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The role of endogenous H2S production during hibernation and forced hypothermia

Towards safe cooling and rewarming in clinical practice
PhD ceremony:Mr G.J. (George) Dugbartey
When:July 01, 2015
Supervisor:prof. dr. R.H. (Rob) Henning
Co-supervisor:dr. H.R. (Hjalmar) Bouma
Where:Academy building RUG
Faculty:Medical Sciences / UMCG
The role of endogenous H2S production during hibernation
and forced hypothermia

Therapeutic hypothermia as employed during transplantation, surgery or trauma, unavoidably leads to organ damage due to ischemia/reperfusion injury (IRI). Interestingly, hibernating mammals have solved this problem, as they manage to periodically lower their metabolism and body temperature during periods referred to as torpor. Torpor periods are regularly intersected by brief periods (‘arousals’), during which these parameters are restored without organ damage. Several adaptive physiological mechanisms in hibernators may underlie this resistance to organ damage during these period of physiological extremes. We recently identified a reversible remodeling of lung tissue in hibernating Syrian hamsters with regulation of the H2S-producing enzyme, cystathionine-β-synthase (CBS) as one of the adaptive mechanisms. Therefore, this PhD aimed at investigating mechanisms that confer resistance to hypothermia/rewarming with a focus on the role of endogenous hydrogen sulfide gas (H2S) and its synthesizing enzymes in the kidney, representing an organ highly susceptible to hypothermic damage. Main findings are that torpid animals show an upregulation of H2S-synthesizing enzymes and increased blood H2S level. Further, pharmacological inhibition of the H2S-synthesizing pathways prevented entrance into torpor and induced renal injury. Together, this suggests that the H2S pathway is essential not only in inducing hibernation but also in protecting the kidney during these temperature extremes. Further, we found that pharmacological induction of H2S formation by dopamine also protected from kidney damage in rats subjected to forced hypothermia/rewarming. Therefore, maintenance or upregulation of endogenous H2S-synthesizing pathways may offer a novel therapeutic approach in preventing renal IRI associated with clinical conditions which require cooling/rewarming.