Hydrogen sulfide improves vascular endothelial function in hypertensive states through SIRT6 anti-inflammatory signaling

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 has been identified as the most important risk factor for death worldwide, with approximately 9.4 million people dying of hypertension every year globally [1]. In China, hypertension remains the leading cause of cardiovascular morbidity and mortality; therefore, effective management of hypertension is needed [2]. Endothelial dysfunction plays a key role in the pathogenesis of hypertension [3]. In particular, endothelial dysfunction can enhance contraction and vascular remodeling, which increases peripheral resistance and leads to hypertension. Angiotensin II (Ang II), a critical component of the renin–angiotensin–aldosterone system, controls blood pressure by impairing endothelial function and inducing smooth muscle cell contraction [4]. Recent studies have shown that both salt-induced and Ang II-mediated hypertension are associated with increased inflammation and cytokine production, as well as endothelial dysfunction [5]. In addition to its role as a potent vasoconstrictor and regulator of blood pressure and fluid homeostasis, Ang II is involved in the development of vascular lesions in cardiovascular disease through the activation of various immune cells and cellular inflammation [6]. Ang II has been shown to facilitate the adhesion and infiltration of inflammatory cells into the aortic wall [7]. Numerous studies have demonstrated that inflammation affects nitric oxide (NO) synthesis and vascular smooth muscle function. Specifically, the influence of inflammation on endothelium-dependent vasodilation is mediated by delaying NO synthesis and degrading NO, promoting an increase in the levels of vasoconstrictive factors and a decrease in the levels of diastolic factors. Despite extensive research on the etiology and pathogenesis of hypertension, new therapeutic mechanisms remain underexplored.

SIRT6, a member of the mammalian sirtuin family, is a protease with multiple catalytic activities in the nucleus, including histone deacetylation, ADP-ribosylation, and lysine deacylation. SIRT6 plays a critical role in maintaining genome stability and DNA repair [8] and participates in numerous physiological regulatory mechanisms, such as cell proliferation, differentiation, and aging. SIRT6 overexpression inhibits various inflammatory responses, such as collagen-induced arthritis and hypoxia-induced inflammation [9]. Studies have also shown that SIRT6 reduces endothelial cell inflammation induced by tiny cholesterol crystals and reverses endothelial dysfunction by increasing the level of angiotensin-converting enzyme 2 [10].

H2S, the third gas transmitter discovered after NO and carbon monoxide, has attracted considerable attention because of its ability to preserve blood vessel function, regulate vascular tone, and inhibit cell proliferation [11]. Studies have shown that H2S restores endothelial NO-dependent vascular function in patients with hyperglycemia via a cAMP response element-binding (CREB)-dependent pathway [12], attenuates disturbed flow-induced vascular remodeling by inhibiting LDHB-mediated autophagic flux [13], stimulates NO production and protects human umbilical vein endothelial cells (HUVECs) by inducing the protein kinase B (Akt) endothelial nitric oxide synthase (eNOS) signaling pathway [14]. Moreover, H2S has been found to preserve cellular function through SIRT6. In particular, exogenous H2S inhibits cellular senescence through the SIRT6/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, thereby alleviating myocardial fibrosis associated wi