biomedicines Review H2S as a Bridge Linking Inflammation, Oxidative Stress and Endothelial Biology: A Possible Defense in the Fight against SARS-CoV-2 Infection? Francesca Gorini 1,* , Serena Del Turco 1,* , Laura Sabatino 1 , Melania Gaggini 1 and Cristina Vassalle 2,* 1 Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; [email protected] (L.S.); [email protected] (M.G.) 2 Fondazione CNR-Regione Toscana G. Monasterio, 56124 Pisa, Italy * Correspondence: [email protected] (F.G.); [email protected] (S.D.T.); [email protected] (C.V.) Abstract: The endothelium controls vascular homeostasis through a delicate balance between secre- tion of vasodilators and vasoconstrictors. The loss of physiological homeostasis leads to endothelial dysfunction, for which inflammatory events represent critical determinants. In this context, ther- apeutic approaches targeting inflammation-related vascular injury may help for the treatment of cardiovascular disease and a multitude of other conditions related to endothelium dysfunction, including COVID-19. In recent years, within the complexity of the inflammatory scenario related to loss of vessel integrity, hydrogen sulfide (H2S) has aroused great interest due to its importance in different signaling pathways at the endothelial level. In this review, we discuss the effects of H2S, a molecule which has been reported to demonstrate anti-inflammatory activity, in addition to Citation: Gorini, F.; Del Turco, S.; many other biological functions related to endothelium and sulfur-drugs as new possible therapeutic Sabatino, L.; Gaggini, M.; Vassalle, C. options in diseases involving vascular pathobiology, such as in SARS-CoV-2 infection. H2S as a Bridge Linking Inflammation, Oxidative Stress and Keywords: endothelium; hydrogen sulfide; inflammation; therapeutic target; SARS-CoV-2; COVID-19 Endothelial Biology: A Possible Defense in the Fight against SARS-CoV-2 Infection? Biomedicines 2021, 9, 1107. https://doi.org/ 1. Introduction 10.3390/biomedicines9091107 The endothelium is the inner lining that covers all blood vessels with a very large Academic Editors: Byeong Hwa Jeon spatial distribution, and consequently with potentially different characteristics depending and Marika Cordaro on its position in the body. Not just an inert barrier, the endothelium is recognized as a biologically active tissue that regulates vascular tone and structure through autocrine, Received: 14 July 2021 paracrine, and hormone-like mechanisms [1]. In fact, it may respond to various stimuli Accepted: 26 August 2021 (e.g., shear stress on the endothelial surface) and release numerous vasoactive substances Published: 28 August 2021 with vasodilator or vasoconstrictor properties [1]. Loss of physiological homeostasis leads to endothelial dysfunction, a condition underlying micro- and macrovascular diseases, Publisher’s Note: MDPI stays neutral characterized by reduced capacity for vasodilation, recruitment of neutrophils, enhanced with regard to jurisdictional claims in inflammation and oxidative stress, prothrombotic properties, impaired cell growth and published maps and institutional affil- vessel permeability [1]. Inflammatory processes remain critical determinants which can iations. provoke increases in prothrombotic and pro-oxidative events. Therefore, endothelial dys- function has been observed associated with different clinical diseases, such as chronic kidney disease, liver failure, atherosclerosis, hypertension, dyslipidemia, diabetes, and obesity [2]. This implies that endothelial dysfunction can have important repercussions on Copyright: © 2021 by the authors. health and on the onset and development of practically all diseases. In particular, endothe- Licensee MDPI, Basel, Switzerland. lial dysfunction can be promoted or exacerbated by severe acute respiratory syndrome This article is an open access article coronavirus-2 (SARS-CoV-2) infection, either by direct (interaction of SARS-CoV-2 virus distributed under the terms and with endothelial angiotensin-converting enzyme 2 (ACE2)) or indirect mechanisms (e.g., conditions of the Creative Commons systemic inflammation, leukocyte recruitment, immune dysregulation, procoagulant state, Attribution (CC BY) license (https:// impaired fibrinolysis, or activation of the complement system) [3–6]. Conversely, preex- creativecommons.org/licenses/by/ isting endothelial dysfunction underlies cardiovascular risk factors (e.g., hypertension, 4.0/). Biomedicines 2021, 9, 1107. https://doi.org/10.3390/biomedicines9091107 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, 1107 2 of 14 diabetes, obesity, and aging), all conditions which may favor the risk and severity of novel coronavirus disease 2019 (COVID-19) [4]. Increasing experimental, clinical, and