Beneficial effect of tetrahydrobiopterin on ischemia-reperfusion injury in isolated perfused rat hearts

Yamashiro, Satoshi; Noguchi, Katsuhiko; Matsuzaki, Toshihiro; Miyagi, Koichi; Nakasone, Junko; Sakanashi, Mayuko; Koja, Kageharu; Sakanashi, Matao

doi:10.1067/mtc.2002.124393

Cited by 53 publications

(49 citation statements)

References 28 publications

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“…It has been demonstrated that BH 4 improves I/R injury in isolated perfused rat hearts (35,160). In ApoE Ϫ/Ϫ mice, BH 4 supplementation reduces vascular immune cell infiltration in atherosclerosis through maintaining eNOS coupling and NO bioavailability, thus preventing the progression of atherosclerosis (115).…”

Section: The Role Of Nos Cofactor Bhmentioning

confidence: 99%

Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

Zhang¹,

Janssens

Wingler

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Zhang Y, Janssens SP, Wingler K, Schmidt HH, Moens AL. Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy. Am J Physiol Heart Circ Physiol 301: H634 -H646, 2011. First published May 27, 2011 doi:10.1152/ajpheart.01315.2010.-The pathogenesis of many cardiovascular diseases is associated with reduced nitric oxide (NO) bioavailability and/or increased endothelial NO synthase (eNOS)-dependent superoxide formation. These findings support that restoring and conserving adequate NO signaling in the heart and blood vessels is a promising therapeutic intervention. In particular, modulating eNOS, e.g., through increasing the bioavailability of its substrate and cofactors, enhancing its transcription, and interfering with other modulators of eNOS pathway, such as netrin-1, has a high potential for effective treatments of cardiovascular diseases. This review provides an overview of the possibilities for modulating eNOS and how this may be translated to the clinic in addition to describing the genetic models used to study eNOS modulation.endothelial nitric oxide synthase uncoupling; modulators; superoxide; tetrahydrobiopterin; enhancers; nitric oxide donors THE REVALENCE AND SEVERITY of incipient or overt cardiovascular diseases associated with reduced nitric oxide (NO) bioavailability has resulted in efforts to restore and conserve adequate NO signaling in the heart and blood vessels through therapeutic interventions. In the cardiovascular system, the signaling molecule NO, which is produced by the enzyme endothelial NO synthase (eNOS, NOS3), has a crucial role in maintaining normal vascular function, mediated by its vasodilating capacity and through a variety of antiatherogenic effects. eNOS is not only expressed in endothelial cells of the heart and blood vessels, in both atrial and ventricular myocytes, but also in specialized pacemaker tissue.Uncoupling of bioactive, i.e., dimeric eNOS to an inactive monomeric form (73) is caused by oxidative stress, which reduces the bioavailability of tetrahydrobiopterin (BH 4 ), an essential cofactor of eNOS. In this uncoupled state, NADPH consumption and oxygen reduction are uncoupled from L-arginine oxidation and NO formation with a subsequently decreased NO production and increased superoxide generation (157). eNOS generated superoxide, further oxidizes BH 4 , and hence enhances the uncoupling of eNOS. However, it is unclear which source of superoxide initiates eNOS uncoupling.Uncoupling of eNOS has been described in 1) situations associated with endothelial dysfunction such as atherosclerosis (3, 70), diabetes mellitus (135), ischemia-reperfusion (I/R) injury (35,138), hypertension (68), and chronic flow overload (78); 2) cardiac hypertrophy with ventricular remodeling (133); and 3) diastolic heart failure (149). eNOS also uncouples physiologically. For example, eNOS may uncouple postnatal in the lung, possibly leading to a developmental adaptation of the pulmonary vascular system to produce reactive oxygen species (ROS) (81). In addition, it ...

