Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

The recent discovery that hydrogen sulfide (H2S) is an endogenously produced gaseous second messenger capable of modulating many physiological processes, much like nitric oxide, prompted us to investigate the potential of H2S as a cardioprotective agent. In the current study, we demonstrate that the delivery of H2S at the time of reperfusion limits infarct size and preserves left ventricular (LV) function in an in vivo model of myocardial ischemiareperfusion (MI-R). This observed cytoprotection is associated with an inhibition of myocardial inflammation and a preservation of both mitochondrial structure and function after I-R injury. Additionally, we show that modulation of endogenously produced H2S by cardiac-specific overexpression of cystathionine ␥-lyase (␣-MHC-CGL-Tg mouse) significantly limits the extent of injury. These findings demonstrate that H2S may be of value in cytoprotection during the evolution of myocardial infarction and that either administration of H2S or the modulation of endogenous production may be of clinical benefit in ischemic disorders.

Rationale: The recent emergence of hydrogen sulfide (H 2 S) as a potent cardioprotective signaling molecule necessitates the elucidation of its cytoprotective mechanisms. Objective: The present study evaluated potential mechanisms of H 2 S-mediated cardioprotection using an in vivo model of pharmacological preconditioning. Methods and Results: H 2 S (100 g/kg) or vehicle was administered to mice via an intravenous injection 24 hours before myocardial ischemia. Treated and untreated mice were then subjected to 45 minutes of myocardial ischemia followed by reperfusion for up to 24 hours, during which time the extent of myocardial infarction was evaluated, circulating troponin I levels were measured, and the degree of oxidative stress was evaluated. In separate studies, myocardial tissue was collected from treated and untreated mice during the early (30 minutes and 2 hours) and late (24 hours) preconditioning periods to evaluate potential cellular targets of H 2 S. Initial studies revealed that H 2 S provided profound protection against ischemic injury as evidenced by significant decreases in infarct size, circulating troponin I levels, and oxidative stress. During the early preconditioning period, H 2 S increased the nuclear localization of Nrf2, a transcription factor that regulates the gene expression of a number of antioxidants and increased the phosphorylation of protein kinase C and STAT-3. During the late preconditioning period, H 2 S increased the expression of antioxidants (heme oxygenase-1 and thioredoxin 1), increased the expression of heat shock protein 90, heat shock protein 70, Bcl-2, Bcl-xL, and cyclooxygenase-2 and also inactivated the proapoptogen Bad. Key Words: hydrogen sulfide Ⅲ cardioprotection Ⅲ antioxidant signaling Ⅲ myocardial infarction Ⅲ Nrf2 H ydrogen sulfide (H 2 S) is an endogenously produced gaseous signaling molecule with a diverse physiological profile. Its production in mammalian systems has been attributed to 2 key enzymes in the cysteine biosynthesis pathway, cystathionine ␤-synthase (CBS) and cystathionine ␥-lyase (CGL). The rate of H 2 S production in tissue homogenates is in the range of 1 to 10 pmol per second per milligram of protein, resulting in low micromolar extracellular concentrations. 1,2 It is at these physiological concentrations that H 2 S is cytoprotective in various models of cellular injury. 3,4 The reported cytoprotective effects of H 2 S are partially related to its ability to neutralize reactive oxygen species (ROS), to inhibit leukocyte-endothelial cell interactions, to promote vascular smooth muscle relaxation, to reduce apoptotic signaling, and to reversibly modulate mitochondrial respiration. 5 Pretreatment with NaHS has been reported to reduce the number and duration of arrhythmias in isolated hearts subjected to global ischemia/reperfusion (I/R) 6 and to enhanced the viability of isolated rat ventricular myocytes exposed to glucose deprivation and 2-deoxyglucose. 4 Recently, Elrod et al 7 reported that the administration of H 2 S at the time of reperfu...