Involvement of inducible nitric oxide synthase and estrogen receptor ESR2 (ERβ) in the vascular dysfunction in female type 1 diabetic rats

Transient reduction in coronary perfusion pressure in the isolated mouse heart increases microvascular resistance (paradoxical vasoconstriction) by an endothelium-mediated mechanism. To assess the presence and extent of paradoxical vasoconstriction in hearts from normal and diabetic rats and to determine whether increased heme oxygenase (HO)-1 expression and HO activity, using cobalt protoporphyrin (CoPP), attenuates coronary microvascular response, male Wistar rats were rendered diabetic with nicotinamide/streptozotocin for 2 wk and either CoPP or vehicle was administered by intraperitoneal injection weekly for 3 wk (0.5 mg/100 g body wt). The isolated beating nonworking heart was submitted to transient low perfusion pressure (20 mmHg), and coronary resistance (CR) was measured. During low perfusion pressure, CR increased and was associated with increased lactate release. In diabetic rats, CR was higher, HO-1 expression and endothelial nitric oxide synthase were downregulated, and inducible nitric oxide synthase and O2− were upregulated. After 3 wk of CoPP treatment, HO activity was significantly increased in the heart. Upregulation of HO-1 expression and HO activity by CoPP resulted in the abolition of paradoxical vasoconstriction and a reduction in oxidative ischemic damage. In addition, there was a marked increase in serum adiponectin. Elevated HO-1 expression was associated with increased expression of cardiac endothelial nitric oxide synthase, B-cell leukemia/lymphoma extra long, and phospho activator protein kinase levels and decreased levels of inducible nitric oxide synthase and malondialdehyde. These results suggest a critical role for HO-1 in microvascular tone control and myocardial protection during ischemia in both normal and mildly diabetic rats through the modulation of constitutive and inducible nitric oxide synthase expression and activity, and an increase in serum adiponectin.

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Linkage of the Human Inducible Nitric Oxide Synthase Gene to Type 1 Diabetes1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.6.7559 ◽

2001 ◽

Vol 86 (6) ◽

pp. 2792-2796

Author(s):

Jesper Johannesen ◽

Angeles Pie ◽

Flemming Pociot ◽

Ole Peter Kristiansen ◽

Allan Ertmann Karlsen ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Oxide Synthase ◽

Inducible Nitric Oxide

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Human Immunodeficiency Virus Type 1 Tat Protein Stimulates Inducible Nitric Oxide Synthase Expression and Nitric Oxide Production in Microglial Cultures

Journal of Neuropathology & Experimental Neurology ◽

10.1097/00005072-199908000-00005 ◽

1999 ◽

Vol 58 (8) ◽

pp. 825-831 ◽

Cited By ~ 48

Author(s):

Elisabetta Polazzi ◽

Giulio Levi ◽

Luisa Minghetti

Keyword(s):

Nitric Oxide ◽

Human Immunodeficiency Virus ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Nitric Oxide Production ◽

Tat Protein ◽

Immunodeficiency Virus ◽

Oxide Synthase ◽

Inducible Nitric Oxide

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Regulation of the inducible nitric oxide synthase and sodium pump in type 1 diabetes

Medical Hypotheses ◽

10.1016/j.mehy.2006.11.045 ◽

2007 ◽

Vol 69 (2) ◽

pp. 302-306 ◽

Cited By ~ 4

Author(s):

Zorica Zakula ◽

Goran Koricanac ◽

Biljana Putnikovic ◽

Ljiljana Markovic ◽

Esma R. Isenovic

Keyword(s):

Nitric Oxide ◽

Type 1 Diabetes ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Sodium Pump ◽

Oxide Synthase ◽

Inducible Nitric Oxide

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The inhibition of inducible nitric oxide synthase and oxidative stress by agmatine attenuates vascular dysfunction in rat acute endotoxemic model

Environmental Toxicology and Pharmacology ◽

10.1016/j.etap.2017.08.009 ◽

2017 ◽

Vol 55 ◽

pp. 74-80 ◽

Cited By ~ 13

Author(s):

Mohammed S. El-Awady ◽

Manar A. Nader ◽

Maha H. Sharawy

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Vascular Dysfunction ◽

Oxide Synthase ◽

And Oxidative Stress ◽

Inducible Nitric Oxide

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Gene-Targeted Mice Reveal a Critical Role for Inducible Nitric Oxide Synthase in Vascular Dysfunction During Diabetes

Stroke ◽

10.1161/01.str.0000099123.55171.3f ◽

2003 ◽

Vol 34 (12) ◽

pp. 2970-2974 ◽

Cited By ~ 36

Author(s):

Carol A. Gunnett ◽

Donald D. Heistad ◽

Frank M. Faraci

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Vascular Dysfunction ◽

Critical Role ◽

Oxide Synthase ◽

Inducible Nitric Oxide

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Differential regulation of the inducible nitric oxide synthase gene by estrogen receptors 1 and 2

Journal of Endocrinology ◽

10.1677/joe-07-0292 ◽

2008 ◽

Vol 199 (2) ◽

pp. 267-273 ◽

Cited By ~ 30

Author(s):

Seiji Tsutsumi ◽

Xi Zhang ◽

Keiko Takata ◽

Kazuhiro Takahashi ◽

Richard H Karas ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Estrogen Receptors ◽

Inducible Nitric Oxide Synthase ◽

Vascular Dysfunction ◽

Differential Regulation ◽

No Production ◽

Reporter Activity ◽

Oxide Synthase ◽

Inducible Nitric Oxide

Estrogen has both rapid and longer term direct effects on cardiovascular tissues mediated by the two estrogen receptors, ESR1 and ESR2. Previous work identified that estrogen regulates the expression of inducible nitric oxide synthase (NOS2A) in vascular smooth muscle cells (VSMC). ESR2 knockout mice have vascular dysfunction due to dysregulation of NOS2A expression and these mice are hypertensive (Zhu et al. Science 2002 295 505–508). Here, we report studies to examine the differential regulation of NOS2A gene expression by ESR1 and 2. Immunoblotting and RT-PCR studies revealed that different VSMC lines expressed different levels of ESR1 and ESR2 protein and mRNA. VSMC from different vascular beds were studied, including aortic VSMC expressing ESR1 and radial (Rad) VSMC expressing ESR2. E2 inhibited NO production and NOS2A protein expression in aortic VSMC. Human NOS2A promoter–reporter studies revealed suppression of NOS2A reporter activity by E2 in aortic VSMC, and stimulation of NOS2A reporter activity by E2 in Rad arterial VSMC. In heterologous expression studies of COS-7 cells lacking endogenous ER, E2 treatment of COS-7 cells did not alter NOS2A reporter activity in the presence of ESR1, while reporter activity increased 2.3-fold in the presence of ESR2. Similar experiments in COS-7 cells using the selective estrogen receptor modulator raloxifene showed that raloxifene caused a reduction in NOS2A reporter activity with ESR1 coexpression and an increase with ESR2 coexpression. Rat VSMC expressing ESR2 but not ESR1 also showed increased NOS2A reporter activity with E2 treatment, an effect lost when ESR1 was introduced into the cells. Taken together, these data support that hNOS2A transcription is regulated positively by ESR2 and negatively by ESR1 in VSMC, supporting differential actions of these two estrogen receptors on a physiologically relevant gene in VSMC.

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