Inhibition of vascular smooth muscle growth via signaling crosstalk between AMP-activated protein kinase and cAMP-dependent protein kinase.
Inhibition of vascular smooth muscle growth via signaling crosstalk between AMP-activated protein kinase and cAMP-dependent protein kinase.
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DOI：
10.3389/fphys.2012.00409
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发表时间：
2012
影响因子：
4
通讯作者：
Tulis DA
中科院分区：
文献类型：
--
作者：
Stone JD;Narine A;Tulis DA
异常血管平滑肌（VSM）生长是血管疾病病理生理的中心，但缺乏完全有效的治疗方法来抑制这种生长。我们的实验室和其他人最近的研究结果支持通过基于单磷酸腺苷（AMP）的方法来控制VSM的生长，包括代谢传感器AMP激活的蛋白激酶（AMPK）和camp依赖的蛋白激酶（PKA）。AMPK和PKA之间的分子串扰先前已被提出，但这种情况发生的程度及其在VSM中的生物学意义尚不清楚。考虑到它们共同的AMP主干和相似的信号特征，我们假设AMPK和PKA在调节VSM生长过程中存在串扰。在大鼠原代VSM细胞（VSMC）中，AMPK激动剂AICAR增加了AMPK活性和AMPK上催化Thr172位点的磷酸化。有趣的是，AICAR还磷酸化了AMPK上一个可疑的PKA抑制Ser485位点，这些累积事件被PKA抑制剂PKI逆转，这表明可能是PKA介导的AMPK调控。AICAR也以可逆的方式增加PKA活性。cAMP刺激剂forskolin增加了PKA活性，完全改善了Ser/Thr蛋白磷酸酶- 2c活性，提示PKA调控AMPK的潜在机制，因为PKI抑制PKA会降低AMPK活性。在功能上，AMPK抑制血清刺激的细胞周期进程和细胞增殖；然而，PKA没有这样做。此外，AMPK和PKA减少了PDGF-β刺激的VSMC迁移。总之，这些结果表明AMPK能够以抗增殖和抗迁移的方式抑制VSM的生长。此外，这些数据表明AMPK可能被PKA调制，并且这两个系统之间可能存在正反馈。这些发现揭示了VSM中AMPK和PKA之间的离散联系，并为代谢定向靶点减少病理性VSM生长提供了基础。
Abnormal vascular smooth muscle (VSM) growth is central in the pathophysiology of vascular disease yet fully effective therapies to curb this growth are lacking. Recent findings from our lab and others support growth control of VSM by adenosine monophosphate (AMP)-based approaches including the metabolic sensor AMP-activated protein kinase (AMPK) and cAMP-dependent protein kinase (PKA). Molecular crosstalk between AMPK and PKA has been previously suggested, yet the extent to which this occurs and its biological significance in VSM remain unclear. Considering their common AMP backbone and similar signaling characteristics, we hypothesized that crosstalk exists between AMPK and PKA in the regulation of VSM growth. Using rat primary VSM cells (VSMC), the AMPK agonist AICAR increased AMPK activity and phosphorylation of the catalytic Thr172 site on AMPK. Interestingly, AICAR also phosphorylated a suspected PKA-inhibitory Ser485 site on AMPK, and these cumulative events were reversed by the PKA inhibitor PKI suggesting possible PKA-mediated regulation of AMPK. AICAR also increased PKA activity in a reversible fashion. The cAMP stimulator forskolin increased PKA activity and completely ameliorated Ser/Thr protein phosphatase-2C activity, suggesting a potential mechanism of AMPK modulation by PKA since inhibition of PKA by PKI reduced AMPK activity. Functionally, AMPK inhibited serum-stimulated cell cycle progression and cellular proliferation; however, PKA failed to do so. Moreover, AMPK and PKA reduced PDGF-β-stimulated VSMC migration. Collectively, these results show that AMPK is capable of reducing VSM growth in both anti-proliferative and anti-migratory fashion. Furthermore, these data suggest that AMPK may be modulated by PKA and that positive feedback may exist between these two systems. These findings reveal a discrete nexus between AMPK and PKA in VSM and provide basis for metabolically-directed targets in reducing pathologic VSM growth.
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作者：
Mendelev NN;Williams VS;Tulis DA
通讯作者：
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