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Short AIP1 (ASK1-Interacting Protein-1) Isoform Localizes to the Mitochondria and Promotes Vascular Dysfunction

Zheng Li¹, Li Li^1,2, Haifeng Zhang¹

¹From the Vascular Biology and Therapeutics Program, Department of Pathology, Yale University School of Medicine, New Haven, CT (Z.L., L.L., H.Z., H.J.Z., W.M.).

Arteriosclerosis, Thrombosis, and Vascular Biology

|October 18, 2019

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 TNFα (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.

Insights

A shift from anti-inflammatory AIP1A to proinflammatory AIP1B during chronic inflammation drives vascular disease. This change in apoptosis signal-regulating kinase 1-interacting protein-1 (AIP1) forms promotes endothelial cell activation and reactive oxygen species generation.

Area of Science:

Vascular Biology
Molecular Biology
Genetics

Background:

Vascular endothelial cells (ECs) maintain homeostasis, regulated by inflammation and reactive oxygen species (ROS).
Genetic variants in apoptosis signal-regulating kinase 1-interacting protein-1 (AIP1) are linked to cardiovascular disease susceptibility.
The precise mechanism linking AIP1 to vascular disease remains unclear.

Purpose of the Study:

To investigate the role of different AIP1 protein isoforms in vascular homeostasis and disease.
To elucidate the molecular mechanisms by which AIP1 influences endothelial cell function during inflammation.

Main Methods:

Detection and characterization of AIP1 isoforms (AIP1A and AIP1B) in healthy and diseased human aortae.
Analysis of AIP1B transcription regulation via epigenetic modifications (H3K9 trimethylation) and inflammatory signals.
Investigation of AIP1 isoform localization, stability, and function in endothelial cells.
Assessment of vascular remodeling in EC-specific AIP1B transgenic (AIP1B-ECTG) mice.

Main Results:

A shorter AIP1 isoform (AIP1B) was identified in diseased aortae, contrasting with the normal form (AIP1A) in healthy vessels.
AIP1B transcription is epigenetically suppressed in resting ECs but upregulated by proinflammatory cytokines.
AIP1A is degraded during inflammation, leading to AIP1B dominance under inflammatory conditions.
AIP1B localizes to mitochondria, enhancing TNFα-induced ROS production and EC activation.
AIP1B-ECTG mice showed increased ROS, EC activation, and neointima formation.

Conclusions:

A shift from anti-inflammatory AIP1A to proinflammatory AIP1B occurs during chronic inflammation.
This isoform switch is a key mechanism in inflammatory vascular diseases.
AIP1B promotes vascular remodeling by increasing ROS generation and EC activation.

Read full analysis

Keywords:

animals aorta atherosclerosis epigenomics mice

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