Decrease in cystathionine‐gamma‐lyase (CSE) activity mediates the impaired H2S homeostasis in U937 monocytes, livers of type 1 diabetic rats and peripheral blood mononuclear cells of type 1 diabetic patients: role of hyperglycemia and hyperketo (767.5)

Abstract

H2S is a novel signaling molecule. This study investigated the molecular mechanism that causes impaired H2S levels in diabetes using U937 monocytes, livers from streptozotocin‐treated type 1 (T1D) diabetic rats, and PBMC from T1D patients. T1D is associated with both hyperketonemia (acetoacetate, AA and β‐hydroxybutyrate, BHB) and hyperglycemia. Treatment of monocytes with high glucose (HG, 25 mM) and/or AA (4 mM) increased ROS (44%), and decreased CSE (a major enzyme that catalyzes H2S formation) protein expression (53%) and activity (39%), and reduced H2S levels (45%); however, BHB treatment had no effect (n=4). Signal silencing studies with CSE siRNA (71% knock down) showed a decrease in H2S levels (83%) in monocytes compared to controls. Liver plays a major role in the H2S homeostasis. Livers from T1D rats showed a significantly higher ROS production, lower CSE protein expression (48%) and activity (0.268±0.032 vs 0.175±0.014 nmol/min/mg protein), and lower H2S levels (46%) compared to controls (n=6). Further studies with T1D patients (n=17) also demonstrated a decrease in CSE protein expression (44%) and activity (0.099±0.023 vs 0.044±0.005 nmol/min/mg protein) in PBMC compared to those of age‐matched normals (n=18). This study demonstrates for the first time that both hyperglycemia and hyperketonemia mediate a reduction in CSE activity which can contribute to the impaired H2S signaling in diabetes.Grant Funding Source: Supported by NIH RO1 AT007442 and Malcolm Feist Chair in Diabetes