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Arteriosclerosis, thrombosis, and vascular biology (1)
PLoS ONE (1)
Zheng, Xi-Long (2)
Catharina, Elisabeth Petronella (1)
Chen, Jie (1)
Chen, Yong (1)
Gui, Yu (1)
Hong, Bing (1)
Huang, Zhan-Peng (1)
Jiang, Fen-Jun (1)
Jiang, Yulan (1)
Klionsky, Daniel J. (1)
Li, Jingjing (1)
Liang, Yongheng (1)
Ni, Tao (1)
Park, Min (1)
Radhakrishnan, Sarvan Kumar (1)
Shi, Zhan (1)
Srivastava, Rakesh K. (1)
Sweeney, Gary (1)
Wang, Da-Zhi (1)
Wang, Hai-Yan (1)
Wu, Donghai (1)
Xie, Zhiping (1)
Xu, Aimin (1)
Yin, Hao (1)
Youn, ByungSoo (1)
Yu, Zhong-Qiu (1)
Zheng, Xi-long (1)
Zou, Shenshen (1)
Year of Publication
Dual roles of Atg8−PE deconjugation by Atg4 in autophagy
Klionsky, Daniel J.
Modification of target molecules by ubiquitin or ubiquitin-like (Ubl) proteins is generally reversible. Little is known, however, about the physiological function of the reverse reaction, deconjugation. Atg8 is a unique Ubl protein whose conjugation target is the lipid phosphatidylethanolamine (PE). Atg8 functions in the formation of double-membrane autophagosomes, a central step in the well-conserved intracellular degradation pathway of macroautophagy (hereafter autophagy). Here we show that the deconjugation of Atg8−PE by the cysteine protease Atg4 plays dual roles in the formation of autophagosomes. During the early stage of autophagosome formation, deconjugation releases Atg8 from non-autophagosomal membranes to maintain a proper supply of Atg8. At a later stage, the release of Atg8 from intermediate autophagosomal membranes facilitates the maturation of these structures into fusion-capable autophagosomes. These results provide new insights into the functions of Atg8−PE and its deconjugation.
autophagy; ubiquitin-like proteins; deconjugation; Atg4; Atg8
Induction of MicroRNA-1 by Myocardin in Smooth Muscle Cells Inhibits Cell Proliferation
Radhakrishnan, Sarvan Kumar
Catharina, Elisabeth Petronella
Arteriosclerosis, thrombosis, and vascular biology
Myocardin is a cardiac- and smooth muscle-specific transcription factor that potently activates the expression of downstream target genes. Previously, we demonstrated that overexpression of myocardin inhibited the proliferation of smooth muscle cells (SMCs). Recently, myocardin was reported to induce the expression of microRNA-1 (miR-1) in cardiomyocytes. In this study, we investigate whether myocardin induces miR-1 expression to mediate its inhibitory effects on SMC proliferation.
Methods and Results
Using T-REx inducible system expressing myocardin in human vascular SMCs, we found that overexpression of myocardin resulted in significant induction of miR-1 expression and inhibition of SMC proliferation, which was reversed by miR-1 inhibitors. Consistently, introduction of miR-1 into SMCs dramatically inhibited their proliferation. We have isolated spindle-shaped and epithelioid human SMCs and demonstrated that spindle-shaped SMCs were more differentiated and less proliferative. Correspondingly, spindle-shaped SMCs had significantly higher expression levels of both myocardin and miR-1 than epithelioid SMCs. We identified Pim-1, a serine/threonine kinase, as a target gene for miR-1 in SMCs. Western blot and luciferase reporter assays further confirmed that miR-1 targets Pim-1 directly. Furthermore, neointimal lesions of mouse carotid arteries display down-regulation of myocardin and miR-1 with up-regulation of Pim-1.
Our data demonstrate that miR-1 participates myocardin-dependent SMC proliferation inhibition.
microRNA-1; myocardin; Pim-1; proliferation; vascular smooth muscle cells
Globular Adiponectin, Acting via AdipoR1/APPL1, Protects H9c2 Cells from Hypoxia/Reoxygenation-Induced Apoptosis
Srivastava, Rakesh K.
Cardiomyocyte apoptosis is an important remodeling event contributing to heart failure and adiponectin may mediate cardioprotective effects at least in part via attenuating apoptosis. Here we used hypoxia-reoxygenation (H/R) induced apoptosis in H9c2 cells to examine the effect of adiponectin and cellular mechanisms of action. We first used TUNEL labeling in combination with laser scanning cytometry to demonstrate that adiponectin prevented H/R-induced DNA fragmentation. The anti-apoptotic effect of adiponectin was also verified via attenuation of H/R-induced phosphatidylserine exposure using annexin V binding. H/R-induced apoptosis via the mitochondrial-mediated intrinsic pathway of apoptosis as assessed by cytochrome c release into cytosol and caspase-3 activation, both of which were attenuated by adiponectin. Mechanistically, we demonstrated that adiponectin enhanced anti-oxidative potential in these cells which led to attenuation of the increase in intracellular reactive oxygen species (ROS) caused by H/R. To further address the mechanism of adiponctins anti-apoptotic effects we used siRNA to efficiently knockdown adiponectin receptor (AdipoR1) expression and found that this attenuated the protective effects of adiponectin on ROS production and caspase 3 activity. Knockdown of APPL1, an important intracellular binding partner for AdipoR, also significantly reduced the ability of adiponectin to prevent H/R-induced ROS generation and caspase 3 activity. In summary, H/R-induced ROS generation and activation of the intrinsic apoptotic pathway was prevented by adiponectin via AdipoR1/APPL1 signaling and increased anti-oxidant potential.
Results 1-3 (3)
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