Nitric oxide synthase expression and role during cardiomyogenesis

Bloch, Wilhelm; Fleischmann, Bernd K.; Lorke, Dietrich; Andressen, Christian; Hops, B; Hescheler, Jürgen; Addicks, Klaus

doi:10.1016/s0008-6363(99)00160-1

Cited by 126 publications

(94 citation statements)

References 26 publications

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“…Mujoo et al also demonstrated an increase of sGC subunits during the course of differentiation of human ESCs for 14 days, but the authors reported a progressive decrease in sGCβ 2 mRNA from day 0 to day 14 [ 10 ]. These observed differences may be attributed to differences in the ESC species and strains, or l -nitroarginine, the number of EB-derived cardiomyocytes is not affected, but fi brillogenesis in the cardiomyocytes is reduced [ 32 ]. This effect is mimicked by ODQ (an antagonist of soluble guanylate cyclase).…”

Section: Discussionmentioning

confidence: 96%

Role of Nitric Oxide Signaling in Endothelial Differentiation of Embryonic Stem Cells

Huang

Fleißner

Sun

et al. 2010

Stem Cells and Development

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Signaling pathways that govern embryonic stem cell (ESCs) differentiation are not well characterized. Nitric oxide (NO) is a potent vasodilator that modulates other signaling pathways in part by activating soluble guanylyl cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP). Because of its importance in endothelial cell (EC) growth in the adult, we hypothesized that NO may play a critical role in EC development. Accordingly, we assessed the role of NO in ESC differentiation into ECs. Murine ESCs differentiated in the presence of NO synthase (NOS) inhibitor NG-nitroarginine methyl ester ( l -NAME) for up to 11 days were not signifi cantly different from vehicle-treated cells in EC markers. However, by 14 days, l -NAME-treated cells manifested modest reduction in EC markers CD144, FLK1, and endothelial NOS. ESC-derived ECs generated in the presence of l -NAME exhibited reduced tube-like formation in Matrigel. To understand the discrepancy between early and late effects of l -NAME, we assessed the NOS machinery and observed low mRNA expression of NOS and sGC subunits in ESCs, compared to differentiating cells after 14 days. In response to NO donors or activation of NOS or sGC, cellular cGMP levels were undetectable in undifferentiated ESCs, at low levels on day 7, and robustly increased in day 14 cells. Production of cGMP upon NOS activation at day 14 was inhibited by l -NAME, confi rming endogenous NO dependence. Our data suggest that NOS elements are present in ESCs but inactive until later stages of differentiation, during which period NOS inhibition reduces expression of EC markers and impairs angiogenic function.

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Section: Discussionmentioning

confidence: 96%

Role of Nitric Oxide Signaling in Endothelial Differentiation of Embryonic Stem Cells

Huang

Fleißner

Sun

et al. 2010

Stem Cells and Development

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“…Immunoreactivity for eNOS or nNOS was faint in non-diabetic and diabetic groups. Although it has been reported that E9.5 embryos display eNOS expression in the murine heart and limb skeletal myocytes [33,34], these studies did not analyse eNOS expression in the neural tube. It is well known that the expression of iNos mRNA is regulated by nuclear factor kappa B (NFκB) activated by proinflammatory cytokines such as TNF-α and IFN-γ.…”

Section: Discussionmentioning

confidence: 99%

“…Failure of NCC migration results in CVMs, particularly those involving malformations of the great vessels and cardiac outflow tract defects, such as truncus arteriosus [44]. Bloch et al reported that iNOS expression starts at an early stage (E8.5) of murine/rat heart development [33]. Several lines of evidence show that iNOS expression is induced by proinflammatory cytokines, such as TNF-α and IL-1β, and that the resulting increase in nitric oxide generation causes cardiac cell degeneration and apoptosis [45,46].…”

