Dataset Information
Short AIP1 (ASK1-Interacting Protein-1) Isoform Localizes to the Mitochondria and Promotes Vascular Dysfunction.
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ABSTRACT: Objective
Vascular endothelial cells (ECs) normally maintain vascular homeostasis and are regulated by proinflammatory cytokines and reactive oxygen species. A human genome-wide association study identified that AIP1 (ASK1 [apoptosis signal-regulating kinase 1]-interacting protein-1; also identified as DAB2IP) gene variants confer susceptibility to cardiovascular disease, but the underlying mechanism is unknown. Approach and Results: We detected a normal AIP1 form (named AIP1A) in the healthy aorta, but a shorter form of AIP1 (named AIP1B) was found in diseased aortae that contained atherosclerotic plaques and graft arteriosclerosis. AIP1B transcription in resting ECs was suppressed through epigenetic inhibition by RIF1 (Rap1 [ras-related protein 1]-interacting factor 1)/H3K9 (histone H3 lysine 9) methyltransferase-mediated H3K9 trimethylation, and this inhibition was released by proinflammatory cytokines. AIP1A, but not AIP1B, was downregulated by proteolytic degradation through a Smurf1 (SMAD [suppressor of mothers against decapentaplegic miscellaneous] ubiquitylation regulatory factor 1)-dependent pathway in ECs under inflammation. Therefore, AIP1B was the major form present during inflammatory conditions. AIP1B, which lacks the N-terminal pleckstrin homology domain of AIP1A, localized to the mitochondria and augmented TNF? (tumor necrosis factor alpha)-induced mitochondrial reactive oxygen species generation and EC activation. AIP1B-ECTG (EC-specific AIP1B transgenic) mice exhibited augmented reactive oxygen species production, EC activation, and neointima formation in vascular remodeling models.Conclusions
Our current study suggests that a shift from anti-inflammatory AIP1A to proinflammatory AIP1B during chronic inflammation plays a key role in inflammatory vascular diseases.
SUBMITTER: Li Z
PROVIDER: S-EPMC7204498 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
Publications
Short AIP1 (ASK1-Interacting Protein-1) Isoform Localizes to the Mitochondria and Promotes Vascular Dysfunction.
Arteriosclerosis, thrombosis, and vascular biology 20191017 1
<h4>Objective</h4>Vascular endothelial cells (ECs) normally maintain vascular homeostasis and are regulated by proinflammatory cytokines and reactive oxygen species. A human genome-wide association study identified that <i>AIP1</i> (ASK1 [apoptosis signal-regulating kinase 1]-interacting protein-1; also identified as <i>DAB2IP</i>) gene variants confer susceptibility to cardiovascular disease, but the underlying mechanism is unknown. Approach and Results: We detected a normal AIP1 form (named AI ...[more]