COMMENTARY A new gaseous signaling molecule emerges: Cardioprotective role of hydrogen sulfide David J. Lefer* Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, New York, NY 10461 ardiovascular (CV) research has largely been focused on two endogenously produced gaseous signaling molecules, Cnamely, nitric oxide (NO) and carbon monoxide (CO). These gaseous messen- gers are both highly conserved evolu- tionarily and synthesized by endogenous enzyme systems. Extensive research ef- forts have uniformly demonstrated that CO- and NO-based therapeutics protect the brain, heart, and circulation against a number of CV disease states (1–3). However, controversy exists regarding the therapeutic value of both CO and NO, with some studies citing NO cyto- toxicity at very high levels and under certain conditions (2). The toxic effects of NO are related to the highly reactive nature of NO and its interaction with superoxide to form the potent oxidant peroxynitrite (ONOOϪ) (2). Very re- cently, a third endogenously produced gaseous signaling molecule, hydrogen sulfide (H2S), has emerged as a poten- tially important mediator of CV homeo- stasis and cytoprotection (3). In this Fig. 1. Summary of the physiological actions of hydrogen sulfide (H2S). H2S is produced in micromolar issue of PNAS, Benavides et al. (4) re- (i.e., 10–100 ␮M) concentrations in the circulation and exerts a number of critical effects on the CV system. veal that the vasculoprotective and anti- H2S has been shown to induce vasodilation and inhibit leukocyte-endothelial cell interactions in the circulation. H2S is a potent antioxidant and inhibits cellular apoptosis. H2S also has been shown to hypertensive effects of dietary garlic transiently and reversibly inhibit mitochondrial respiration. Taken together, this physiological profile is (Allium sativum) are mediated in large ideally suited for protection of the CV system against disease states. part via the generation of H2S. Previous studies indicate that dietary garlic consumption is inversely corre- leads to vasorelaxation via vascular wise, thiocysteine generated by CGL can lated with the progression and severity smooth muscle KATP channel-mediated interact with thiols to generate H2S(6– of CV disease and that it affects a lower hyperpolarization (3). These novel ex- 8). The endogenous production of H2S incidence of hypertension (5). However, perimental studies provide important was initially described in the brain and the mechanism(s) by which consumption information regarding the mechanisms attributed to CBS (7–9). In addition, of garlic attenuates CV disease has in responsible for garlic-mediated attenua- H2S is produced in the vasculature by large part remained a mystery. Benav- tion of hypertension and serve to high- CGL, where it mediates smooth muscle ides et al. (4) elegantly demonstrate that light the potential importance of H2S relaxation and subsequent vasodilation garlic-derived organic polysulfides are therapy in CV disease. (3). At present, the distribution of CGL converted by red blood cells (RBCs) H2S is well known as a toxic gas with and CBS throughout the body are not into hydrogen sulfide gas. Interestingly, a repulsive odor often used to describe well characterized. Furthermore, very the garlic bulbs used for this study were the smell of rotten eggs (3). Experimen- little is currently known regarding the obtained from local supermarkets in the tal studies reveal that H2S is produced functions of CBS and CGL under physi- city of Birmingham, AL, and then enzymatically at micromolar levels in ological and pathophysiological condi- pressed by the investigators to obtain mammals and exerts a number of physi- tions. As this rapidly emerging field garlic juice on the day of the experiment. ological actions in the CV system (3, 6, advances, we are likely to learn a great The bioconversion of polysulfides to 7). H2S production has been attributed H2S is enhanced by glucose-maintained to two key enzymes in the cysteine bio- Author contributions: D.J.L. wrote the paper. cytosolic glutathione levels and depends synthesis pathway, cystathionine ␤- Conflict of interest statement: The author is currently on reduced thiols in close proximity to synthase (CBS) and cystathionine funded by Ikaria Corporation for a research grant and the RBC membrane. The authors dem- ␥-lyase (CGL). CBS and CGL are both serves as a paid Consultant for Ikaria Corporation. Ikaria is onstrate that generation of H2S after heme-containing enzymes whose activity currently developing hydrogen sulfide therapy for a num- bioconversion of garlic-derived polysul- depends on the cofactor pyridoxal 5Ј- ber of disease states. fides results in potent vasorelaxation of phosphate (6–8). CBS is