β-Hydroxybutyrate inhibits histone deacetylase 3 to promote claudin-5 generation and attenuate cardiac microvascular hyperpermeability in diabetes.

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.

• Authors: Bin Li, Yijin Yu, Kun Liu, Yuping Zhang, Qi Geng, Feng Zhang, Yanning Li, Jinsheng Qi
• Journal: Diabetologia (Diabetologia) Vol. 64 Issue 1 Pg. 226-239 (01 2021) ISSN: 1432-0428 [Electronic] Germany
• PMID: 33106900 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Claudin-5
• Histone Deacetylase Inhibitors
• beta Catenin
• Histone Deacetylases
• histone deacetylase 3
• 3-Hydroxybutyric Acid

Topics

• 3-Hydroxybutyric Acid (pharmacology)
• Animals
• Capillary Permeability (drug effects, physiology)
• Claudin-5 (biosynthesis, genetics)
• Coronary Vessels (physiopathology)
• Diabetes Complications (prevention & control)
• Diabetes Mellitus, Experimental (physiopathology)
• Endothelium, Vascular (physiopathology)
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases (drug effects, metabolism)
• Male
• Microvessels (physiopathology)
• Promoter Regions, Genetic (physiology)
• Rats
• Rats, Sprague-Dawley
• beta Catenin (metabolism)