transla- tional findings suggest that many common drugs, such as lipid-lowering, antihypertensive, and antidiabetic drugs, and also antioxidants (e.g., vitamin C and E, N-acetylcysteine-NAC) and anti-inflammatories (e.g., cyclooxygenase-2 inhibitors, and glucocorticoids) may target the endothelium [2]. Consequently, further knowledge of endothelium pathophysiology may greatly help in patient care, given its enormous diagnostic and therapeutic potential. In this context, the role of hydrogen sulfide (H2S), defined as the third endogenous gaseous signaling molecule besides nitric oxide (NO) and carbon monoxide (CO), in recent years has aroused a great interest due to its importance on different signaling pathways at the endothelial level [5]. In particular, given the close interaction between reduced H2S levels and endothelial dysfunction and inflammation, and the relationship between NO and H2S, the therapeutic release of H2S may represent a new and intriguing development in the prevention and treatment of inflammatory-related endothelial dysfunction conditions [6]. In this review, we discuss the effects of H2S and the use of sulfur-drugs as a new possible therapeutic option in diseases involving vascular pathobiology, such as in the SARS-CoV-2 infection. 2. Hydrogen Sulfide: An Additive Key Factor in Vascular Homeostasis In the last few years, the role of H2S as an interesting novel mediator involved in inflammation and endothelial function has emerged [7], in terms of the relaxation of blood vessels, regulation of blood pressure, reduction of inflammatory response, and induction of antioxidant defense [8]. This gasotransmitter is mostly produced through the reverse trans-sulfuration path- way by three different enzymes. Two enzymes, cystathionine beta synthase (CBS) and cystathionine gamma lyase (CSE), use piridoxal 50 phosphate (PLP) as a cofactor, while 3-mercaptopiruvate sulfur transferase (3-MST), primarily located in the mitochondria, is not dependent on PLP [9,10]. The protective effect of H2S is mediated by many different cellular and molecular mechanisms (Figure1). S-sulfhydration, a chemical modification on specific cysteine residues of target pro- teins to form a persulfide group (–SSH), is considered a primary mechanism through which H2S alters the function of signaling proteins [11,12]. A striking example is the S-sulfhydration of endothelial nitric oxide synthase (eNOS), which promotes eNOS dimer stability, NO production, and consequent vasorelaxation [13]. Indeed, sulfhydration of the Kir 6.1 subunit of ATP-sensitive potassium (KATP) channels activates the channel, causing vascular endothelial and smooth muscle cell hyperpolarization and vasorelaxation [14]. Accordingly, exogenous administration of H2S attenuates the rise of blood pressure in both spontaneously hypertensive rats [15] and in mice rendered hypertensive with angiotensin II (AngII) [16]. Although H2S may directly inactivate reactive oxygen species (ROS), e.g., through the inhibition of peroxynitrite-mediated processes in vivo [17], it also protects cells via the upregulation of antioxidant defense systems [6,8]. Specifically, sodium hydrosulfide (NaHS, an H2S donor) induces the sulfhydration of Kelch-like ECH-associating protein 1 (Keap1), a repressor of nuclear-factor-E2-related factor-2 (Nrf2), which is the main regulator of the antioxidant response. This action results in Keap1/Nrf2 disassociation, Nrf2 nuclear translocation, and increased mRNA expression of Nrf2-targeted downstream genes [18,19]. In human umbilical vein endothelial cells (HUVECs) exposed to H2O2,H2S upregulates a wide range of enzymes attenuating oxidative stress, such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase, and glutathione-S-transferase [20]. Moreover, in endothelial cells (ECs) and fibroblasts, H2S-induced S-sulfhydration and activation of mitogen-activated extracellular signal-regulated kinase 1 are followed by phosphorylated ERK1/2 translocation into the nucleus to stimulate activity of PARP-1, a nuclear protein that exerts an important role in DNA damage repair [21]. H2S is further implicated in Biomedicines 2021, 9, 1107 3 of 14 the regulation of the other major cellular inflammatory signaling pathway, namely the nuclear factor-κB (NF-κB) pathway [22]. The multifunctional pro-inflammatory cytokine, Biomedicines 2021, 9, 1107 tumor necrosis factor α (TNF-α), stimulates the transcription of CSE. Consequently, the4 H of2 S-15 induced sulfhydration of the p65 subunit of NF-κB, promotes transcription of anti-apoptotic genes by enhancing its ability to bind the co-activator ribosomal protein S3 [23]. On the other hand, NaHS can exert an anti-inflammatory effect in ECs by inhibiting the expression an in vitro study