The biological role of endogenous hydrogen sulfide

Endogenous hydrogen sulfide is formed in the body from cysteine using the enzymes cystathionine-β-synthetase and cystathionine-γ-lyase. It is an antispasmodic (relaxes smooth muscles ) and a vasodilator , like nitric oxide and carbon monoxide. ^[1] It is also active in the central nervous system , where it increases NMDA-mediated neurotransmission and promotes long-term storage of information. ^[2]

Subsequently, hydrogen sulfide is oxidized to sulfite in the mitochondria using the enzyme thiosulfate reductase. Sulfite is subsequently oxidized to thiosulfate and then sulfate by the sulfite oxidase enzyme. Sulfates, as the end product of metabolism, are excreted in the urine. ^[3]

Due to properties similar to those of nitric oxide (but without its ability to form peroxides by reacting with superoxide ), endogenous hydrogen sulfide is now considered one of the important factors protecting the body from cardiovascular diseases. ^[1] Known cardioprotective properties of garlic are associated with the catabolism of the polysulfide groups of allicin in hydrogen sulfide, and this reaction is catalyzed by the reducing properties of glutathione . ^[four]

Although nitric oxide and hydrogen sulfide can relax muscles and cause vasodilation, their mechanisms of action appear to be different. While nitric oxide activates the guanylate cyclase enzyme, hydrogen sulfide activates ATP-sensitive potassium channels in smooth muscle cells. Researchers are still unclear how physiological roles are distributed in the regulation of vascular tone between nitric oxide, carbon monoxide and hydrogen sulfide. However, there is some evidence to suggest that nitric oxide under physiological conditions mainly dilates large vessels, while hydrogen sulfide is responsible for a similar expansion of small blood vessels ^[5] .

Recent studies suggest significant intracellular cross-communication between the signaling pathways of nitric oxide and the signaling pathways of hydrogen sulfide ^[6], demonstrating that the vasodilating, antispasmodic, anti-inflammatory and cytoprotective properties of these gases are interdependent and mutually reinforcing. In addition, it was shown that hydrogen sulfide is able to react with intracellular S-nitrosothiols, resulting in the formation of the smallest possible S-nitrosothiol - HSNO. This suggests that hydrogen sulfide plays a role in controlling the intracellular level of S-nitrosothiols. ^[7]

Like nitric oxide, hydrogen sulfide plays a role in the expansion of the vessels of the penis , necessary for an erection , which creates new opportunities for the treatment of erectile dysfunction with the help of various drugs that increase the production of endogenous hydrogen sulfide. ^{[8] [9]}

With myocardial infarction , a pronounced deficiency of endogenous hydrogen sulfide is detected, which can have adverse consequences for blood vessels. ^[10] Myocardial infarction leads to cardiac muscle necrosis in the heart attack zone through two different mechanisms: one is increased oxidative stress and increased formation of free radicals, and the other is reduced bioavailability of endogenous vasodilators and tissue “protectors” from free radical damage - nitric oxide and hydrogen sulfide. ^{[11] The} increased formation of free radicals occurs due to the increased unbound electron transport in the active site of the enzyme endothelial synthase nitric oxide - the enzyme responsible for the conversion of L-arginine to nitric oxide. ^{[10] [11]} During a heart attack, the oxidative degradation of tetrahydrobiopterin, a cofactor during the production of nitric oxide, limits the availability of tetrahydrobiopterin and accordingly limits the ability of nitric oxide synthase to produce NO. ^[11] As a result, nitric oxide synthase reacts with oxygen, another cosubstrate needed to produce nitric oxide. The result of this is the formation of superoxides, increased formation of free radicals and intracellular oxidative stress. ^[10] A hydrogen sulfide deficiency further aggravates this situation by disrupting the activity of nitric oxide synthase by limiting Akt activity and inhibiting the phosphorylation of Akt nitric oxide synthase at the eNOSS1177 site, which is necessary for its activation. ^{[10] [12]} Instead, with hydrogen sulfide deficiency, Akt activity changes so that Akt phosphorylates the inhibitory site of nitric oxide synthase - eNOST495 - which leads to even greater inhibition of nitric oxide biosynthesis. ^{[10] [12]}

