A hydrogen sulfide (H2S) deficiency can be detrimental to the vascular function after an acute myocardial infarction (AMI).[72] AMIs can lead to cardiac dysfunction through two distinct changes; increased oxidative stress via free radical accumulation and decreased NO bioavailability.[73] Free radical accumulation occurs due to increased electron transport uncoupling at the active site of endothelial nitric oxide synthase (eNOS), an enzyme involved in converting L-arginine to NO.[72][73] During an AMI, oxidative degradation of tetrahydrobiopterin (BH4), a cofactor in NO production, limits BH4 availability and limits NO productionby eNOS.[73] Instead, eNOS reacts with oxygen, another cosubstrates involved in NO production. The products of eNOS are reduced to superoxides, increasing free radical production and oxidative stress within the cells.[72] A H2S deficiency impairs eNOS activity by limiting Akt activation and inhibiting Akt phosphorylation of the eNOSS1177 activation site.[72][74] Instead, Akt activity is increased to phosphorylate the eNOST495 inhibition site, downregulating eNOS production of NO.[72][74]
H2S therapy uses a H2S donor, such as diallyl trisulfide (from garlic), to increase the supply of H2S to an AMI patient. H2S donors reduce myocardial injury and reperfusion complications.[72] Increased H2S levels within the body will react with oxygen to produce sulfane sulfur, a storage intermediate for H2S.[72] H2S pools in the body attracts oxygen to react with excess H2S and eNOS to increase NO production.[72] With increased use of oxygen to produce more NO, less oxygen is available to react with eNOS to produce superoxides during an AMI, ultimately lowering the accumulation of reactive oxygen species (ROS).[72] Furthermore, decreased accumulation of ROS lowers oxidative stress in vascular smooth muscle cells, decreasing oxidative degeneration of BH4.[73] Increased BH4 cofactor contributes to increased production of NO within the body.[73] Higher concentrations of H2S directly increase eNOS activity through Akt activation to increase phosphorylation of the eNOSS1177 activation site, and decrease phosphorylation of the eNOST495 inhibition site.[72][74] This phosphorylation process upregulates eNOS activity, catalyzing more conversion of L-arginine to NO.[72][74] Increased NO production enables soluble guanylyl cyclase (sGC) activity, leading to an increased conversion of guanosine triphosphate (GTP) to 3′,5′-cyclic guanosine monophosphate (cGMP).[75] In H2S therapy immediately following an AMI, increased cGMP triggers an increase in protein kinase G (PKG) activity.[76] PKG reduces intracellular Ca2+ in vascular smooth muscle to increase smooth muscle relaxation and promote blood flow.[76] PKG also limits smooth muscle cell proliferation, reducing intima thickening following AMI injury, ultimately decreasing myocardial infarct size.[72][75]
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