P5388Redox-sensitive regulation of cystathionine gamma-lyase (CSE) and the potential protective role of hydrogen sulfide (H2S) in the human heart

Background: The human heart has self-regulatory mechanisms that influence myocardial redox state, but the mechanisms underlying these processes are still largely unknown. Cystathionine γ-Lyase (CSE) and its generation of hydrogen sulfide (H2S) are increasingly being recognized as important players in the regulation of myocardial redox signaling. Purpose: We explore whether CSE itself is a redox-sensitive enzyme and whether its expression relates to human myocardial redox state. We further examine the effects of H2S on the regulation of human myocardial redox state. Methods: In study 1, biopsies of right atrial appendage (RAA) obtained from 179 patients undergoing cardiac surgery were used to quantify the expression of CSE and its transcription factor specificity protein 1 (SP1) using qRTPCR, as well as myocardial O2.- (using lucigenin chemiluminescence). In study 2, H9C2 cardiomyocytes were exposed to NADPH (1mM, 18h), to study the acute effects of oxidative stress on CSE expression. In study 3, RAA biopsies from 20 additional CABG patients were exposed to H2S donor NaHS (30μM, 1h) in an ex vivo system, and O2.- was measured in the presence and absence of NOS inhibitor L-NAME. Peroxynitrite (ONOO-) was measured using urate-inhibitable luminol chemiluminescence.