Beta-adrenergic receptor-stimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of the mitochondrial pathway

Circ Res. 2003 Feb 7;92(2):136-8. doi: 10.1161/01.res.0000054624.03539.b4.

Abstract

Stimulation of beta-adrenergic receptors (betaARs) causes apoptosis in adult rat ventricular myocytes (ARVMs). The role of reactive oxygen species (ROS) in mediating betaAR-stimulated apoptosis is not known. Stimulation of betaARs with norepinephrine (10 micromol/L) in the presence of prazosin (100 nmol/L) for 24 hours increased the number of apoptotic myocytes as determined by TUNEL staining by 3.6- fold. The superoxide dismutase/catalase mimetics Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP; 10 micromol/L) and Euk-134 decreased betaAR-stimulated apoptosis by 89+/-6% and 76+/-10%, respectively. Infection with an adenovirus expressing catalase decreased betaAR-stimulated apoptosis by 82+/-15%. The mitochondrial permeability transition pore inhibitor bongkrekic acid (50 micromol/L) decreased betaAR-stimulated apoptosis by 76+/-8%, and the caspase inhibitor zVAD-fmk (25 micromol/L) decreased betaAR-stimulated apoptosis by 62+/-11%. betaAR-stimulated cytochrome c release was inhibited by MnTMPyP. betaAR stimulation caused c-Jun NH2-terminal kinase (JNK) activation, which was abolished by MnTMPyP. Transfection with an adenovirus expressing dominant-negative JNK inhibited betaAR-stimulated apoptosis by 81+/-12%, and the JNK inhibitor SP600125 inhibited both betaAR-stimulated apoptosis and cytochrome c release. Thus, betaAR-stimulated apoptosis in ARVMs involves ROS/JNK-dependent activation of the mitochondrial death pathway.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Bongkrekic Acid / pharmacology
  • Caspase Inhibitors
  • Catalase / biosynthesis
  • Catalase / genetics
  • Catalase / pharmacology
  • Cells, Cultured
  • Cytochrome c Group / metabolism
  • Enzyme Inhibitors / pharmacology
  • Free Radical Scavengers / pharmacology
  • Ion Channels / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases
  • Metalloporphyrins / pharmacology
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Norepinephrine / pharmacology
  • Organometallic Compounds / pharmacology
  • Prazosin / pharmacology
  • Rats
  • Reactive Oxygen Species / metabolism*
  • Receptors, Adrenergic, beta / drug effects
  • Receptors, Adrenergic, beta / metabolism*
  • Salicylates / pharmacology
  • Signal Transduction / physiology

Substances

  • Caspase Inhibitors
  • Cytochrome c Group
  • EUK-134
  • Enzyme Inhibitors
  • Free Radical Scavengers
  • Ion Channels
  • Metalloporphyrins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Organometallic Compounds
  • Reactive Oxygen Species
  • Receptors, Adrenergic, beta
  • Salicylates
  • Bongkrekic Acid
  • tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex
  • Catalase
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Norepinephrine
  • Prazosin