Abstract
Uncoupling of nitric oxide synthase (NOS) has been implicated in left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). We hypothesized that inducible NOS (iNOS) plays a crucial role in LV remodeling after MI, depending on its coupling status. MI was created in wild-type, iNOS-knockout (iNOS(-/-)), endothelial NOS-knockout (eNOS(-/-)), and neuronal NOS-knockout (nNOS(-/-)) mice. iNOS and nNOS expressions were increased after MI associated with an increase in nitrotyrosine formation. The area of myocardial fibrosis and LV end-diastolic volume and ejection fraction were more deteriorated in eNOS(-/-) mice compared with other genotypes of mice 4 wk after MI. The expression of GTP cyclohydrolase was reduced, and tetrahydrobiopterin (BH(4)) was depleted in the heart after MI. Oral administration of sepiapterin after MI increased dihydrobiopterin (BH(2)), BH(4), and BH(4)-to-BH(2) ratio in the infarcted but not sham-operated heart. The increase in BH(4)-to-BH(2) ratio was associated with inhibition of nitrotyrosine formation and an increase in nitrite plus nitrate. However, this inhibition of NOS uncoupling was blunted in iNOS(-/-) mice. Sepiapterin increased capillary density and prevented LV remodeling and dysfunction after MI in wild-type, eNOS(-/-), and nNOS(-/-) but not iNOS(-/-) mice. N(ω)-nitro-L-arginine methyl ester abrogated sepiapterin-induced increase in nitrite plus nitrate and angiogenesis and blocked the beneficial effects of sepiapterin on LV remodeling and function. These results suggest that sepiapterin enhances angiogenesis and functional recovery after MI by activating the salvage pathway for BH(4) synthesis and increasing bioavailable nitric oxide predominantly derived from iNOS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Angiogenesis Inducing Agents / administration & dosage
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Angiogenesis Inducing Agents / pharmacology*
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Animals
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Biopterins / analogs & derivatives
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Biopterins / metabolism
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Blood Pressure / drug effects
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Cardiotonic Agents / administration & dosage
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Cardiotonic Agents / pharmacology*
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Disease Models, Animal
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Enzyme Inhibitors / pharmacology
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Fibrosis
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GTP Cyclohydrolase / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myocardial Infarction / diagnostic imaging
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Myocardial Infarction / drug therapy*
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Myocardial Infarction / enzymology
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Myocardial Infarction / genetics
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Myocardial Infarction / physiopathology
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Myocardium / enzymology*
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Myocardium / pathology
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NG-Nitroarginine Methyl Ester / pharmacology
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Neovascularization, Physiologic / drug effects*
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Nitric Oxide / metabolism
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Nitric Oxide Synthase Type I / genetics
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Nitric Oxide Synthase Type I / metabolism
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Nitric Oxide Synthase Type II / antagonists & inhibitors
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Nitric Oxide Synthase Type II / deficiency
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type II / metabolism*
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Nitric Oxide Synthase Type III / genetics
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Nitric Oxide Synthase Type III / metabolism
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Pterins / administration & dosage
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Pterins / pharmacology*
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Recovery of Function
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Stroke Volume / drug effects
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Time Factors
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Tyrosine / analogs & derivatives
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Tyrosine / metabolism
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Ultrasonography
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Ventricular Function, Left / drug effects*
Substances
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Angiogenesis Inducing Agents
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Cardiotonic Agents
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Enzyme Inhibitors
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Pterins
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Biopterins
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Nitric Oxide
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3-nitrotyrosine
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Tyrosine
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sepiapterin
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Nitric Oxide Synthase Type I
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Nitric Oxide Synthase Type II
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Nitric Oxide Synthase Type III
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Nos1 protein, mouse
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Nos2 protein, mouse
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Nos3 protein, mouse
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GTP Cyclohydrolase
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sapropterin
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NG-Nitroarginine Methyl Ester