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Protective effect of SERCA2a-SUMOylation by SUMO-1 on diabetes-induced atherosclerosis and aortic vascular injury

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Abstract

Diabetes is a major risk factor for cardiovascular disease. However, the exact mechanism by which diabetes contributes to vascular damage is not fully understood. The aim of this study was to investigate the role of SUMO-1 mediated SERCA2a SUMOylation in the development of atherosclerotic vascular injury associated with diabetes mellitus. ApoE−/− mice were treated with streptozotocin (STZ) injection combined with high-fat feeding to simulate diabetic atherosclerosis and vascular injury. Human aortic vascular smooth muscle cells (HAVSMCs) were treated with high glucose (HG, 33.3 mM) and palmitic acid (PA, 200 µM) for 24 h to mimic a model of diabetes-induced vascular injury in vitro. Aortic vascular function, phenotypic conversion, migration, proliferation, intracellular Ca2+ concentration, the levels of small ubiquitin-like modifier type 1 (SUMO1), SERCA2a and SUMOylated SERCA2a were detected. Diabetes-induced atherosclerotic mice presented obvious atherosclerotic plaques and vascular injury, companied by significantly lower levels of SUMO1 and SERCA2a in aorta. HG and PA treatment in HAVSMCs reduced the expressions of SUMO1, SERCA2a and SUMOylated SERCA2a, facilitated the HAVSMCs phenotypic transformation, proliferation and migration, attenuated the Ca2+ transport, and increased the resting intracellular Ca2+ concentration. We also confirmed that SUMO1 directly bound to SERCA2a in HAVSMCs. Overexpression of SUMO1 restored the function and phenotypic contractile ability of HAVSMCs by upregulating SERCA2a SUMOylation, thereby alleviating HG and PA-induced vascular injury. These observations suggest an essential role of SUMO1 to protect diabetes-induced atherosclerosis and aortic vascular injury by the regulation of SERCA2a-SUMOylation and calcium homeostasis.

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Data availability

The data and materials of the current study are available from the corresponding author upon reasonable request.

Abbreviations

CVDs :

Cardiovascular diseases

CAD :

Coronary artery disease

CHD :

Coronary heart disease

STZ :

Streptozotocin

HAVSMCs :

Human aortic vascular smooth muscle cells

HG :

High glucose

PA :

Palmitic acid

BSA :

Bovine serum albumin

HFD :

High-fat diet

IP :

Immunoprecipitation

IF :

Immunofluorescence

SERCA2a :

Sarcoplasmic/endoplasmic reticulum calcium ATPase 2a

SUMO :

Small ubiquitin-like modifier

eNOS :

Endothelial nitric oxide synthase

RUNX2 :

Runt-related transcription factor 2

αSMA :

α-Smooth muscle actin

SM22α :

Smooth muscle 22α

RyR2 :

Ryanodine receptor 2

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Funding

This work was supported by the National Natural Science Foundation of China (#32171181 and #31900534), the Natural Science Foundation of Hebei Province (#C2019201349), the Hundred Talents Funding Program of Hebei Province (#E2019050010), the Interdisciplinary Research Program of Natural Science of Hebei University (#DXK202105) and the Advanced Talents Incubation Program of the Hebei University (#801260201282).

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Author notes

  1. Jinlin Liu and Shifang Xu have contributed equally to this work.

Authors and Affiliations

  1. College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding, 071002, China

    Jinlin Liu, Shifang Xu, Bin Gao, Meng Yuan, Li Zhong & Rui Guo

  2. College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, USA

    Li Zhong

  3. The Key Laboratory of Zoological Systematics and Application, College of Life Sciences, Hebei University, Baoding, China

    Rui Guo

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  1. Jinlin Liu
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Contributions

Conceptualization was performed by RG. Study design and methodology were performed by JL and RG. Result validation and interpretation were performed by JL, SX and RG. Data analysis and figures preparation were performed by JL, SX, BG and MY. Writing—original draft preparation were performed by JL and SX. Writing—review and editing were performed by LZ and RG. All authors read and approved the final manuscript.

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Correspondence to Rui Guo.

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All experimental procedures and methods were approved by the Hebei University Animal Care and Use Committee (Approval No. IACUC-2021XG032).

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Liu, J., Xu, S., Gao, B. et al. Protective effect of SERCA2a-SUMOylation by SUMO-1 on diabetes-induced atherosclerosis and aortic vascular injury. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-04953-x

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