Honokiol ameliorates angiotensin II‐induced hypertension and endothelial dysfunction by inhibiting HDAC6‐mediated cystathionine γ‐lyase degradation

• Published in: Journal of cellular and molecular medicine 2020-09, Vol.24 (18), p.10663-10676
• Main Authors: Chi, Zhexi, Le, Truc Phan Hoang, Lee, Sang Ki, Guo, Erling, Kim, Dongsoo, Lee, Sanha, Seo, Seung‐Yong, Lee, Sook Young, Kim, Jae Hyung, Lee, Sang Yoon
• Format: Article
• Language: English
• Subjects: Acetylation; Angiotensin; Angiotensin II; Angiotensin II - toxicity; Animals; Antibodies; Aorta; Biphenyl Compounds - pharmacology; Blood pressure; Cardiovascular diseases; Cell culture; Coronary vessels; Cystathionine g-lyase; Cystathionine gamma-Lyase - genetics; Cystathionine gamma-Lyase - metabolism; cystathionine γ‐lyase; Deacetylation; Degradation; Endothelial Cells - drug effects; HEK293 Cells; Histone deacetylase; histone deacetylase 6; Histone Deacetylase 6 - antagonists & inhibitors; Histone Deacetylase 6 - genetics; Histone Deacetylase 6 - physiology; honokiol; Humans; Hydrogen sulfide; Hydrogen Sulfide - metabolism; hydrogen sulphide; Hypertension; Hypertension - chemically induced; Hypertension - enzymology; Hypertension - physiopathology; Hypertension - prevention & control; Inflammation; Laboratory animals; Lignans - pharmacology; Lysine; Male; Mice; Mice, Inbred C57BL; Mutation; Original; Plasmids; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein Processing, Post-Translational; Proteins; Proteolysis - drug effects; Recombinant Proteins - metabolism; Ubiquitination; Vasoconstriction
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.15686

Hypertension and endothelial dysfunction are associated with various cardiovascular diseases. Hydrogen sulphide (H2S) produced by cystathionine γ‐lyase (CSE) promotes vascular relaxation and lowers hypertension. Honokiol (HNK), a natural compound in the Magnolia plant, has been shown to retain multifunctional properties such as anti‐oxidative and anti‐inflammatory activities. However, a potential role of HNK in regulating CSE and hypertension remains largely unknown. Here, we aimed to demonstrate that HNK co‐treatment attenuated the vasoconstriction, hypertension and H2S reduction caused by angiotensin II (AngII), a well‐established inducer of hypertension. We previously found that histone deacetylase 6 (HDAC6) mediates AngII‐induced deacetylation of CSE, which facilitates its ubiquitination and proteasomal degradation. Our current results indicated that HNK increased endothelial CSE protein levels by enhancing its stability in a sirtuin‐3‐independent manner. Notably, HNK could increase CSE acetylation levels by inhibiting HDAC6 catalytic activity, thereby blocking the AngII‐induced degradative ubiquitination of CSE. CSE acetylation and ubiquitination occurred mainly on the lysine 73 (K73) residue. Conversely, its mutant (K73R) was resistant to both acetylation and ubiquitination, exhibiting higher protein stability than that of wild‐type CSE. Collectively, our findings suggested that HNK treatment protects CSE against HDAC6‐mediated degradation and may constitute an alternative for preventing endothelial dysfunction and hypertensive disorders.