capable of cat- See the companion article on page 17977. isolated blood vessels. The authors pro- alyzing the reaction of cysteine with *E-mail: [email protected]. pose that H2S produced from garlic other free thiols to generate H2S; like- © 2007 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0709010104 PNAS ͉ November 13, 2007 ͉ vol. 104 ͉ no. 46 ͉ 17907–17908 Downloaded by guest on September 30, 2021 deal regarding the biochemistry and during myocardial ischemia and reperfu- left ventricular (LV) function in a clini- physiology of these H2S-producing en- sion (I/R) (10). The mitochondrial ef- cally relevant, in vivo model of acute zyme systems. fects of H2S have been shown to be myocardial infarction. Furthermore, car- Since the recent discovery that H2Sis mediated in part by reversible and po- diac-specific overexpression of the H2S- a powerful gaseous signaling molecule, tent inhibition of cytochrome c oxidase generating enzyme CGL significantly studies have begun to characterize the (complex IV of the mitochondrial elec- reduces myocardial I/R injury and simi- biological profile of this promiscuous tron transport chain) (10, 13). The de- larly preserves LV function (10). The gas. Fig. 1 summarizes some of the fined physiological profile of H2S makes authors propose that preservation of physiological actions of H2S in the CV cardiac mitochondrial structure and system. H2S has been shown to relax function is central in the cardioprotec- vascular smooth muscle, induce vaso- It appears that H2S tive actions of H2S in I/R injury. dilation of isolated blood vessels, and Recent investigations into the vascular reduce blood pressure (3, 10). In this possesses all of the effects of H2S have revealed that this regard, H2S might be an important regula- physiologically produced gas has pro- tor of blood pressure. H2S has also been positive effects of NO found effects on vascular growth or for- shown to inhibit leukocyte–endothelial mation and neointimal hyperplasia. cell interactions in vivo. Zanardo et al. without the capacity to Meng et al. (18) have very recently (11) used intravital microscopy to dem- demonstrated that H2S ameliorates the onstrate that H2S donors inhibit leuko- form a toxic metabolite. intimal hyperplasia response in blood cyte adherence in the rat mesenteric vessels after balloon-mediated vascular microcirculation during vascular inflam- injury. Furthermore, Cai et al. (19) have mation, suggesting that H2S is a potent this novel gaseous signaling molecule an reported that physiologically relevant antiinflammatory molecule. It has also ideal pharmacological candidate for the dosages of H2S promote a highly robust become evident that H2S is as a potent treatment of CV disease states. angiogenic response that is largely de- antioxidant and, under chronic condi- A number of recent studies have pro- pendent on activation of Akt. Thus, H2S tions, can up-regulate antioxidant de- vided insights into the protective actions may prove beneficial for the inhibition fenses (9). In addition, it has been of H2S in the setting of myocardial I/R of coronary artery restenosis and the demonstrated that H2S effectively inhib- injury (10, 14–17). Pretreatment with induction of therapeutic angiogenesis. its apoptosis of a number of cell types, the H2S donor (NaHS) reduces arrhyth- Clearly, additional research is war- and this effect has been shown to pro- mias in isolated hearts subjected to ranted to further our understanding of mote cytoprotection (9). global cardiac I/R and improves myocyte the synthesis, metabolism, and physio- Research interest in H2S has also survival (14, 15). Similarly, Johansen et logical and potentially pathophysiologi- been focused on its profound metabolic al. (16) reported that NaHS pretreat- cal actions of endogenously produced effects, which result in a state of sus- ment significantly attenuates myocardial H2S in mammalian systems. The biologi- pended animation with drastic reduction injury in isolated, perfused rat hearts cal profile of H2S strongly suggests that in metabolic demand (12). Initiating sus- subjected to cardiac I/R. An article by this gaseous signaling molecule is likely pended animation may prove to be an Sivarajah et al. (17) represents the first to protect a variety of organs despite its ideal therapy for various shock or report of the cardioprotective actions of prior reputation as a noxious gas with a trauma states in which dramatic reduc- H2Sinanin vivo model of myocardial repulsive odor. It appears that H2S pos- tions in metabolic demands may be I/R injury. The authors reported a 25% sesses all of the positive effects of NO highly protective. Studies investigating reduction in myocardial infarct size after without the