title: Regulation of mitochondrial poly(ADP-Ribose) polymerase activation by the β-adrenoceptor/cAMP/protein kinase A axis during oxidative stress.
abstract: We investigated the regulation of mitochondrial poly(ADP-ribose) polymerase 1 (PARP1) by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) system during oxidative stress in U937 monocytes. Oxidative stress induced an early (10 minutes) mitochondrial DNA damage, and concomitant activation of PARP1 in the mitochondria. These early events were followed by a progressive mitochondrial oxidant production and nuclear PARP1 activation (by 6 hours). These processes led to a functional impairment of mitochondria, culminating in cell death of mixed (necrotic/apoptotic) type. β-Adrenoceptor blockade with propranolol or inhibition of its downstream cAMP/PKA signaling attenuated, while β-adrenoceptor agonists and cAMP/PKA activators enhanced, the oxidant-mediated PARP1 activation. In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain). Inhibition of the β-adrenergic receptor/cAMP/PKA axis protected against the oxidant-mediated cell injury. Propranolol also suppressed PARP1 activation in peripheral blood leukocytes during bacterial lipopolysaccharide (LPS)-induced systemic inflammation in mice. We conclude that the activation of mitochondrial PARP1 is an early, active participant in oxidant-induced cell death, which is under the control of β-adrenoceptor/cAMP/PKA axis through the regulation of PARP1 activity by PARP1 phosphorylation.
authors: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas.
authors: Attila
authors: A
authors: Brunyanszki
authors: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas.
authors: Gabor
authors: G
authors: Olah
authors: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas.
authors: Ciro
authors: C
authors: Coletta
authors: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas.
authors: Bartosz
authors: B
authors: Szczesny
authors: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas szabocsaba@aol.com.
authors: Csaba
authors: C
authors: Szabo
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011433:Propranolol / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
chemical_list: D000319:Adrenergic beta-Antagonists; D004272:DNA, Mitochondrial; D008070:Lipopolysaccharides; D024101:Mitochondrial Proteins; D011943:Receptors, Adrenergic, beta; D011433:Propranolol; D000242:Cyclic AMP; D011065:Poly(ADP-ribose) Polymerases; D017868:Cyclic AMP-Dependent Protein Kinases