Apolipoprotein L6, Induced in Atherosclerotic Lesions, Promotes Apoptosis and Blocks Beclin 1-dependent Autophagy in Atherosclerotic Cells

Abstract

Inflammatory cytokine-regulated apoptosis and autophagy play pivotal roles in plaque rupture and thrombosis of atherosclerotic lesions. However, the molecular interplay between apoptosis and autophagy in vascular cells has not been investigated. Our prior study showed that human apolipoprotein L6 (ApoL6), a pro-apoptotic BH3-only member of the Bcl-2 family, was one of the downstream targets of interferon-␥ (INF␥), which sensitizes atherosclerotic lesion-derived cells (LDCs) to Fas-induced apoptosis. To investigate whether ApoL6 plays a causal role in atherosclerotic apoptosis and autophagy, in this study, we demonstrate that IFN␥ treatment itself strongly induces ApoL6, and ApoL6 is highly expressed and partially colocalized with activated caspase 3 in activated smooth muscle cells in atherosclerotic lesions. In addition, overexpression of ApoL6 promotes reactive oxygen species (ROS) generation, caspase activation, and subsequent apoptosis, which can be blocked by pan caspase inhibitor and ROS scavenger. Knockdown of ApoL6 expression by siApoL6 suppresses INF␥-and Fas-mediated apoptosis. Further, ApoL6 binds Bcl-X L , one of the most abundant anti-death proteins in LDCs. Interestingly, forced ApoL6 expression in LDCs induces degradation of Beclin 1, accumulation of p62, and subsequent attenuation of LC3-II formation and translocation and thus autophagy, whereas siApoL6 treatment reverts the phenotype. Taken together, our results suggest that ApoL6 regulates both apoptosis and autophagy in SMCs. IFN␥-initiated, ApoL6-induced apoptosis in vascular cells may be an important factor causing plaque instability and a potential therapeutic target for treating atherosclerosis and cardiovascular disease.Atherosclerosis, a chronic inflammatory disease and the principal cause of heart attack and stroke, contributes to at least 30% of all mortality in the United States (1, 2). The atherosclerotic lesion results from a dynamic interplay involving many elements of dysfunctional wound repair, including proliferation, matrix synthesis, autophagy (self-eating), and apoptosis, in response to insult of the vascular endothelial cells (ECs) 2 and smooth muscle cells (SMCs) of the artery wall (3, 4). The crosstalk between cytokines, chemokines, growth factors, oxidized lipid species/low density lipoproteins (LDLs), and reactive oxygen species (ROS) in atherosclerotic lesions determine cell survival and death (5, 6). Inflammation, based on the particular cellular context, can modulate proliferation or apoptosis (type I programmed cell death) of different cell-types, such as ECs, SMCs, and the inflammatory infiltrate (lymphocytes, and monocytes/macrophages) in atherosclerotic lesions (7,8). With regard to cell death, it has been well documented that during the early stages of lesion development, apoptosis of macrophages contributes to the accumulation of extracellular LDLs and protein debris, while in the later stages, activated SMCs encapsulate the lipid-rich regions, and their persistence contributes to collagen synthesis, matrix accu...

Low MiR-187 Expression Promotes Resistance to Chemoradiation Therapy In Vitro and Correlates with Treatment Failure in Patients with Esophageal Adenocarcinoma

“…APOL1, 3 and 6 were also downregulated with miR-187 overexpression. APOL1 and APOL6 proteins have been identified as regulators of autophagy (40,41). OAS1 encodes a protein of the 2′-5′ OAS family, which is involved in the innate immune response, the OAS2 and OASL genes were also downregulated with miR-187 overexpression.…”

Inefficient Type I Interferon-Mediated Antiviral Protection of Primary Mouse Neurons Is Associated with the Lack of Apolipoprotein L9 Expression

“…Other members of the ApoL family are predicted to lack a signal peptide, and it is unclear whether they are secreted. Human ApoL6 was reported to promote apoptosis and to inhibit autophagy (46,47), both of which might affect viral replication. In a broad ISG screen for antiviral activity, Schoggins et al (39) observed an antiviral activity for several members of the human ApoL family.…”

APOL1 Kidney Disease Risk Variants: An Evolving Landscape

“…For this reason, extracellular pathogens are thought to have shaped the evolution of APOL1, whereas intracellular pathogens would have driven evolution of the other APOL genes [7]. The up-regulation of APOL genes by pro-inflammatory cytokines (e.g., interferon-γ [IFNγ] and tumor necrosis factor [TNF]) and their involvement in autophagy and apoptosis suggest that most APOL genes may be involved in innate immune defense[10,12,13,15]. …”

“…Multiple mechanisms have been proposed for how APOL1 might contribute to glomerulopathies, including lysosomal membrane permeabilization [24,25], autophagic cell death [10,12,26], apoptosis [7,11], and necrosis [24], but clearly much emphasis has been placed on cell death. Non-risk APOL1 (G0) induces autophagic cell death in p53-null human colorectal cancer cells [10], but this pathway of programmed cell death is not well understood and remains controversial [27–29].…”