Hydrogen Sulfide Metabolism and Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a severe and multifactorial disease characterized by a progressive elevation of pulmonary arterial resistance and pressure due to remodeling, inflammation, oxidative stress, and vasoreactive alterations of pulmonary arteries (PAs). Currently, the etiology of these pathological features is not clearly understood and, therefore, no curative treatment is available. Since the 1990s, hydrogen sulfide (H2S) has been described as the third gasotransmitter with plethoric regulatory functions in cardiovascular tissues, especially in pulmonary circulation. Alteration in H2S biogenesis has been associated with the hallmarks of PH. H2S is also involved in pulmonary vascular cell homeostasis via the regulation of hypoxia response and mitochondrial bioenergetics, which are critical phenomena affected during the development of PH. In addition, H2S modulates ATP-sensitive K+ channel (KATP) activity, and is associated with PA relaxation. In vitro or in vivo H2S supplementation exerts antioxidative and anti-inflammatory properties, and reduces PA remodeling. Altogether, current findings suggest that H2S promotes protective effects against PH, and could be a relevant target for a new therapeutic strategy, using attractive H2S-releasing molecules. Thus, the present review discusses the involvement and dysregulation of H2S metabolism in pulmonary circulation pathophysiology.

Implications of Hydrogen Sulfide in Development of Pulmonary Hypertension

“…Endogenous H 2 S as a third gaseous molecule plays a crucial part in the pathophysiology responsible for PH. H 2 S attenuates the vascular endothelial cell inflammatory response, inhibits PASMC proliferation, modulates vascular cell apoptosis and inhibits collagen remodeling, opens the K ATP channel to relax pulmonary vessels [ 11 , 17 , 18 ], and interacts with CO and NO signaling pathways to exert vascular function and maintain normal pulmonary circulation [ 19 ]. Under certain pathologic stimuli, the endogenous H 2 S pathway is downregulated, thus inducing the development of PH.…”

“…The potential therapeutic effect is mainly established in H 2 S supplementation experiments using H 2 S donors. The most widely used H 2 S donors are NaHS and Na 2 S [ 19 , 51 , 52 , 53 , 54 , 55 ]. They have several advantages, such as being inexpensive, water-soluble, and having the ability to rapidly release a large amount of H 2 S under physiological conditions.…”

“…They have several advantages, such as being inexpensive, water-soluble, and having the ability to rapidly release a large amount of H 2 S under physiological conditions. While GYY4137 or dithiolthione compounds work as slow-releasing H 2 S donors, are actively developed, and exhibit promising effects on cardiovascular diseases [ 19 , 56 , 57 ], some other H 2 S donors have been demonstrated to protect against cardiac dysfunction, vascular remodeling, and PH. Recently, investigators have revealed that the designed microfluidics-assisted H 2 S-releasing aspirin derivative (ACS14)-containing large porous microspheres showed promising potential as an inhaled and efficacious H 2 S donor in treating MCT-induced PH [ 58 ].…”

“…The endogenous gasotransmitters, including nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H 2 S), and sulfur dioxide (SO 2 ) [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ], with unique properties, such as rapid generation, fast transmission, extensive functions, and short half-lives, play vital roles in the pathogenesis of PH [ 19 , 20 , 21 ]. Great progress has been made in understanding the involvement of these gasotransmitters in the pathogenesis of PH [ 17 , 18 , 21 ].…”

Hydrogen Sulfide-Induced Vasodilation: The Involvement of Vascular Potassium Channels

“…In the vascular system, H 2 S is principally synthesized by CES ( Szabo, 2012 ). Biogenesis of H 2 S or downregulation of H 2 S pathway has been found in a variety of vascular diseases, such as hypertension, atherosclerosis, diabetes and pulmonary hypertension ( Barton and Meyer, 2019 ; Dillon et al, 2021 ; Dorofeyeva et al, 2021 ; Roubenne et al, 2021 ). H 2 S plays an important role in regulation vascular homeostasis, such as angiogenesis, proliferation of vascular smooth muscle cells, leukocyte adhesion, oxidative stress and vascular dilation ( Wang et al, 2015 ).…”