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

Abstract

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.

Endocannabinoid system: An untold story in hypertensive nephropathy

“…Increased oxidative stress in the kidney lead to the increased inflammatory mediator and loss of renal function in normotensive and hypertensive rats [80]. Hydrogen sulphide is well known gaseous transmitter with known ang II blocking effects [81][82][83] have been found to reduce the degree of renal IRI by potentiating its antioxidant and anti-inflammatory mechanism, as evidenced by decreased NF-kB concentration and downregulation of ICAM-1 expression in normotensive and hypertensive rats [80]. Reversal of oxidative stress locally in the kidney and globally can minimize the injury produced by elevated levels of ang II.…”

Impact of the Gastrointestinal Tract Microbiota on Cardiovascular Health and Pathophysiology

“…Dietary interventions, probiotics, symbiotics, antibiotics, fecal microbiota transplantation, bioengineering, and herbal medicine are the most common approaches for restoration of the gut microbiome. [192][193][194] Fermented soy protein, 75 quinoa protein, 76 honokiol, 77 and S. platensis 78 are potential approaches for lowering blood pressure. Lactobacillus supplementation, 80 Zn(II)-Curcumin, 81 glabridin, 82 phenylalanine-butyramide, 83 The transplantation of vegan fecal microbiota had positive effects in intestinal microbiota composition, although no changes were observed in TMAO production and vascular inflammation parameters.…”

Histone Deacetylases (HDACs) and Atherosclerosis: A Mechanistic and Pharmacological Review

“…On the one hand, HDAC6 regulated chromatin remodeling and promoted ET-1 expression ( Li et al, 2016 ). On the other hand, it was upregulated in AngII-treated aortas and HAECs, which induced cystathionine γ-lyase ubiquitination and degradation, and was implicated in AngII-induced hypertension ( Chi et al, 2019 , 2020 ). Moreover, PAH was significantly ameliorated in HDAC6 –/– mice.…”