Inhibition of nitric oxide synthase uncoupling by sepiapterin improves left ventricular function in streptozotocin-induced diabetic mice

Jo, Hiromi; Otani, Hajime; Jo, Fusakazu; Shimazu, Takayuki; Okazaki, Takeo; Yoshioka, Kei; Fujita, Masanori; Kosaki, Atsushi; Iwasaka, Toshiji

doi:10.1111/j.1440-1681.2011.05535.x

Cited by 42 publications

(38 citation statements)

References 43 publications

(25 reference statements)

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“…In contrast, heart rate was significantly smaller in the eNOS Ϫ/Ϫ mice than the WT mice at baseline and after sham surgery. These hemodynamic differences are consistent with the previous study using the same genotypes of mice (24). Although heart rate and blood pressures did not significantly change after MI in the WT and iNOS Ϫ/Ϫ mice, blood pressures significantly decreased after MI in the eNOS Ϫ/Ϫ mice compared with baseline and the time-matched WT and eNOS Ϫ/Ϫ mice with Table 1.…”

Section: Resultssupporting

confidence: 91%

Sepiapterin enhances angiogenesis and functional recovery in mice after myocardial infarction

Shimazu

Otani

Yoshioka

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Shimazu T, Otani H, Yoshioka K, Fujita M, Okazaki T, Iwasaka T. Sepiapterin enhances angiogenesis and functional recovery in mice after myocardial infarction. Am J Physiol Heart Circ Physiol 301: H2061-H2072, 2011. First published September 2, 2011; doi:10.1152/ajpheart.00525.2011.-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 Ϫ/Ϫ ), endothelial NOS-knockout (eNOS Ϫ/Ϫ ), and neuronal NOS-knockout (nNOS Ϫ/Ϫ ) 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 Ϫ/Ϫ 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), BH4, and BH4-to-BH2 ratio in the infarcted but not sham-operated heart. The increase in BH 4-to-BH2 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 Ϫ/Ϫ mice. Sepiapterin increased capillary density and prevented LV remodeling and dysfunction after MI in wild-type, eNOS Ϫ/Ϫ , and nNOS Ϫ/Ϫ but not iNOS Ϫ/Ϫ mice. N -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 BH4 synthesis and increasing bioavailable nitric oxide predominantly derived from iNOS. nitric oxide synthase; tetrahydrobiopterin; left ventricular CARDIAC REMODELING REMAINS an important primary therapeutic target in patients with myocardial infarction (MI). Strategies to prevent or halt adverse left ventricular remodeling after MI include pharmacotherapy, cell-based therapy, percutaneous interventions, and surgical procedures. Despite the use of evidence-based strategies to post-MI, heart failure supervenes and is attended by an unacceptably high mortality rate. Despite the multitude of agents available for the treatment of heart failure such as the inhibitors of renin-angiotensin-aldosterone system, ␤-blockers, G protein receptor kinase inhibition, administration of growth factors, and cytokines, it remains a highly prevalent clinical syndrome with substantial morbidity and mortality, necessitating alternative pharmacological tools of targeted management. One such area of interest is the ability to modulate the bioavailability of nitric oxide (NO).Accumulating evidence indicates that NO plays a central role in cardiac...

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Section: Resultssupporting

confidence: 91%

Sepiapterin enhances angiogenesis and functional recovery in mice after myocardial infarction

Shimazu

Otani

Yoshioka

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Although we did not measure BH 4 in the present study, the increase in NO x , an index for NO generation, and the decrease in nitrotyrosine, an index for peroxynitrite generation, in hearts that received sepiapterin suggests that oral administration of sepiapterin inhibited NOS uncoupling. These findings are consistent with our previous studies (18,37) demonstrating that sepiapterin is an effective tool in inhibiting NOS uncoupling and increasing the bioavailability of NO.…”

Section: Discussionsupporting

confidence: 82%

“…Rats were randomized to receive oral administration of sepiapterin (10 mg·kg Ϫ1 ·day Ϫ1 ) together with or without N-nitro-L-arginine methyl ester (L-NAME; Sigma Chemical, St. Louis, MO), a nonselective inhibitor of NOS, at a dose of 100 mg·kg Ϫ1 ·day Ϫ1 for 8 wk immediately after TAC (protocol A) or between 8 and 16 wk after TAC (protocol B). We chose sepiapterin at a dose of 10 mg·kg Ϫ1 ·day Ϫ1 because our previous studies (18,37) demonstrated that this dose of sepiapterin is effective in increasing the BH4-to-BH2 ratio in the mouse heart. Additional rats were randomly assigned to receive oral administration of MPG (100 mg·kg Ϫ1 ·day Ϫ1 ) for the same duration as described above.…”

