Key Takeaways & Executive Findings
- •• • GYY4137 (H₂S donor) reverses Ang II-induced endothelial damage by restoring SIRT6 expression, suppressing IL-6 and ICAM-1, and improving vasodilation; this identifies a druggable pathway for hypertension where current therapies fail to target inflammation. • • Endothelial-specific CSE-deficient mice display spontaneous inflammation and endothelial dysfunction, reversed by H₂S supplementation, establishing CSE/H₂S as a critical endogenous brake on vascular inflammation. • • SIRT6 inhibitors completely block the protective effects of H₂S, confirming that SIRT6 is the obligatory downstream mediator; this suggests SIRT6 activators could mimic H₂S benefits without gas-donor liabilities. • • The study provides mechanistic evidence that H₂S supplementation restores NO bioavailability and reduces adhesion molecule expression, offering a potential adjunct to angiotensin receptor blockers for resistant hypertension.
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Abstract
Hypertension is commonly accompanied by endothelial dysfunction, characterized by an imbalance between vasodilatation and constriction, increased levels of the proinflammatory factors interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1), and decreased nitric oxide (NO) bioavailability. Using an angiotensin II (Ang II)-induced endothelial dysfunction model, we show that treatment with the hydrogen sulfide (H₂S) donor GYY4137 significantly reverses Ang II-induced damage. GYY4137 restores sirtuin 6 (SIRT6) expression, suppresses inflammation, and improves vasodilatory function. Furthermore, endothelial-specific cystathionine-γ-lyase (CSE)-deficient mice exhibit inflammation and endothelial dysfunction in blood vessels, which is reversed by H₂S supplementation. Critically, SIRT6 inhibitors block the protective effects of H₂S in the endothelium. This study demonstrates that H₂S protects vascular endothelial function by activating the SIRT6 anti-inflammatory pathway.
1. Introduction
Hypertension remains the leading global risk factor for cardiovascular morbidity and mortality, with approximately 9.4 million deaths annually. Endothelial dysfunction—characterized by reduced nitric oxide (NO) bioavailability, elevated interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1), and impaired vasodilation—is a hallmark of hypertension and a key driver of vascular remodeling and increased peripheral resistance. Angiotensin II (Ang II), a principal effector of the renin–angiotensin–aldosterone system, promotes endothelial dysfunction by activating immune cell infiltration and cytokine production in the aortic wall. Despite the widespread use of antihypertensive agents, none specifically target the inflammatory cascade that sustains endothelial injury, leaving a therapeutic gap for patients with refractory hypertension.
Hydrogen sulfide (H₂S), a gasotransmitter synthesized by cystathionine-γ-lyase (CSE) in endothelial cells, has emerged as a regulator of vascular tone and inflammation. However, the precise molecular mechanism by which H₂S protects endothelial function in hypertensive states remains undefined. This study tests the hypothesis that H₂S, via the H₂S donor GYY4137, restores endothelial function by activating sirtuin 6 (SIRT6), a nuclear deacetylase with anti-inflammatory properties. Using Ang II-induced endothelial dysfunction models and endothelial-specific CSE-deficient mice, we demonstrate that H₂S supplementation reverses inflammatory and functional deficits in a SIRT6-dependent manner. These findings position the H₂S–SIRT6 axis as a novel therapeutic target for hypertension-associated endothelial dysfunction.
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LU Fan, QIN Xueyuan, LU Shanshan, WAN Jie, MIAO Yuxin, TENG Xu, JIN Sheng, XIAO Lin, XUE Hongmei, GUO Qi, TIAN Danyang, WU Yuming (2025). Hydrogen Sulfide Improves Vascular Endothelial Function in Hypertensive States Through SIRT6 Anti-Inflammatory Signaling. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025221
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Frequently Asked Questions
What is the precise mechanism by which H₂S restores endothelial function in Ang II-induced hypertension?
H₂S, delivered via GYY4137, restores SIRT6 expression, which suppresses the proinflammatory cytokines IL-6 and ICAM-1, thereby reducing immune cell adhesion and improving NO bioavailability. This cascade reverses Ang II-induced endothelial dysfunction, as evidenced by improved vasodilation and reduced inflammatory markers.
How does endothelial-specific CSE deficiency affect vascular function, and is it reversible?
Endothelial-specific CSE-deficient mice exhibit spontaneous inflammation and endothelial dysfunction, including elevated IL-6 and ICAM-1 and impaired vasodilation. H₂S supplementation reverses these deficits, confirming that endogenous H₂S production by CSE is critical for maintaining endothelial homeostasis.
What is the evidence that SIRT6 is the obligatory mediator of H₂S protection?
SIRT6 inhibitors completely block the protective effects of H₂S in the endothelium, as shown by the loss of anti-inflammatory and vasodilatory benefits. This demonstrates that SIRT6 activation is required for H₂S-mediated endothelial protection.
What are the translational challenges for H₂S-based therapies in hypertension?
Key challenges include precise dosing of H₂S donors to avoid toxicity, potential off-target effects, and the need for selective SIRT6 activators. The study's use of GYY4137 provides a proof-of-concept, but clinical development requires optimizing delivery and targeting to endothelial cells.
How does this study compare with existing antihypertensive therapies?
Current antihypertensives primarily target vasoconstriction or volume overload but do not directly address inflammation. This study identifies the H₂S–SIRT6 pathway as a complementary target, potentially offering additive benefits for patients with inflammation-driven endothelial dysfunction.
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