title: NOX2-derived reactive oxygen species are crucial for CD29-induced pro-survival signalling in cardiomyocytes.
abstract: OBJECTIVE
  The highly expressed cell adhesion receptor CD29 (β(1)-integrin) is essential for cardiomyocyte growth and survival, and its loss of function causes severe heart disease. However, CD29-induced signalling in cardiomyocytes is ill defined and may involve reactive oxygen species (ROS). A decisive source of cardiac ROS is the abundant NADPH oxidase (NOX) isoform NOX2. Because understanding of NOX-derived ROS in the heart is still poor, we sought to test the role of ROS and NOX in CD29-induced survival signalling in cardiomyocytes.
  
  
  RESULTS
  In neonatal rat ventricular myocytes, CD29 activation induced intracellular ROS formation (oxidative burst) as assessed by flow cytometry using the redox-sensitive fluorescent dye dichlorodihydrofluorescein diacetate. This burst was inhibited by apocynin and diphenylene iodonium. Further, activation of CD29 enhanced NOX activity (lucigenin-enhanced chemiluminescence) and activated the MEK/ERK and PI3K/Akt survival pathways. CD29 also induced phosphorylation of the inhibitory Ser9 on the pro-apoptotic kinase glycogen synthase kinase-3β in a PI3K/Akt- and MEK-dependent manner, and improved cardiomyocyte viability under conditions of oxidative stress. The ROS scavenger MnTMPyP or adenoviral co-overexpression of the antioxidant enzymes superoxide dismutase and catalase inhibited CD29-induced pro-survival signalling. Further, CD29-induced protective pathways were lost in mouse cardiomyocytes deficient for NOX2 or functional p47(phox), a regulatory subunit of NOX.
  
  
  CONCLUSIONS
  p47(phox)-dependent, NOX2-derived ROS are mandatory for CD29-induced pro-survival signalling in cardiomyocytes. These findings go in line with a growing body of evidence suggesting that ROS can be beneficial to the cell and support a crucial role for NOX2-derived ROS in cell survival in the heart.
authors.affiliation: Myocardial Research,  Department of Biomedicine, University and University Hospital Basel, Hebelstrasse 20, 4031 Basel,  Switzerland.
authors.forename: Berit I
authors.initials: BI
authors.lastname: Rosc-Schlüter
authors.forename: Stéphanie P
authors.initials: SP
authors.lastname: Häuselmann
authors.forename: Vera
authors.initials: V
authors.lastname: Lorenz
authors.forename: Michika
authors.initials: M
authors.lastname: Mochizuki
authors.forename: Federica
authors.initials: F
authors.lastname: Facciotti
authors.forename: Otmar
authors.initials: O
authors.lastname: Pfister
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Kuster
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009861:Onium Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D000098:Acetophenones; D000975:Antioxidants; D019012:Integrin beta1; D008562:Membrane Glycoproteins; D009861:Onium Compounds; D017382:Reactive Oxygen Species; C007517:diphenyleneiodonium; C056165:acetovanillone; C488842:Cybb protein, mouse; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3