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Section: The Role Of Nos Cofactor Bhmentioning

confidence: 99%

Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

Zhang¹,

Janssens

Wingler

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Ischemia time-dependently decreases cardiac BH 4 content and endothelial NOS (NOS3) activity and increases NOS-derived superoxide (O 2 •Ϫ ) production, which is believed to contribute to postischemic endothelial dysfunction and myocardial injury (7). BH 4 supplementation has been shown to restore endothelium-dependent coronary flow and decrease I/R injury in isolated perfused rat hearts (26,32,33), whereas inhibiting BH 4 synthesis has been shown to increase I/R injury (13). These observations suggest the importance of myocardial BH 4 bioavailability in cardioprotection and provide support for the notion that BH 4 may be a novel therapeutic target for treating I/R injury.…”

mentioning

confidence: 99%

“…BH 4 supplementation has been shown to restore endothelium-dependent coronary flow and decrease I/R injury in isolated perfused rat hearts (26,32,33), whereas inhibiting BH 4 synthesis has been shown to increase I/R injury (13). These observations suggest the importance of myocardial BH 4 bioavailability in cardioprotection and provide support for the notion that BH 4 may be a novel therapeutic target for treating I/R injury.…”

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confidence: 99%

Role of tetrahydrobiopterin in resistance to myocardial ischemia in Brown Norway and Dahl S rats

Wei

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Previously we showed that Brown Norway (BN/Mcw) rats are more resistant to myocardial ischemiareperfusion (I/R) injury than Dahl S (SS/Mcw) rats due to increased nitric oxide ( ⅐ NO) generation secondary to increased heat shock protein 90 (HSP90) association with endothelial nitric oxide synthase (NOS3). Here we determined whether increased resistance to I/R injury in BN/Mcw hearts is also related to tetrahydrobiopterin (BH4) and GTP cyclohydrolase I (GCH-1), the rate-limiting enzyme for BH4 synthesis. We observed that BH4 supplementation via sepiapterin (SP) and inhibition of GCH-1 via 2,4-diamino-6-hydroxypyrimidine (DAHP) differentially modulate cardioprotection and that SP alters the association of HSP90 with NOS3. BH4 levels were significantly higher and 7,8-dihydrobiopterin (BH2) levels were significantly lower in BN/Mcw than in SS/Mcw hearts. The BH4-to-BH2 ratio in BN/ Mcw was more than two times that in SS/Mcw hearts. After I/R, BH4 decreased and BH2 increased in hearts from both strains compared with their preischemia levels. However, the increase in BH2 in SS/Mcw hearts was significantly higher than in BN/Mcw hearts. These data indicate that BH4 mediates resistance to I/R by acting as a cofactor and enhancing HSP90-NOS3 association. nitric oxide; cardioprotection; guanosine 5Ј-triphosphate cyclohydrolase I NITRIC oxide ( ⅐NO) is a key signaling molecule in the cardiovascular system (3, 34). ⅐NO, both endogenous and exogenous, has been shown to increase cardioprotection during cardiac ischemia-reperfusion (I/R) injury in recent studies (2,5,18).⅐NO is produced from the guanidine group of L-arginine in a NADPH-dependent reaction catalyzed by a family of nitric oxide synthase (NOS), which requires Ca 2ϩ /calmodulin, flavin adenine dinucleotide, flavin mononucleotide, and tetrahydrobiopterin (BH 4 ) as cofactors. Ischemia time-dependently decreases cardiac BH 4 content and endothelial NOS (NOS3) activity and increases NOS-derived superoxide (O 2•Ϫ ) production, which is believed to contribute to postischemic endothelial dysfunction and myocardial injury (7). BH 4 supplementation has been shown to restore endothelium-dependent coronary flow and decrease I/R injury in isolated perfused rat hearts (26,32,33), whereas inhibiting BH 4 synthesis has been shown to increase I/R injury (13). These observations suggest the importance of myocardial BH 4 bioavailability in cardioprotection and provide support for the notion that BH 4 may be a novel therapeutic target for treating I/R injury. BH 4 is synthesized by either the de novo pathway or the salvage pathway (Fig. 1). De novo synthesis starts with GTP in a Mg 2ϩ -, Zn 2ϩ -, and NADPH-dependent reaction to form 7,8-dihydroneopterin by GTP cyclohydrolase I (GCH-1), which is subsequently converted to 6-pyruvoyl-5,6,7,8-tetrahydropterin by 6-pyruvoyl-tetrahydropterin synthase (PTS), which is then converted to BH 4 by sepiapterin reductase (SR) (9). GCH-1 is the rate-limiting enzyme in BH 4 synthesis. The salvage pathway metabolizes sepiapterin (SP) and 7,8-dihydrobi...

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“…27) We previously confirmed that the NOx level in the coronary effluent of isolated rat heart clearly decreases after I/R injury. 28) Our results suggested that impaired cardiac function after I/R injury was mainly affected by microvascular dysfunction, which decreased CF. However, we could not identify a significant correlation between CF and cardiac dysfunction.…”

Section: Discussionmentioning

confidence: 71%

Determination of Oxidative Stress and Cardiac Dysfunction after Ischemia/Reperfusion Injury in Isolated Rat Hearts

Ichikawa

Kuniyoshi

Yamashiro

et al. 2013

Ann Thorac Cardiovasc Surg

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Background: Oxidative stress due to reactive oxygen species (ROS) is thought to play a considerable role in ischemia/reperfusion (I/R) injury that impairs cardiac function. The present study examined oxidative damage in I/R injury and investigated the correlation between oxidative stress and impaired cardiac function after I/R injury of the isolated rat heart. Methods: Hearts isolated from male Sprague-Dawley rats were mounted on a Langendorff apparatus. Hearts arrested using St. Thomas cardioplegic solution and then they were reperfused. The hearts were divided into three groups depending on the frequency (0-2) of I/R. After I/R, left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), positive maximum left ventricular developing pressure (max LV dP/dt) and coronary flow (CF) were measured. Creatine kinase (CK) was measured in the coronary effluent and 8-hydroxy-2'deoxyguanosine (8OHdG), a marker of oxidative DNA damage, was measured. Adenosine triphosphate (ATP) was measured from frozen myocardial tissue after experiment. Results: We immunohistochemically demonstrated and quantified levels of 8-OHdG after I/ R injury of the heart. The frequency of I/R injury and cardiac dysfunction significantly and negatively correlated. The ATP products were similar among the three groups. The incidence of ventricular arrhythmias was not by affected oxidative stress. Conclusion: The frequency of I/R injury had more of an effect on 8-OHdG products and on impaired cardiac function with less myocyte damage than ischemic duration within 30 minutes of ischemia.Keywords: oxidative stress, ischemia/reperfusion injury, 8-hydroxy-2'deoxyguanosine (8OHdG), cardiac dysfunction tion might cause negative effects and a worse prognosis, with myocardial dysfunction (stunning) and coronary noreflow phenomenon. 1) Reactive oxygen species (ROS), which can be produced from reperfusion of the ischemic myocardium 2) and Ca 2 + overload in myocytes, contribute to cardiac ischemia/reperfusion (I/R) injury. 3)Reactive oxygen species cause the oxidation of DNAs, membranous phospholipids and proteins, and these are implicated in the pathogenesis of I/R injury, degenerative disease, carcinogenesis and aging. In particular, ROS have the potential to injure cardiac myocytes, endothelial cells and initiate chemical reactions in myocardial I/R injury.

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Beneficial effect of tetrahydrobiopterin on ischemia-reperfusion injury in isolated perfused rat hearts

Cited by 53 publications

References 28 publications

Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

Role of tetrahydrobiopterin in resistance to myocardial ischemia in Brown Norway and Dahl S rats

Determination of Oxidative Stress and Cardiac Dysfunction after Ischemia/Reperfusion Injury in Isolated Rat Hearts

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