By Matthew Lee ‘21

Modern industrialized countries are plagued by diseases that usually manifest their worst symptoms after many years. One such condition is hyperglycemia, in which high blood glucose may lead to diabetes and/or atherosclerosis. Jiaqiong Lin of Guangdong General Hospital and a team of researchers investigated how hydrogen sulfide (H2S) could protect human umbilical vein endothelial cells (HUVECs) against injury from high glucose. The team paid particular attention to how H2S affected the expression of receptor-interacting protein (RIP3), which promotes necroptosis, a harmful result of hyperglycemia. Necroptosis is a recently identified mechanism of cell death, taking its place among apoptosis, necrosis, and autophagy.

Using 40 mM glucose as the condition for high glucose (HG), it was found that the expression level of RIP3 in HUVECs peaked 9 hours after delivery (~1.2 RIP3/GAPDH ratio). The increased RIP3 was indicative of necroptosis. The team then found that adding exogenous H2S prior to HG treatment exhibited cytoprotective effects, as cell viability was highest at 400 µM H2S (~76% as compared to 45% with HG alone). These effects were confirmed as the expression level of RIP3 decreased from ~0.9 ratio for HG alone to ~0.7 ratio for HG + H2S treatment.

In addition, H2S with HG was found to mitigate the loss of mitochondrial membrane potential, anothr indicator of cell death, more than HG alone. The team also concluded that H2S works by inhibiting necroptosis because neither H2S nor the necroptosis inhibitor Nec-1, alone were able to change the MMP. Only when given in combination with HG was the loss of MMP attenuated.

The importance of understanding how cells die in response to hyperglycemic conditions is critical to developing future treatments.  Future studies could examine the benefits of cell exposure to hydrogen sulfide beyond inhibiting cell death. Investigating this treatment could have wider implications as well, considering that this mechanism of cell death has been recently linked to other conditions, such as atheroscelerosis.

References:

1. J. Lin, et. al., Exogenous hydrogen sulfide protects human umbilical vein endothelial cells against high glucose-induced injury by inhibiting the necroptosis pathway. International Journal of Molecular Medicine 41, 1477-1486 (2018). doi: 10.3892/ijmm.2017.3330
2. Image retrieved from: https://upload.wikimedia.org/wikipedia/commons/9/99/Necroptosis_Pathway_Diagram.png