Programmed cell death 5 suppresses AKT-mediated cytoprotection of endothelium

Abstract

Programmed cell death 5 (PDCD5) has been associated with human cancers as a regulator of cell death; however, the role of PDCD5 in the endothelium has not been revealed. Thus, we investigated whether PDCD5 regulates protein kinase B (PKB/AKT)-endothelial nitric oxide synthase (eNOS)-dependent signal transduction in the endothelium and affects atherosclerosis. Endothelial-specific PDCD5 knockout mice showed significantly reduced vascular remodeling compared with wild-type (WT) mice after partial carotid ligation. WT PDCD5 competitively inhibited interaction between histone deacetylase 3 (HDAC3) and AKT, but PDCD5, an HDAC3-binding-deficient mutant, did not. Knockdown of PDCD5 accelerated HDAC3-AKT interaction, AKT and eNOS phosphorylation, and nitric oxide (NO) production in human umbilical vein endothelial cells. Moreover, we found that serum PDCD5 levels reflect endothelial NO production and are correlated with diabetes mellitus, high-density lipoprotein cholesterol, and coronary calcium in human samples obtained from the cardiovascular high-risk cohort. Therefore, we conclude that PDCD5 is associated with endothelial dysfunction and may be a novel therapeutic target in atherosclerosis.

The Role of Ceramide and Sphingosine-1-Phosphate in Alzheimer’s Disease and Other Neurodegenerative Disorders

“…The prevailing role of elevated ceramide in cell degeneration/death is mediated by multiple signals: inhibition of mitochondrial respiration and increased production of reactive oxygen species [55]; the release of AIF, cytochrome c , or SMAC from mitochondria; the Bcl-2-binding protein beclin1; autophagosomal LC3-II (which binds mitochondrial ceramide to induce lethal mitophagy) [56–58]. While inhibition of HDAC1 and -2 is engaged in the pro-survival signaling of S1P, the role of HDAC3 is more ambiguous [59–62]. AIF, apoptosis-inducing factor; AP-1, activator protein-1; aSMase, acid SMase; LC3-II, lipidated microtubule-associated protein 1 light chain 3β; C1P, ceramide-1-phosphate; C1PP, C1P phosphatase; CERS, ceramide synthase; DEGS, dihydroceramide desaturase; ERK, extracellular signal-regulated kinase; FOXO, forkhead box protein O; GSK-3β, glycogen synthase kinase 3β; HDAC, histone deacetylase; Jnk, c-Jun N-terminal kinase; MRC, mitochondrial respiratory chain; NF-κB, nuclear factor κB; PI3K, phosphoinositide 3-kinase; PP2A, protein phosphatase 2A; ROS, reactive oxygen species; S1P, sphingosine-1-phosphate; S1PR, S1P receptors; SMAC, second mitochondria-derived activator of caspases; SMase, sphingomyelinase; SPHK, sphingosine kinase; SPT, serine palmitoyltransferase; TRAF2, TNF receptor-associated factor 2…”

Club cell-specific role of programmed cell death 5 in pulmonary fibrosis

“…PDCD5 inhibits the function of HDAC3 and promotes activation of p53 to induce apoptosis 9 . In addition, PDCD5 reduces nitric oxide production by inhibiting the physical interaction between AKT and HDAC3 in endothelial cells without affecting apoptosis 10 . Thus, PDCD5 participates in varied cellular signaling pathways via regulation of protein–protein interactions.…”

Reproducible large-scale synthesis of surface silanized nanoparticles as an enabling nanoproteomics platform: Enrichment of the human heart phosphoproteome

“…5b and S8). PDCD5 is an important modulator of the apoptotic pathway required for normal cardiovascular development, and serum PDCD5 has been recently shown to reflect vascular endothelial status, which is significantly correlated with cardiovascular risk [57–59]. Along with a N-terminal methionine excision and a coexisting acetylation, the most probable phosphorylation site was determined to be Ser119 (Fig.…”