Section: Discussionmentioning

confidence: 99%

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

et al. 2009

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Aims/hypothesis Maternal diabetes during pregnancy increases the risk of congenital malformations such as neural tube defects (NTDs). Although the mechanism of this effect is uncertain, it is known that levels of nitric oxide synthase (NOS) and nitric oxide are elevated in embryos of a mouse model of diabetes. We postulated that overproduction of nitric oxide causes diabetes-induced congenital malformations and that inhibition of inducible NOS (iNOS) might prevent diabetic embryopathy. Methods Mice were rendered hyperglycaemic by intraperitoneal injection of streptozotocin. The incidence of congenital malformations including NTDs was evaluated on gestational day 18.5. We assessed the involvement of iNOS in diabetesinduced malformation by administering ONO-1714, a specific inhibitor of iNOS, to pregnant mice with streptozotocininduced diabetic mice and by screening mice with iNOS deficiency due to genetic knockout (iNos −/− ). Results ONO-1714 markedly reduced the incidence of congenital anomalies, including NTDs, in fetuses of a mouse model of diabetes. It also prevented apoptosis in the head region of fetuses, indicating that iNOS is involved in diabetesrelated congenital malformations. Indeed, no NTDs were observed in fetuses of diabetic iNos −/− mice and the incidence of other malformations was also markedly reduced. Conclusions/interpretation We conclude that increased iNOS activity during organogenesis plays a crucial role in the pathogenesis of diabetes-induced malformations and suggest that inhibitors of iNOS might help prevent malformations, especially NTDs, in diabetic pregnancy.

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“…10 Mice deficient in eNOS also possess limb reduction defects, possibly due to vascular insufficiency. These limb abnormalities were seen in Ϸ10% of the null animals, and they resemble the limb reduction defects seen in patients with Holt-Oram Syndrome.…”

Section: Lee Et Al Bicuspid Aortic Valve In Enos Knockout Mice 2347mentioning

confidence: 99%

Abnormal Aortic Valve Development in Mice Lacking Endothelial Nitric Oxide Synthase

et al. 2000

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Background-Endothelium-derived nitric oxide (NO) is produced by an oxidative reaction catalyzed by endothelial NO synthase (eNOS). NO plays a crucial role in controlling cell growth and apoptosis, as well as having well-characterized vasodilator and antithrombotic actions. More recently, endothelium-derived NO was shown to be involved in postdevelopmental vascular remodeling and angiogenesis, as well as in the formation of limb vasculature during embryogenesis. Therefore, we investigated the role of endothelium-derived NO during cardiovascular development using mice deficient in eNOS. Methods and Results-We examined the hearts of 12 mature eNOS-deficient and 26 mature wild-type mice. Five of the mature eNOS-deficient mice had a bicuspid aortic valve; none of the 26 wild-type animals exhibited identifiable valvular or cardiac abnormalities. Immunohistochemical analysis revealed prominent eNOS expression localized to the endothelium lining the valve cusps of the aorta in mature wild-type mice; expression was localized to the myocardium and endothelial cell monolayer lining the valve leaflets in the developing embryo. Conclusions-These results show a strong association between eNOS deficiency and the presence of a bicuspid aortic valve; they provide the first molecular insight into one of the most common types of congenital cardiac abnormality. Key Words: nitric oxide Ⅲ endothelium Ⅲ mice, knockout Ⅲ heart defects, congenital Ⅲ valves N itric oxide (NO) is a free radical gas that is synthesized from L-arginine in a complex oxidative reaction catalyzed by 3 distinct isoforms of NO synthase: endothelial (eNOS), inducible (iNOS), and neuronal (nNOS). 1 The neuronal isoform is highly expressed in neuronal cells and skeletal muscle, whereas the endothelial isoform is predominantly expressed in endothelial cells and produces small amounts of NO in response to intimal shear stress or agonists such as bradykinin. 2,3 The inducible isoform is expressed in many cell types, including macrophages and smooth muscle cells, primarily in response to inflammatory cytokines. Once expressed, this isoform can produce large amounts of NO in a continuous manner. 1,2 Endothelium-derived NO is crucial in the regulation of cell growth and apoptosis; it also has a well-characterized role as a vasodilator and antithrombotic agent. 1 More recently, NO derived from the endothelium was shown to be involved in postdevelopmental vascular remodeling and angiogenesis, as well as in the formation of limb vasculature during embryogenesis. 4 -6 The valve leaflets of the heart originate from mesenchymal outgrowths known as cardiac cushions. Cushion formation is localized to the atrioventricular canal and ventricular outflow tract regions of the primary heart tube. These formations arise from regional thickenings of the cardiac jelly, the extracellular matrix that resides between the myocardium and endocardium of the primitive heart tube. This event involves the transformation of a subset of endothelial cells of the endocardium into mesenchyme. The mo...

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Nitric oxide synthase expression and role during cardiomyogenesis

Cited by 126 publications

References 26 publications

Role of Nitric Oxide Signaling in Endothelial Differentiation of Embryonic Stem Cells

Role of Nitric Oxide Signaling in Endothelial Differentiation of Embryonic Stem Cells

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

Abnormal Aortic Valve Development in Mice Lacking Endothelial Nitric Oxide Synthase

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