Glucose fluctuations promote vascular BK channels dysfunction via PKCα/NF-κB/MuRF1 signaling

Autor: Qiang Chai, Tian-You Ling, Li Xiaoyan, Zhen-Ye Zhang, Fu Yi, Ru-Xing Wang, Xin Ma, L L Qian, Ning Wang, Ling-Feng Miao, Min Pan, Ying Wu, Liu Xiaoyu, Shipeng Dang
Rok vydání: 2020
Předmět:
0301 basic medicine
medicine.medical_specialty
BK channel
Protein Kinase C-alpha
Ubiquitin-Protein Ligases
Myocytes
Smooth Muscle
Down-Regulation
chemistry.chemical_element
030204 cardiovascular system & hematology
Calcium
Rats
Sprague-Dawley
03 medical and health sciences
0302 clinical medicine
Malondialdehyde
Internal medicine
Diabetes mellitus
medicine
Animals
Humans
Insulin
Large-Conductance Calcium-Activated Potassium Channels
Patch clamp
Molecular Biology
Cells
Cultured
biology
NF-kappa B
Iberiotoxin
Streptozotocin
medicine.disease
Coronary Vessels
Coronary arteries
Protein Subunits
Glucose
030104 developmental biology
Endocrinology
medicine.anatomical_structure
chemistry
Proteolysis
biology.protein
Reactive Oxygen Species
Cardiology and Cardiovascular Medicine
Signal Transduction
medicine.drug
Artery
Zdroj: Journal of Molecular and Cellular Cardiology. 145:14-24
ISSN: 0022-2828
Popis: Glucose fluctuations may contribute to large conductance calcium activated potassium (BK) channel dysfunction. However, the underlying mechanisms remain elusive. The aim of this study was to investigate the molecular mechanisms involved in BK channel dysfunction as a result of glucose fluctuations. A rat diabetic model was established through the injection of streptozotocin. Glucose fluctuations in diabetic rats were induced via consumption and starvation. Rat coronary arteries were isolated and coronary vascular tensions were measured after three weeks. Rat coronary artery smooth muscle cells were isolated and whole-cell BK channel currents were recorded using a patch clamp technique. Human coronary artery smooth muscle cells in vitro were used to explore the underlying mechanisms. After incubation with iberiotoxin (IBTX), the Δ tensions (% Max) of rat coronary arteries in the controlled diabetes mellitus (C-DM), the uncontrolled DM (U-DM) and the DM with glucose fluctuation (GF-DM) groups were found to be 84.46 ± 5.75, 61.89 ± 10.20 and 14.77 ± 5.90, respectively (P .05), while the current densities of the BK channels in the three groups were 43.09 ± 4.35 pA/pF, 34.23 ± 6.07 pA/pF and 17.87 ± 4.33 pA/pF, respectively (P .05). The Δ tensions (% Max) of rat coronary arteries after applying IBTX in the GF-DM rats injected with 0.9% sodium chloride (NaCl) (GF-DM + NaCl) and the GF-DM rats injected with N-acetyl-L-cysteine (NAC) (GF-DM + NAC) groups were found to be 8.86 ± 1.09 and 48.90 ± 10.85, respectively (P .05). Excessive oxidative stress and the activation of protein kinase C (PKC) α and nuclear factor (NF)-κB induced by glucose fluctuations promoted the decrease of BK-β1 expression, while the inhibition of reactive oxygen species (ROS), PKCα, NF-κB and muscle ring finger protein 1 (MuRF1) reversed this effect. Glucose fluctuations aggravate BK channel dysfunction via the ROS overproduction and the PKCα/NF-κB/MuRF1 signaling pathway.
Databáze: OpenAIRE
Externí odkaz: