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

被引：43

作者：

Jo, Hiromi ^{[1
]}

Otani, Hajime ^{[1
]}

Jo, Fusakazu ^{[1
]}

Shimazu, Takayuki ^{[1
]}

Okazaki, Toru ^{[1
]}

Yoshioka, Kei ^{[1
]}

Fujita, Masanori ^{[1
]}

Kosaki, Atsushi ^{[1
]}

Iwasaka, Toshiji ^{[1
]}

机构：

[1] Kansai Med Univ, Dept Internal Med 2, Moriguchi, Osaka 5708507, Japan

来源：

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY | 2011年 / 38卷 / 08期

关键词：

cardiomyopathy; diabetes mellitus; nitric oxide synthase; oxidative stress; tetrahydrobiopterin; GTP-CYCLOHYDROLASE-I; CARDIOVASCULAR-DISEASE; ISCHEMIA-REPERFUSION; ENDOTHELIAL FUNCTION; TETRAHYDROBIOPTERIN; OVEREXPRESSION; CARDIOMYOPATHY; MELLITUS; HEART; ACTIVATION;

D O I：

10.1111/j.1440-1681.2011.05535.x

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

1. Uncoupling of nitric oxide synthase (NOS) has been implicated in the pathogenesis of left ventricular (LV) dysfunction in diabetes mellitus. In the present study, we investigated the role of NOS uncoupling in oxidative/nitrosative stress and LV dysfunction in the diabetic mouse heart. 2. Diabetes was induced in wild-type (WT), endothelial (e) NOS knockout (eNOS(-/-)), inducible (i) NOS knockout (iNOS(-/-)) and neuronal (n) NOS knockout (nNOS(-/-)) mice by streptozotocin (STZ) treatment. 3. In the diabetic heart, iNOS, but not eNOS or nNOS, expression was increased. Levels of malondialdehyde (MDA), 4-hydroxy-noneal (HNE) and nitrotyrosine (NT), as markers of oxidative/nitrosative stress, were increased in the diabetic mouse heart, but the increase in oxidative/nitrosative stress was significantly repressed in the iNOS(-/-) diabetic mouse heart. Levels of nitrite and nitrate (NOx), as an index of nitric oxide, bioavailability were significantly decreased in the iNOS(-/-) diabetic mouse heart. 4. Oral administration of sepiapterin (10 mg/kg per day), a precursor of tetrahydrobiopterin (BH4), significantly increased BH4 and the BH4/BH2 ratio in diabetic mouse heart. Similarly, sepiapterin inhibited the formation of HNE, MDA and NT in diabetic hearts from all three genotypes, but the increase in NOx following sepiapterin treatment was significantly attenuated in the iNOS(-/-) diabetic mouse heart. Percentage fractional shortening (FS), evaluated by echocardiography, decreased significantly in all genotypes of diabetic mice. Sepiapterin significantly increased percentage FS in diabetic mice, except in iNOS(-/-) mice. 5. These results suggest that sepiapterin inhibits uncoupling of NOS and improves LV function presumably by increasing iNOS-derived nitric oxide in the diabetic heart.

引用

页码：485 / 493

页数：9

共 43 条

[1] Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression [J].

Alp, NJ ;

Mussa, S ;

Khoo, J ;

Cai, SJ ;

Guzik, T ;

Jefferson, A ;

Goh, N ;

Rockett, KA ;

Channon, KM .

JOURNAL OF CLINICAL INVESTIGATION, 2003, 112 (05) :725-735

[2] The effect of Zn(II) and streptozotocin administration in the mouse brain [J].

Beltramini, Mariano ;

Zambenedetti, Pamela ;

Raso, Michelangelo ;

Ibnlkayat, Meryem Idrissi ;

Zatta, Paolo .

BRAIN RESEARCH, 2006, 1109 :207-218

[3] APOPTOSIS AND NECROSIS - 2 DISTINCT EVENTS INDUCED, RESPECTIVELY, BY MILD AND INTENSE INSULTS WITH N-METHYL-D-ASPARTATE OR NITRIC-OXIDE SUPEROXIDE IN CORTICAL CELL-CULTURES [J].

BONFOCO, E ;

KRAINC, D ;

ANKARCRONA, M ;

NICOTERA, P ;

LIPTON, SA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (16) :7162-7166

[4] Diabetic cardiomyopathy revisited [J].

Boudina, Sihem ;

Abel, E. Dale .

CIRCULATION, 2007, 115 (25) :3213-3223

[5] Oxidative stress and diabetic cardiomyopathy: A brief review [J].

Cai L. ;

Kang Y.J. .

Cardiovascular Toxicology, 2001, 1 (3) :181-193

[6] NADPH oxidases in cardiovascular health and disease [J].

Cave, Alison C. ;

Brewer, Alison C. ;

Narayanapanicker, Anilkumar ;

Ray, Robin ;

Grieve, David J. ;

Walker, Simon ;

Shah, Ajay M. .

ANTIOXIDANTS & REDOX SIGNALING, 2006, 8 (5-6) :691-728

[7] Endothelium-specific GTP cyclohydrolase I overexpression attenuates blood pressure progression in salt-sensitive low-renin hypertension [J].

Du, Yan-Hua ;

Guan, Yong-Yuan ;

Alp, Nicholas J. ;

Channon, Keith M. ;

Chen, Alex F. .

CIRCULATION, 2008, 117 (08) :1045-1054

[8] Myocardial ischemia results in tetrahydrobiopterin (BH4) oxidation with impaired endothelial function ameliorated by BH4 [J].

Dumitrescu, Cristian ;

Biondi, Roberto ;

Xia, Yong ;

Cardounel, Arturo J. ;

Druhan, Lawrence J. ;

Ambrosio, Giuseppe ;

Zweier, Jay L. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (38) :15081-15086

[9] Increasing cardiovascular disease burden due to diabetes mellitus - The Framingham Heart Study [J].

Fox, Caroline S. ;

Coady, Sean ;

Sorlie, Paul D. ;

D'Agostino, Ralph B. ;

Pencina, Michael J. ;

Vasan, Ramachandran S. ;

Meigs, James B. ;

Levy, Daniel ;

Savage, Peter J. .

CIRCULATION, 2007, 115 (12) :1544-1550

[10] ECHOCARDIOGRAPHIC EVIDENCE FOR THE EXISTENCE OF A DISTINCT DIABETIC CARDIOMYOPATHY (THE FRAMINGHAM-HEART-STUDY) [J].

GALDERISI, M ;

ANDERSON, KM ;

WILSON, PWF ;

LEVY, D .

AMERICAN JOURNAL OF CARDIOLOGY, 1991, 68 (01) :85-89

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