Myocardial ischemia-reperfusion injury is exacerbated  in absence of endothelial cell nitric oxide synthase

Jones, Steven P.; Girod, Wesley G.; Palazzo, Anthony J.; Granger, D. Neil; Grisham, Matthew B.; Jourd’heuil, David; Huang, Paul L.; Lefer, David J.

doi:10.1152/ajpheart.1999.276.5.h1567

Cited by 201 publications

(192 citation statements)

References 47 publications

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“…In myocardial models of I/R, the deficiency of NO • has been shown to exacerbate injury (34). In our study, nitrite protects myoglobin containing wild-type hearts from injury, but is not cytoprotective in myoglobin knockout hearts.…”

Section: Discussioncontrasting

confidence: 46%

“…The heart was then serially sectioned perpendicularly to the long axis in 1-mm slices, and each slice was weighed. The sections were incubated in 1% TTC for 5 min at 37°C for demarcation of the viable and nonviable myocardium within the risk zone (34). The areas of infarction, AAR, and nonischemic left ventricle (LV) were assessed with computer-assisted planimetry by an observer blinded to sample identity.…”

Section: Hemodynamic Parameters See Si Textmentioning

confidence: 99%

“…The areas of infarction, AAR, and nonischemic left ventricle (LV) were assessed with computer-assisted planimetry by an observer blinded to sample identity. The size of the myocardial infarction was expressed as a percentage of the AAR as described (34).…”

Section: Hemodynamic Parameters See Si Textmentioning

confidence: 99%

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Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury

Hendgen‐Cotta

Merx

Shiva

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

366

353

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The nitrite anion is reduced to nitric oxide (NO • ) as oxygen tension decreases. Whereas this pathway modulates hypoxic NO • signaling and mitochondrial respiration and limits myocardial infarction in mammalian species, the pathways to nitrite bioactivation remain uncertain. Studies suggest that hemoglobin and myoglobin may subserve a fundamental physiological function as hypoxia dependent nitrite reductases. Using myoglobin wild-type ( +/+ ) and knockout ( −/− ) mice, we here test the central role of myoglobin as a functional nitrite reductase that regulates hypoxic NO • generation, controls cellular respiration, and therefore confirms a cytoprotective response to cardiac ischemia-reperfusion (I/R) injury. We find that myoglobin is responsible for nitrite-dependent NO • generation and cardiomyocyte protein iron-nitrosylation. Nitrite reduction to NO • by myoglobin dynamically inhibits cellular respiration and limits reactive oxygen species generation and mitochondrial enzyme oxidative inactivation after I/R injury. In isolated myoglobin +/+ but not in myoglobin −/− hearts, nitrite treatment resulted in an improved recovery of postischemic left ventricular developed pressure of 29%. In vivo administration of nitrite reduced myocardial infarction by 61% in myoglobin +/+ mice, whereas in myoglobin −/− mice nitrite had no protective effects. These data support an emerging paradigm that myoglobin and the heme globin family subserve a critical function as an intrinsic nitrite reductase that regulates responses to cellular hypoxia and reoxygenation. myoglobin knockout mice

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Section: Discussioncontrasting

confidence: 46%

Section: Hemodynamic Parameters See Si Textmentioning

confidence: 99%

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Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury

Hendgen‐Cotta

Merx

Shiva

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

366

353

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“…Based on this pattern of distribution, it is logical to expect multiple phenotypes when these genes are disrupted. (29), normal cerebral glucose utilization (40), normal coronary hemodynamics (27) but abnormal cardiac oxygen consumption (28), and exaggerated myocardial reperfusion injury (32).…”

Section: Discussionmentioning

confidence: 99%

Mice with gene disruption of both endothelial and neuronal nitric oxide synthase exhibit insulin resistance.

et al. 2000

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Studies from our laboratory using acute pharmacologic blockade of nitric oxide synthase (NOS) activity have suggested that nitric oxide (NO) has an important role in regulating carbohydrate metabolism. We now report on insulin sensitivity in mice with targeted disruptions in endothelial NOS (eNOS) and neuronal NOS (nNOS) genes compared with their wild-type (WT) counterparts. Mice underwent hyperinsulinemic-euglycemic clamp studies after a 24-h fast, during an insulin infusion of 20 mU · k g -1 · min -1 . Glucose levels were measured at baseline and every 10 min during the clamp. Insulin levels were measured at baseline and at the end of the clamp study. Glucose infusion rates (GIRs) during the last 30 min of the clamp study were in a steady state. Tritiated glucose infusion was used to measure rates of endogenous glucose output (EGO) both at baseline and during steady-state euglycemia. Glucose disposal rates (GDRs) were computed from the GIR and EGO. Fasting and steady-state glucose and insulin levels were comparable in the 3 groups of mice. No differences in fasting EGO were noted between the groups. GIR was significantly reduced (37%, P = 0.001) in the eNOS knockout (KO) mice compared with the WT mice, with values for the nNOS mice being intermediate. EGO was completely suppressed in the nNOS and WT mice during insulin infusion, but not in the eNOS mice. Even so, the eNOS mice displayed significantly reduced whole-body GDRs compared with those of the WT mice ( 8 2 . 6 7 ± 10.77 vs. 103.67 ± 3.47 m g · k g -1 · min -1 , P = 0.03). eNOS KO mice are insulin resistant at the level of the liver and peripheral tissues, whereas the nNOS KO mice are insulin resistant only in the latter. These data indicate that NO plays a role in modulating insulin sensitivity and carbohydrate metabolism and that the eNOS isoform may play a dominant role relative to nNOS. Diabetes 49:XXX-XXX, 2000 N itric oxide (NO) has emerged as an important molecule with diverse biological functions. In the blood vessels, NO mediates endotheliumdependent vasodilation (1-3) in response to diverse stimuli such as shear stress (4-6), insulin (7), acetylcholine (8,9), and bradykinin (3,10). In the central nervous system (CNS) and peripheral nervous tissue, NO is an unusual neurotransmitter (11-13). NO is generated when the amino acid L-arginine is converted to citrulline by the enzyme NO synthase (NOS) (14,15). Three separate genes encode the known isoforms of NOS (16): endothelial NOS (eNOS or NOS III) and neuronal NOS (nNOS or NOS II) catalyze the constitutive production of NO in a calcium-dependent manner predominantly in the blood vessels and neural tissues, respect i v e l y. The third isoform, inducible NOS (iNOS or NOS I) is located in macrophages and catalyzes NO formation in i n flammatory cells.Intravenous administration of N G -m o n o m e t h y l -L-a r g i n i n e (L-NMMA), a competitive inhibitor of all NOS isoforms, acutely induces hypertension and insulin resistance in rats ( 1 7 ) . M o r e r e c e n t l y, we reported that acute pharm...

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“…Another important downstream target of Akt is endothelial nitric oxide synthase (eNOS), which is phosphorylated and activated by Akt (11,12). Mice with targeted deletion of eNOS have enlarged cerebral and myocardial infarct size after transient ischemia (13,14). Therefore, it is likely that the regulation of eNOS activity by Akt in endothelial cells is an important mediator of vascular function.…”

mentioning

confidence: 99%

Rapid nongenomic actions of thyroid hormone

Hiroi

Kim

Ying

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

334

246

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Myocardial ischemia-reperfusion injury is exacerbated in absence of endothelial cell nitric oxide synthase

Cited by 201 publications

References 47 publications

Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury

Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury

Mice with gene disruption of both endothelial and neuronal nitric oxide synthase exhibit insulin resistance.

Rapid nongenomic actions of thyroid hormone

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