Hsu Bernadette Y, Bae Yong Ho, Mui Keeley L, Liu Shu-Lin, Assoian Richard K
Program in Translational Biomechanics, Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2015 Jun 11;10(6):e0128974. doi: 10.1371/journal.pone.0128974. eCollection 2015.
Apolipoprotein E3 (apoE3) is thought to protect against atherosclerosis by enhancing reverse cholesterol transport. However, apoE3 also has cholesterol-independent effects that contribute to its anti-atherogenic properties. These include altering extracellular matrix protein synthesis and inhibiting vascular smooth muscle cell proliferation. Both of these cholesterol-independent effects result from an apoE3-mediated induction of cyclooxygenase-2 (Cox2). Nevertheless, how apoE3 regulates Cox2 remains unknown. Here, we show that apoE3 inhibits the activation of Rho, which reduces the formation of actin stress fibers and focal adhesions and results in cellular softening. Inhibition of Rho-Rho kinase signaling or direct cellular softening recapitulates the effect of apoE3 on Cox2 expression while a constitutively active Rho mutant overrides the apoE3 effect on both intracellular stiffness and Cox2. Thus, our results describe a previously unidentified mechanism by which an atheroprotective apolipoprotein uses Rho to control cellular mechanics and Cox2.
载脂蛋白E3（apoE3）被认为可通过增强逆向胆固醇转运来预防动脉粥样硬化。然而，apoE3也具有不依赖胆固醇的作用，这些作用有助于其抗动脉粥样硬化特性。这些作用包括改变细胞外基质蛋白合成以及抑制血管平滑肌细胞增殖。这两种不依赖胆固醇的作用均源于apoE3介导的环氧合酶-2（Cox2）的诱导。然而，apoE3如何调节Cox2仍不清楚。在这里，我们表明apoE3抑制Rho的激活，这会减少肌动蛋白应力纤维和粘着斑的形成，并导致细胞软化。抑制Rho-Rho激酶信号传导或直接使细胞软化可重现apoE3对Cox2表达的影响，而组成型活性Rho突变体则可超越apoE3对细胞内硬度和Cox2的影响。因此，我们的结果描述了一种先前未被识别的机制，即一种具有抗动脉粥样硬化作用的载脂蛋白利用Rho来控制细胞力学和Cox2。
