Emergence of hydrogen sulfide as an endogenous gaseous signaling molecule in cardiovascular disease

Abstract

Long recognized as a malodorous and highly toxic gas, recent experimental studies have revealed that hydrogen sulfide (H2S) is produced enzymatically in all mammalian species including man and exerts several critical actions to promote cardiovascular homeostasis and health. During the past 15 years, scientists have determined that H2S is produced by 3 endogenous enzymes and exerts powerful effects on endothelial cells, smooth muscle cells, inflammatory cells, mitochondria, endoplasmic reticulum, and nuclear transcription factors. These effects have been reported in multiple organ systems, and the majority of data clearly indicate that H2S produced by the endogenous enzymes exerts cytoprotective actions. Recent preclinical studies investigating cardiovascular diseases have demonstrated that the administration of physiological or pharmacological levels of H2S attenuates myocardial injury, protects blood vessels, limits inflammation, and regulates blood pressure. H2S has emerged as a critical cardiovascular signaling molecule similar to nitric oxide and carbon monoxide with a profound effect on the heart and circulation. Our improved understanding of how H2S elicits protective actions, coupled with the rapid development of novel H2S-releasing agents, has resulted in heightened enthusiasm for the clinical translation of this ephemeral gaseous molecule. This review will examine our current state of knowledge about the actions of H2S within the cardiovascular system with an emphasis on the therapeutic potential and molecular cross talk between H2S, nitric oxide, and carbon monoxide.

Keywords: carbon monoxide; gasotransmitters; heart failure; nitric oxide.

Figure 1. Currently Recognized Gasotransmitters

Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S) are all produced endogenously via enzymes. NO is synthesized by neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS). CO is generated by the heme oxygenase (HO) family of enzymes (HO-1, HO-2, and HO-3). H₂S is synthesized via the actions of cystathionine beta synthase (CBS), cystathionine gamma lyase (CSE or CGL), and 3-mercaptopyruvate sulfur transferase (3MST). These gaseous molecules are produced in very low concentrations ranging from low nM to low µM and are very labile. Adapted and modified from Calvert et al.

Figure 2. Hydrogen Sulfide Mediated Signaling

H₂S is known to modify proteins, modulate the function of various ion channels, attenuate apoptosis and oxidative stress, and to be a potent modulator of cellular metabolic function. Adapted and modified from King et al.

Figure 3. Crosstalk Between Exogenous Hydrogen Sulfide (H₂S), Nitric Oxide (NO), and Carbon Monoxide (CO)

Proposed interaction between H₂S and eNOS to increase nitric oxide generation. In addition, H₂S can activate heme oxygenase-1 via genetic upregulation and increased activity to enhance levels of carbon monoxide. Nitric oxide and carbon monoxide can ultimately synergize with H₂S to exert both vascular and cardiac protection during cardiovascular disease states.

Figure 4. Endogenous H₂S Regulation of the eNOS-NO Pathway

Proposed actions of CSE derived H₂S under normal conditions and in the setting of cardiovascular disease. H₂S is a potent regulator of cellular redox status that limits oxidative stress thereby preserving eNOS function and promoting nitric oxide (NO) production. Diminished endogenous H₂S results in profound oxidative stress, reduced BH₄ levels and dysfunctional eNOS (i.e., eNOS uncoupling). Reduced nitric oxide levels exacerbate cardiovascular pathology.