“Hydrogen sulfide therapy” uses a donor or precursor of hydrogen sulfide, such as diallyl trisulfide, in order to increase the hydrogen sulfide content in the blood and tissues of a patient with myocardial infarction. Donors or precursors of hydrogen sulfide reduce myocardial damage after ischemia and reperfusion and the risk of complications of myocardial infarction. ^[10] Increased levels of hydrogen sulfide in tissues and blood react with oxygen contained in blood and tissues, resulting in the formation of sulfane-sulfur, an intermediate product in which hydrogen sulfide is “stored”, stored and transported to cells. ^[10] Hydrogen sulfide pools in tissues react with oxygen, increasing the hydrogen sulfide content in tissues activates nitric oxide synthase and thereby increases nitric oxide production. ^[10] Due to the increased use of oxygen for the production of nitric oxide, less oxygen remains to react with endothelial synthase of nitric oxide and the production of superoxides increased during heart attack, which ultimately leads to a decrease in the formation of free radicals. ^[10] In addition, less free radical formation reduces oxidative stress in vascular smooth muscle cells, thereby reducing the oxidative degradation of tetrahydrobiopterin. ^{[11] The} increased availability of the nitric oxide synthase cofactor — tetrahydrobiopterin — also contributes to an increase in nitric oxide production in the body. ^[11] In addition, higher concentrations of hydrogen sulfide directly increase the activity of nitric oxide synthase through Akt activation, which leads to an increase in the phosphorylation of the activating site of eNOSS1177 and a decrease in phosphorylation of the inhibitory site of eNOST495. ^{[10] [12]} This phosphorylation leads to an increase in the catalytic activity of nitric oxide synthase, which leads to a more efficient and faster conversion of L-arginine to nitric oxide and an increase in the concentration of nitric oxide. ^{[10] [12]} An increase in the concentration of nitric oxide increases the activity of soluble guanylate cyclase, which, in turn, leads to an increase in the formation of cyclic guanosine monophosphate cGMP from GTP . ^[13] An increase in the level of cyclic GMF leads to an increase in the activity of protein kinase G (PKG). ^[14] And protein kinase G leads to a decrease in the level of intracellular calcium in the smooth muscles of the vessel walls, which leads to their relaxation and increased blood flow in the vessels. ^[14] In addition, protein kinase G also limits the proliferation of smooth muscle cells in vascular walls, thereby reducing the thickening of vascular intima. Ultimately, "hydrogen sulfide therapy" leads to a decrease in the size of the infarction zone. ^{[10] [13]}

In Alzheimer's disease, the level of hydrogen sulfide in the brain is sharply reduced. ^[15] In the rat model of Parkinson’s disease, the concentration of hydrogen sulfide in the brain of rats was also reduced, and the administration of rats with donors or precursors of hydrogen sulfide improved the condition of animals, up to the complete disappearance of symptoms. ^[16] In trisomy 21 (Down syndrome), the body, on the contrary, produces an excess of hydrogen sulfide. ^[3] Endogenous hydrogen sulfide is also involved in the pathogenesis of type 1 diabetes . Pancreatic beta cells of patients with type 1 diabetes mellitus produce excessively high amounts of hydrogen sulfide, which leads to the death of these cells and to a decrease in insulin secretion by neighboring, still living cells. ^[five]

In 2005, it was shown that the mouse can be immersed in a state of almost suspended animation , artificial hypothermia , by exposing it to low concentrations of hydrogen sulfide (81 ppm) in inhaled air. The animals' breathing slowed down from 120 to 10 respiratory movements per minute, and their body temperature dropped from 37 degrees Celsius to a level that was only 2 degrees Celsius above the ambient temperature (that is, the effect was as if the warm-blooded animal suddenly became cold-blooded). Mice survived this procedure for 6 hours, and after that they did not have any negative health effects, behavioral disorders or any damage to internal organs. ^[17] In 2006, it was shown that the blood pressure in a mouse similarly exposed to hydrogen sulfide does not significantly decrease. ^[18]

A similar process, known as hibernation or "hibernation", is observed in nature in many species of mammals , as well as in toads , but not in mice (although the mouse can fall into a stupor with a long absence of food). It was shown that during the "winter hibernation" the production of endogenous hydrogen sulfide in those animals that fall into hibernation increases significantly. Theoretically, if it were possible to make hibernation caused by hydrogen sulfide work just as effectively in people, it could be very useful in clinical practice to save the lives of seriously injured or undergoing severe hypoxia, heart attacks, strokes of patients, as well as for preserving donor organs. In 2008, it was shown that hypothermia caused by hydrogen sulfide within 48 hours in rats can reduce the degree of brain damage caused by an experimental stroke or brain injury. ^[nineteen]

Hydrogen sulfide binds to cytochrome oxidase C and thereby prevents oxygen from binding to it, which leads to a sharp slowdown in metabolism, but in large quantities "paralyzes" cellular respiration and leads to "suffocation" at the cell level - to cellular hypoxia. In humans and animals, all cells in the body normally produce a certain amount of hydrogen sulfide. A number of researchers have suggested that, in addition to other physiological roles, hydrogen sulfide is also used by the body for natural self-regulation of metabolic rate (metabolic activity), body temperature and oxygen consumption, which may explain the above hibernation in mice and rats at elevated concentrations of hydrogen sulfide, as well as its increase concentration during physiological hibernation in animals. ^[20]

However, the last two studies raise doubts that this effect of hibernation and induction of hypometabolism with the help of hydrogen sulfide can be achieved in larger animals. Thus, a 2008 study could not reproduce the same effect in pigs, which led researchers to conclude that the effect observed in mice was not observed in larger animals. ^[21] Similarly, another article notes that the effect of inducing hypometabolism and hibernation by means of hydrogen sulfide, easily achievable in mice and rats, cannot be achieved in sheep. ^[22]

In February 2010, scientist Mark Roth announced at a conference that human hypothermia caused by hydrogen sulfide passed phase I clinical trials. ^[23] However, the decision to conduct further clinical trials for patients with a heart attack was revoked by Ikaria, founded by him in August 2011, even before the start of the enrollment of test participants without explanation, with reference to the "company decision". ^{[24] [25]}