The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases

Cai, Hua; Griendling, Kathy K.; Harrison, David G.

doi:10.1016/s0165-6147(03)00233-5

Cited by 634 publications

(532 citation statements)

References 79 publications

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“…More importantly, p47 phox and gp91 phox were significantly elevated in membrane fractions of Lep/Lep mouse myocytes. Activation of NADPH oxidase and subsequent accumulation of ROS are key to oxidative injury in cardiovascular diseases [32,33,46]. Oxidative stress has been shown to result in oxidative damage to functional proteins [35].…”

Section: Discussionmentioning

confidence: 99%

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Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch

et al. 2006

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Aims/hypothesis: Obesity is an independent risk factor for heart diseases but the underlying mechanism is not clear. This study examined cardiac contraction, oxidative stress, oxidative modification of sarco(endo) plasmic reticulum Ca 2+ -ATPase (SERCA) and the myosin heavy chain (MHC) isoform switch in obese mice. Methods: Mechanical properties were evaluated in ventricular myocytes from C57BL/6J lean and Lep/Lep obese mice (formerly known as ob/ob mice), including peak shortening (PS), time to 50 or 90% PS, time to 50 or 90% relengthening (TR 50 , TR 90 ), maximal velocity of shortening/relengthening (±dL/dt), intracellular Ca 2+ and its decay (τ). Oxidative stress, lipid peroxidation, protein damage and SERCA activity were assessed by glutathione/glutathione disulfide, malondialdehyde, protein carbonyl and 45 Ca 2+ uptake, respectively. NADPH oxidase was determined by immunoblotting. Results: Myocytes from Lep/Lep mice displayed depressed PS and ± dL/dt, prolonged TR 50 , TR 90 , elevated resting [Ca 2+ ] i , prolonged τ, reduced contractile capacity at high stimulus frequencies and diminished responsiveness to extracellular Ca 2+ compared with lean controls. Cardiac glutathione/glutathione disulfide was decreased whereas malondialdehyde, protein carbonyl, membrane p47 phox and membrane gp91 phox were increased in the Lep/Lep group. SERCA isoenzyme 2a was markedly modified by oxidation in Lep/ Lep hearts and associated with decreased 45 Ca 2+ uptake. The MHC isozyme displayed a shift from the α to the β isoform in Lep/Lep hearts. Short-term incubation of angiotensin II with myocytes mimicked the mechanical defects, SERCA oxidation and 45 Ca 2+ uptake seen in Lep/ Lep myocytes. Incubation of the NADPH oxidase inhibitor apocynin with Lep/Lep myocytes alleviated contractile defects without reversing SERCA oxidation or activity. Conclusions/interpretation: These data indicate that obesity-related cardiac defects may be related to NADPH oxidase activation, oxidative damage to SERCA and the MHC isozyme switch.

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Section: Discussionmentioning

confidence: 99%

“…Role of NADPH oxidase in obesity-associated cardiac mechanical dysfunction NADPH oxidase is a predominant source of ROS [32,33]. Our earlier study revealed that angiotensin receptormediated activation of NADPH oxidase plays a role in hyperglycaemia-induced cardiac dysfunction [34].…”

Section: Mechanical Properties Of Cardiomyocytesmentioning

confidence: 96%

Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch

et al. 2006

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“…These findings further support NADPH oxidase as a functionally relevant source of ROS for regulating coronary vascular tone. As both adenosine and ROS are generated and released under pathophysiological conditions [9,65] and generated ROS mainly exerts a detrimental influence on the coronary vasculature [54][55][56], future studies addressing the role of A 2A AR in ROS-mediated coronary vascular tone regulation in pathophysiological conditions will bring us greater insights into mechanisms underlying ischemic heart disease.…”

Section: Discussionmentioning

confidence: 99%

Involvement of NADPH oxidase in A2A adenosine receptor-mediated increase in coronary flow in isolated mouse hearts

