Activation of Poly-ADP-ribosyl Synthase in Sepsis, Ischemia/Reperfusion, and Inflammation

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Abstract

Shock, reperfusion, and inflammation are associated with the endogenous production of various oxidant species which enter the nucleus and induce DNA injury. Oxidant-induced DNA strand breaks trigger a conformational activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS), which catalyzes the formation of a nucleic acid homopolymer poly (ADP-ribose) from the substrate NAD. Under conditions of severe oxidant stress, PARS activation consumes cytosolic NAD and rapidly leads to ATP depletion and cellular energetic failure. PARS also mediates pro-inflammatory gene expression and is a critical regulator of vascular adhesion molecules and neutrophil infiltration. In sepsis, reperfusion, and inflammation, PARS is strongly activated by damaged DNA, triggering a cascade of intracellular changes which ultimately result in an impairment of mitochondrial respiration and a loss of vascular contractility and myocardial function. The importance of PARS to tissue injury and organ failure is demonstrated by the remarkable improvement in survival and cardiovascular performance in shock models in which PARS activity has been inhibited by pharmacologic means, or ablated by targeted gene disruption. The causal association between acute DNA damage and the hemodynamic instability in shock creates opportunities for a new class of agents to prevent hypotension, ischemia, and end-organ damage.

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