Section: Methodsmentioning

confidence: 99%

“…Tiefenbacher and colleagues (42) first demonstrated that pretreatment with sepiapterin reduces postischemic injury in the rat heart by ameliorating the availability of NO. Our previous studies also demonstrated that prolonged oral administration of sepiapterin is effective to elevate BH 4 levels and the BH 4 -to-BH 2 ratio and ameliorate LV function in the mouse model of myocardial infarction (37) and streptozotocin-induced diabetic LV dysfunction (18). Therefore, we investigated whether sepiapterin prevents LVH when administered at the onset of pressure overload and dilatory remodeling when administered after established LVH by inhibiting uncoupling of NOS and increasing the bioavailability of NO.…”

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confidence: 99%

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Sepiapterin prevents left ventricular hypertrophy and dilatory remodeling induced by pressure overload in rats

Yoshioka

Otani

Shimazu

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Yoshioka K, Otani H, Shimazu T, Fujita M, Iwasaka T, Shiojima I. Sepiapterin prevents left ventricular hypertrophy and dilatory remodeling induced by pressure overload in rats. Am J Physiol Heart Circ Physiol 309: H1782-H1791, 2015. First published September 25, 2015; doi:10.1152/ajpheart.00417.2015.-Uncoupling of nitric oxide (NO) synthase (NOS) has been implicated in left ventricular (LV) hypertrophy (LVH) and dilatory remodeling induced by pressure overload. We investigated whether administration of sepiapterin, a substrate of the salvage pathway of tetrahydrobiopterin synthesis, prevents LVH and dilatory LV remodeling by inhibiting NOS uncoupling and increasing bioavailable NO. Pressure overload was induced in rats by transverse aortic constriction (TAC). Concentric LVH developed during 8 wk after TAC, and dilatory LV remodeling and dysfunction developed between 8 and 16 wk after TAC associated with a decrease in capillary density. Oral administration of sepiapterin or the superoxide/peroxynitrite scavenger N-(2-mercaptopropionyl)-glycine for 8 wk after TAC inhibited oxidative stress, but only sepiapterin increased bioavailable NO and inhibited cardiomyocyte hypertrophy associated with a further increase in capillary density. When sepiapterin was administered between 8 and 16 wk after TAC, cardiomyocyte hypertrophy was regressed and capillary density was restored. This was associated with the inhibition of interstitial fibrosis and dilatory LV remodeling. N-nitro-L-arginine methyl ester abrogated all the beneficial effects of sepiapterin in rats with TAC. These results suggest that sepiapterin prevents concentric LVH and dilatory remodeling after TAC primarily by increasing the bioavailability of NO.

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“…Thus, NOS uncoupling and tetrahydrobiopterin deficiency contribute to the inflammatory and abnormal cytokine milieu in the vasculature (71). Furthermore, hyperglycemia significantly elicits the expression of cytokine-inducible NOS (iNOS) both in vitro and in vivo (36,118). Indeed, hyperglycemia induced by streptozotocin in Nos2 gene knockout mice led to diabetic cardiomyopathy, and sepiapterin, an inhibitor of NOS uncoupling, improved systolic FIG.…”

Section: Inflammation and Oxidative Stress In Endothelial Dysfunctionmentioning

confidence: 99%

Differential Metabolic Actions of Specific Statins: Clinical and Therapeutic Considerations

Lim

Sakuma

Quon

et al. 2014

Antioxidants & Redox Signaling

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Significance: Statins, the most widely prescribed drugs in clinical practice, mainly act by reducing the plasma level of low-density lipoprotein (LDL)-cholesterol. A shift in redox homeostasis to an imbalance between reactive oxygen species generation and endogenous antioxidant mechanisms results in oxidative stress that has been implicated in the pathogenesis of various diseases, including those of the cardiovascular system. Beyond their efficacy in lowering LDL cholesterol, statins modulate redox systems that are implicated in the development of atherosclerosis, cardiovascular morbidity, and mortality. Recent Advances: Differences in specific statins or their dosages result in differential metabolic actions arising from off-target or unknown mechanisms of action that can have important implications for overall patient morbidity and mortality. Critical Issues: A recent meta-analysis and a combined analysis have suggested that high doses of statins increase the risk of developing type 2 diabetes mellitus, but reduce the risk of cardiovascular events. Thus, it is important to consider the cardiovascular and metabolic context and natural history of diseases when choosing a specific statin therapy for optimal individual patient health over the long term. Future Directions: More information is needed regarding the metabolism of statins, and the off-target or unknown actions of statins in affecting insulin resistance and metabolic homeostasis. The differential metabolic effects of specific statins should be considered in formulating optimal therapeutic strategies to reduce not just cardiovascular-related but also overall patient morbidity and mortality. Antioxid. Redox Signal. 20, 1286Signal. 20, -1299

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Inhibition of nitric oxide synthase uncoupling by sepiapterin improves left ventricular function in streptozotocin-induced diabetic mice

Cited by 42 publications

References 43 publications

Sepiapterin enhances angiogenesis and functional recovery in mice after myocardial infarction

Sepiapterin enhances angiogenesis and functional recovery in mice after myocardial infarction

Sepiapterin prevents left ventricular hypertrophy and dilatory remodeling induced by pressure overload in rats

Differential Metabolic Actions of Specific Statins: Clinical and Therapeutic Considerations

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