Promyelocytic leukemia protein promotes the phenotypic switch of smooth muscle cells in atherosclerotic plaques of human coronary arteries

Abstract

Promyelocytic leukemia protein (PML) is a constitutive component of PML nuclear bodies (PML-NBs), which function as stress-regulated SUMOylation factories. Since PML can also act as a regulator of the inflammatory and fibroproliferative responses characteristic of atherosclerosis, we investigated whether PML is implicated in this disease. Immunoblotting, ELISA and immunohistochemistry showed a strong up-regulation of PML in segments of human atherosclerotic coronary arteries compared to non-atherosclerotic ones. In particular, PML was concentrated in PML-NBs from alpha-smooth muscle actin-immunoreactive cells in plaque areas. To identify possible functional consequences of PML-accumulation in this cell-type, differentiated human coronary artery smooth muscle cells (dHCASMCs) were transfected with a vector containing the intact PML-gene. These PML-transfected HCASMCs showed higher levels of SUMO-1-dependent SUMOylated proteins, but lower levels of markers for smooth muscle cell differentiation and revealed more proliferation and migration activities than dHCASMCs transfected with the vector lacking a specific gene insert or with the vector containing a mutated PML-gene coding for a PML-form without SUMOylation activity. When dHCASMCs were incubated with different cytokines, higher PML-levels were observed only after IFN-γ stimulation, while the expression of differentiation markers decreased. However, these phenotypic changes were not observed in dHCASMCs treated with small interfering RNA (siRNA) suppressing PML-expression prior to IFN-γ stimulation. Taken together, our results imply that PML is a previously unknown functional factor in the molecular cascades associated with the pathogenesis of atherosclerosis and is positioned in vascular smooth muscle cells between up-stream IFN-γ activation and downstream SUMOylation.

GUIDE deconstructs genetic architectures using association studies

“…And while TSVD latent 53, the third contributing factor to peripheral vascular disease, does include GO processes related to cardiovascular morphology and function, it only predominantly prioritizes PITX2, and none of the other important genes implicated by GUIDE latent 8. For GUIDE, the third highest factor, GUIDE latent 64, significantly prioritizes genes such as AHR, PML, GDNF, and IRX1-3, which were not tagged by TSVD latent factors, but were recently implicated in important mechanisms contributing to vascular disease, such as vascular inflammatory pathways, atherosclerosis, endothelial dysfunction, and oxidative stress [34,35,36,37]. Running a GUIDE model on an LD-pruned set of FinnGen data [38] (r 2 < 0.2, with 188,140 SNPs and 2408 traits) revealed additional insights not found in the UKB models.…”

Promyelocytic leukemia protein: an atherosclerosis suppressor protein?

“…In terms of dysregulation of gene expression, cell proliferation, inflammatory response, and plaque VSMC clonality, some investigators have begun to focus their attention to proteins traditionally thought of as tumor promotors and tumor suppressor proteins as important players in atherogenesis. In this volume of Clinical Science, Karle et al [7] investigate the expression and functional ramifications of promyelocytic leukemia protein (PML) in development of atherosclerosis. Fittingly named, PML is a protein first detected in acute promyelocytic leukemia initially and classified as a tumor suppressor protein [8,9].…”

Serum-derived exosomal circENC1 inhibits SMC phenotypic switching to stabilize atherosclerotic plaques by interacting with miR-513a-5p and inhibiting MYH9 degradation

“…Previous studies have shown that numerous genes contribute to plaque stabilization by regulating SMC phenotypic switching [20][21][22][23] . Two challenges have been identified.…”