Zhou

Rajamani

Labazi

et al. 2015

Purinergic Signalling

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Adenosine increases coronary flow mainly through the activation of A 2A and A 2B adenosine receptors (ARs). However, the mechanisms for the regulation of coronary flow are not fully understood. We previously demonstrated that adenosine-induced increase in coronary flow is in part through NADPH oxidase (Nox) activation, which is independent of activation of either A 1 or A 3 ARs. In this study, we hypothesize that adenosine-mediated increase in coronary flow through Nox activation depends on A 2A but not A 2B ARs. Functional studies were conducted using isolated Langendorff-perfused mouse hearts. Hydrogen peroxide (H 2 O 2 ) production was measured in isolated coronary arteries from WT, A 2A AR k n o c k o u t ( K O ) , a n d A 2 B A R K O m i c e u s i n g dichlorofluorescein immunofluorescence. Adenosineinduced concentration-dependent increase in coronary flow was attenuated by the specific Nox2 inhibitor gp91 ds-tat or reactive oxygen species (ROS) scavenger EUK134 in both WT and A 2B but not A 2A AR KO isolated hearts. Similarly, the A 2A AR selective agonist CGS-21680-induced increase in coronary flow was significantly blunted by Nox2 inhibition in both WT and A 2B AR KO, while the A 2B AR selective agonist BAY 60-6583-induced increase in coronary flow was not affected by Nox2 inhibition in WT. In intact isolated coronary arteries, adenosine-induced (10 μM) increase in H 2 O 2 formation in both WT and A 2B AR KO mice was attenuated by Nox2 inhibition, whereas adenosine failed to increase H 2 O 2 production in A 2A AR KO mice. In conclusion, adenosine-induced increase in coronary flow is partially mediated by Nox2-derived H 2 O 2 , which critically depends upon the presence of A 2A AR.

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“…The NADPH-oxidase complex is composed of membrane-bound subunits and cytosolic subunits, and the traslocation of cytosolic subunits to the membrane leads to NADPH activation and ROS generation, which is produced as rapid and carefully controlled increases in ROS levels for signaling mechanism in most cells (Li and Shah, 2003;Cai et al, 2003). ROS production is the only known function of NADPH oxidase.…”

Section: Discussionmentioning

confidence: 99%

“…However, the source of ROS and the mechanisms involved in the effects have not yet been elucidated. It is known that the NADPH oxidase complex is the most important intracellular source of ROS apart from mitochondria (Babior, 1999(Babior, , 2004Seshiah et al, 2002;Cai et al, 2003) and that it generates and releases ROS in short oxidative bursts for signaling functions (Bokoch and Knaus, 2003;Ritsick et al, 2004;Leto et al, 2009). In addition, several studies support a critical role for mitochondrial ATP-sensitive potassium channels (mitoKATP) in modulating intracellular ROS (Mattson and Liu, 2003;Costa and Garlid, 2008) by means of regulation of the formation/ release of ROS from the mitochondria, and integration of signals from diverse sources Facundo et al, 2007;Fornazari et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Effect of inhibitors of NADPH oxidase complex and mitochondrial ATP‐sensitive potassium channels on generation of dopaminergic neurons from neurospheres of mesencephalic precursors

Rodríguez‐Pallares

Joglar

Díaz-Ruiz

et al. 2010

Developmental Dynamics

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Reactive oxygen species signaling has been suggested to regulate stem cell development. In the present study, we treated neurospheres of rat mesencephalic precursors with inhibitors of the NADPH oxidase complex and mitochondrial ATP-sensitive potassium (mitoKATP) channel blockers during the proliferation and/or the differentiation periods to study the effects on generation of dopaminergic neurons. Treatment with low doses (100 or 250 mM) of the NADPH inhibitor apocynin during the proliferation period increased the generation of dopaminergic neurons. However, higher doses (1 mM) were necessary during the differentiation period to induce the same effect. Treatment with general (glibenclamide) or mitochondrial (5-hydroxydecanoate) KATP channel blockers during the proliferation and differentiation periods increased the number of dopaminergic neurons. Furthermore, neither increased proliferation rate nor apoptosis had a major role in the observed increase in generation of dopaminergic neurons, which suggests that the redox state is able to regulate differentiation of precursors into dopaminergic neurons. Developmental Dynamics 239:3247-3259,

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The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases

Cited by 634 publications

References 79 publications

Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch

Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch

Involvement of NADPH oxidase in A2A adenosine receptor-mediated increase in coronary flow in isolated mouse hearts

Effect of inhibitors of NADPH oxidase complex and mitochondrial ATP‐sensitive potassium channels on generation of dopaminergic neurons from neurospheres of mesencephalic precursors

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