化型低密度脂蛋白（oxLDL）处理降低了ATP含量、线粒体呼吸活性、氧化磷酸化亚基以及IRS-1/2的mRNA表达，以及胰岛素介导的Akt和AMP激活蛋白激酶（AMPK）的磷酸化。同样，线粒体DNA复制抑制剂双脱氧胞苷（ddC）或氧化磷酸化复合体I抑制剂鱼藤酮，无论有无胰岛素，均抑制胰岛素介导的pAkt，同时增加pAMPK。相反，Akt抑制剂三环己锡（TCN）降低了细胞ATP含量。Akt显性阳性的过表达逆转了oxLDL或ddC介导的ATP降低，但AMPK激活剂没有。Akt激活还使ddC诱导的异常VSMC迁移恢复正常。
胰岛素信号传导和线粒体功能缺陷可能共同导致心血管疾病的发生。
Akt可能是治疗胰岛素抵抗相关动脉粥样硬化的一个潜在治疗靶点。
