Targeting hydrogen sulfide and nitric oxide to repair cardiovascular injury after trauma

Abstract

The systemic cardiovascular effects of major trauma, especially neurotrauma, contribute to death and permanent disability in trauma patients and treatments are needed to improve outcomes. In some trauma patients, dysfunction of the autonomic nervous system produces a state of adrenergic overstimulation, causing either a sustained elevation in catecholamines (sympathetic storm) or oscillating bursts of paroxysmal sympathetic hyperactivity. Trauma can also activate innate immune responses that release cytokines and damage-associated molecular patterns into the circulation. This combination of altered autonomic nervous system function and widespread systemic inflammation produces secondary cardiovascular injury, including hypertension, damage to cardiac tissue, vascular endothelial dysfunction, coagulopathy and multiorgan failure. The gasotransmitters nitric oxide (NO) and hydrogen sulfide (H₂S) are small gaseous molecules with potent effects on vascular tone regulation. Exogenous NO (inhaled) has potential therapeutic benefit in cardio-cerebrovascular diseases, but limited data suggests potential efficacy in traumatic brain injury (TBI). H₂S is a modulator of NO signaling and autonomic nervous system function that has also been used as a drug for cardio-cerebrovascular diseases. The inhaled gases NO and H₂S are potential treatments to restore cardio-cerebrovascular function in the post-trauma period.

Keywords: Brain injury; Cardiovascular; Hydrogen sulfide; Nitric oxide.

Figure 1.. Post-TBI Autonomic Dysfunction Physiopathology and cardiovascular impairments after TBI.

In physiological condition (A), baroreceptors sense changes in blood pressure and send this information to NTS, which in turn activates the NA that regulates parasympathetic outflow and CVLM that inhibits RVLM regulating sympathetic outflow. Moreover, RVLM receives information from the hypothalamus, which is a critical regulator of autonomic response. Descending inhibitory pathway, from thalamus and PAG, regulates efferent responses to non-noxious stimuli. On the other hand, after TBI (B), an increase in hypothalamic stimulation on RVLM and an impaired descending inhibitory pathway could be observed and due to the diffuse axonal injury, cortical, and subcortical networks are damaged. These impairments lead to perceived non noxious stimuli as noxious and, in consequence, induce cardiovascular impairments such as changes in baroreflex sensitivity (1) and central structures damage (2). Thus, increase in sympathetic outflow (3) and catecholamine release (4). Moreover, TBI induces endothelial and cardiac dysfunction (5, 6). CVLM, caudal ventrolateral medulla; NA, nucleus ambiguus; NTS, nucleus tractus solitarius; PAG, periaqueductal grey matter; PVN, paraventricular nucleus; RVLM, rostral ventrolateral medulla; SG, sympathetic ganglion; Xn, vagus nerve.

Figure 2.. Effect of hydrogen sulfide (H2S) in vascular tone and its direct interaction with nitric oxide (NO) signaling.

H2S is synthesized in the vascular endothelial cells from L-Cys through enzymatic pathways including the enzymes cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase. In the vascular endothelium, H2S promotes eNOS synthesis or phosphorylation, as well as PLA2 activation that leads to EETs production. At the same time, the NO produced by eNOS inhibits H2S production in the endothelial cells. Once NO and H2S are synthesized in the endothelium both gasotransmitters interact with each other to form stable intermediates such as HNO or SNO⁻ that can modulate vascular tone. H2S is also synthesized in the vascular smooth muscle cell where it inhibits the PDE5 to increase cGMP and potentiate NO vascular effects. Besides, H2S activates different potassium channels located in the vascular smooth muscle cell which leads to hyperpolarization and relaxation. Lastly, H2S modulates neuronal regulation of the vascular tone by inhibiting vasopressor sympathetic outflow and stimulating the release from perivascular sensory neurons. 3-MST, 3- mercaptopyruvate sulfurtransferase; AA, arachidonic acid; CBS, cystathionine-β-synthase; cGMP, cyclic GMP; CSE, cystathionine-γ-lyase; EETs, epoxyeicosatrienoic acids; eNOS, endothelial nitric oxide synthase; GC, guanylate cyclase; HNO, nitroxyl; L-Arg, L-arginine; L-Cys, L-cysteine; PDE5, phosphodiesterase 5; PLA2, phospholipase A2; SNO-, nitrosothiol.

Figure 3.. Indirect interaction of hydrogen sulfide (H2S) with nitric oxide (NO) signaling through oxidative stress and inflammation regulation.

Traumatic brain injury induces the overproduction of reactive oxygen species (ROS) and pro-inflammatory molecules such as TNF-α. Excessive ROS production causes the oxidation of BH4 and increases BH2, which leads to eNOS uncoupling. The eNOS uncoupling decreases NO bioavailability since uncoupled eNOS generates superoxide radicals rather than NO, and the small amount of NO synthetized reacts with ROS leading to peroxynitrite production. Moreover, the activation of TNF-α receptor reduces eNOS protein expression and impairs the degradation of asymmetric dimethylarginine, an endogenous inhibitor of NOS activity, contributing to the diminishment of NO production. Besides, TNF-α contributes to endothelial dysfunction by inducing NOX expression and activity, and increasing the expression of adhesion molecules on the surface of vascular endothelial cells through the activation of NF-κB. On the other hand, H2S decreases oxidative stress by scavenging ROS and peroxynitrite, and promoting antioxidant enzyme expression through the sulfhydration of Keap1. Furthermore, H2S diminishes TNF-α levels and inhibits NF-κB translocation to the nucleus, which reduces the process associated with TNF-α overproduction. Therefore, H2S restores NO availability, eNOS activity, and endothelial function by decreasing oxidative stress and inflammation.