Bin Li1, Yijin Yu2, Kun Liu1, Yuping Zhang2, Qi Geng2, Feng Zhang1, Yanning Li3,4, Jinsheng Qi5. 1. Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Hebei, People's Republic of China. 2. Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, Hebei, People's Republic of China. 3. Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Hebei, People's Republic of China. liyanning1981@126.com. 4. Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, Hebei, People's Republic of China. liyanning1981@126.com. 5. Department of Biochemistry, College of Integrated Chinese and Western Medicine, Hebei Medical University, Hebei, People's Republic of China. qijinsheng777@163.com.
Abstract
AIMS/HYPOTHESIS: Microvascular endothelial hyperpermeability, mainly caused by claudin-5 deficiency, is the initial pathological change that occurs in diabetes-associated cardiovascular disease. The ketone body β-hydroxybutyrate (BHB) exerts unique beneficial effects on the cardiovascular system, but the involvement of BHB in promoting the generation of claudin-5 to attenuate cardiac microvascular hyperpermeability in diabetes is poorly understood. METHODS: The effects of BHB on cardiac microvascular endothelial hyperpermeability and claudin-5 generation were evaluated in rats with streptozotocin-induced diabetes and in high glucose (HG)-stimulated human cardiac microvascular endothelial cells (HCMECs). To explore the underlying mechanisms, we also measured β-catenin nuclear translocation, binding of β-catenin, histone deacetylase (HDAC)1, HDAC3 and p300 to the Claudin-5 (also known as CLDN5) promoter, interaction between HDAC3 and β-catenin, and histone acetylation in the Claudin-5 promoter. RESULTS: We found that 10 weeks of BHB treatment promoted claudin-5 generation and antagonised cardiac microvascular endothelial hyperpermeability in rat models of diabetes. Meanwhile, BHB promoted claudin-5 generation and inhibited paracellular permeability in HG-stimulated HCMECs. Specifically, BHB (2 mmol/l) inhibited HG-induced HDAC3 from binding to the Claudin-5 promoter, although nuclear translocation or promoter binding of β-catenin did not change with BHB treatment. In addition, BHB prevented the binding and co-localisation of HDAC3 to β-catenin in HG-stimulated HCMECs. Furthermore, using mass spectrometry, acetylated H3K14 (H3K14ac) in the Claudin-5 promoter following BHB treatment was identified, regardless of whether cells were stimulated by HG or not. Although reduced levels of acetylated H3K9 in the Claudin-5 promoter were found following HG stimulation, increased H3K14ac was specifically associated with BHB treatment. CONCLUSIONS/ INTERPRETATION: BHB inhibited HDAC3 and caused acetylation of H3K14 in the Claudin-5 promoter, thereby promoting claudin-5 generation and antagonising diabetes-associated cardiac microvascular hyperpermeability. Graphical abstract.
AIMS/HYPOTHESIS: Microvascular endothelial hyperpermeability, mainly caused by claudin-5 deficiency, is the initial pathological change that occurs in diabetes-associated cardiovascular disease. The ketone body β-hydroxybutyrate (BHB) exerts unique beneficial effects on the cardiovascular system, but the involvement of BHB in promoting the generation of claudin-5 to attenuate cardiac microvascular hyperpermeability in diabetes is poorly understood. METHODS: The effects of BHB on cardiac microvascular endothelial hyperpermeability and claudin-5 generation were evaluated in rats with streptozotocin-induced diabetes and in high glucose (HG)-stimulated human cardiac microvascular endothelial cells (HCMECs). To explore the underlying mechanisms, we also measured β-catenin nuclear translocation, binding of β-catenin, histone deacetylase (HDAC)1, HDAC3 and p300 to the Claudin-5 (also known as CLDN5) promoter, interaction between HDAC3 and β-catenin, and histone acetylation in the Claudin-5 promoter. RESULTS: We found that 10 weeks of BHB treatment promoted claudin-5 generation and antagonised cardiac microvascular endothelial hyperpermeability in rat models of diabetes. Meanwhile, BHB promoted claudin-5 generation and inhibited paracellular permeability in HG-stimulated HCMECs. Specifically, BHB (2 mmol/l) inhibited HG-induced HDAC3 from binding to the Claudin-5 promoter, although nuclear translocation or promoter binding of β-catenin did not change with BHB treatment. In addition, BHB prevented the binding and co-localisation of HDAC3 to β-catenin in HG-stimulated HCMECs. Furthermore, using mass spectrometry, acetylated H3K14 (H3K14ac) in the Claudin-5 promoter following BHB treatment was identified, regardless of whether cells were stimulated by HG or not. Although reduced levels of acetylated H3K9 in the Claudin-5 promoter were found following HG stimulation, increased H3K14ac was specifically associated with BHB treatment. CONCLUSIONS/ INTERPRETATION: BHB inhibited HDAC3 and caused acetylation of H3K14 in the Claudin-5 promoter, thereby promoting claudin-5 generation and antagonising diabetes-associated cardiac microvascular hyperpermeability. Graphical abstract.
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