Kim Seul Gi, Sung Jin Young, Kang Young Jin, Choi Hyoung Chul
Department of Pharmacology, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Nam-Gu, Daegu 42415, Republic of Korea; Senotherapy-based Metabolic Disease Control Research Center, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Nam-Gu, Daegu 42415, Republic of Korea.
Department of Pharmacology, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Nam-Gu, Daegu 42415, Republic of Korea.
Arch Gerontol Geriatr. 2023 May;108:104927. doi: 10.1016/j.archger.2023.104927. Epub 2023 Jan 11.
Reactive oxygen species (ROS) are a key risk factor of cellular senescence and age-related diseases, and protein kinase C (PKC) has been shown to activate NADPH oxidases (NOXs), which generate ROS. Although PKC activation induces oxidative stress, leading to the cellular dysfunction in various cell types, the correlation between PKC and senescence has not been reported in vascular smooth muscle cell (VSMC). Several studies have indicated cellular senescence is accompanied by phosphatase and tensin homolog (PTEN) loss and that an interaction exists between PTEN and PKC. Therefore, we aimed to determine whether PTEN and PKC are associated with VSMC senescence and to investigate the mechanism involved. We found hydrogen peroxide (HO) decreased PTEN expression and increased PKCδ phosphorylation. Moreover, HO upregulated the NOX1 subunits, p22 and p47, and induced VSMC senescence via p53-p21 signaling pathway. We identified PKCδ activation contributed to VSMC senescence through activation of NOX1 and ROS production. However, fisetin inhibited cellular senescence induced by the PTEN-PKCδ-NOX1-ROS signaling pathway, and this anti-aging effect was attributed to reduced ROS production caused by suppressing NOX1 activation. These results suggest that the PTEN-PCKδ signaling pathway is directly related to senescence via NOX1 activation and that the downregulation of PKCδ by flavonoids provides a potential means of treating age-associated diseases.
活性氧（ROS）是细胞衰老和年龄相关疾病的关键危险因素，蛋白激酶C（PKC）已被证明可激活产生ROS的NADPH氧化酶（NOXs）。尽管PKC激活会诱导氧化应激，导致多种细胞类型出现细胞功能障碍，但PKC与血管平滑肌细胞（VSMC）衰老之间的相关性尚未见报道。多项研究表明，细胞衰老伴随着磷酸酶和张力蛋白同源物（PTEN）的缺失，且PTEN与PKC之间存在相互作用。因此，我们旨在确定PTEN和PKC是否与VSMC衰老相关，并研究其中涉及的机制。我们发现过氧化氢（HO）降低了PTEN的表达并增加了PKCδ的磷酸化。此外，HO上调了NOX1亚基p22和p47，并通过p53-p21信号通路诱导VSMC衰老。我们确定PKCδ激活通过激活NOX1和产生ROS促进了VSMC衰老。然而，非瑟酮抑制了由PTEN-PKCδ-NOX1-ROS信号通路诱导的细胞衰老，这种抗衰老作用归因于通过抑制NOX1激活而减少的ROS产生。这些结果表明，PTEN-PCKδ信号通路通过激活NOX1与衰老直接相关，类黄酮对PKCδ的下调提供了一种治疗年龄相关疾病的潜在方法。
