Long-Term Cyclic Strain Downregulates Endothelial Nox4

Goettsch, Claudia; Göettsch, Winfried; Arsov, Alexander; Hofbauer, Lorenz C.; Bornstein, Stefan R.; Morawietz, Henning

doi:10.1089/ars.2009.2561

Cited by 36 publications

(31 citation statements)

References 61 publications

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“…In adult rat thoracic aortic SMC, cyclic stretch increased Nox1 expression only when cells were coincubated with angiotensin II (22), while stretch alone was sufficient to activate Nox2 via membrane translocation of p47 phox in juvenile PASMC (32). In human umbilical vein endothelial cells, 12% cyclic stretch downregulated Nox4 expression (16), although a contrasting recent report found that 20% cyclic stretch at 0.5 Hz increased Nox4 expression in neonatal rat PASMC (8). Similar to this report in neonatal rats, our data indicate that, in PASMC isolated from late gestation fetal lambs, 15% stretch at 1 Hz increases Nox4 expression and ROS generation.…”

Section: Discussionmentioning

confidence: 95%

Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells

Wedgwood

Lakshminrusimha

Schumacker

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Wedgwood S, Lakshminrusimha S, Schumacker PT, Steinhorn RH. Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 309: L196 -L203, 2015. First published May 29, 2015 doi:10.1152/ajplung.00097.2014.-This study was designed to determine whether cyclic stretch induces a persistent pulmonary hypertension of the newborn (PPHN) phenotype of increased NADPH oxidase (Nox) 4 signaling in control pulmonary artery smooth muscle cells (PASMC), and to identify the signal transduction molecules involved. To achieve this, PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs and PASMC were isolated from control (twin) and PPHN lambs. Control PASMC were exposed to cyclic stretch at 1 Hz and 15% elongation for 24 h. Stretch-induced Nox4 expression was attenuated by inhibition of mitochondrial complex III and NF-B, and stretch-induced protein thiol oxidation was attenuated by Nox4 small interfering RNA and complex III inhibition. NF-B activity was increased by stretch in a complex III-dependent fashion, and stretch-induced cyclin D1 expression was attenuated by complex III inhibition and Nox4 small interfering RNA. This is the first study to show that cyclic stretch increases Nox4 expression via mitochondrial complex III-induced activation of NF-B in fetal PASMC, resulting in ROS signaling and increased cyclin D1 expression. Targeting these signaling molecules may attenuate pulmonary vascular remodeling associated with PPHN. pulmonary hypertension; reactive oxygen species; NADPH oxidase AT BIRTH, PULMONARY VASCULAR resistance must rapidly decrease, to allow pulmonary blood flow to increase 10-fold and establish the lung as the organ of gas exchange. This fetal-tonewborn transition is regulated by complex physiological and biochemical processes, which are necessary to promote pulmonary artery (PA) vasodilation. Abnormalities in the transition at birth produce persistent pulmonary hypertension of the newborn (PPHN), a life-threatening clinical disorder of newborn infants (41). PPHN is characterized by elevated pulmonary vascular resistance (PVR), right-to-left extrapulmonary shunting of deoxygenated blood, and life-threatening hypoxemia. Pathological findings include pulmonary vascular remodeling and smooth muscle hyperplasia (20), and the severity of the disease correlates with the extent of vascular remodeling. However, the abnormal in utero events that trigger the development of PPHN are poorly understood.A lamb model involving antenatal ligation of the ductus arteriosus followed by delivery at near-term gestation has been used to simulate PPHN. These newborn lambs display pulmonary vascular remodeling, increased PA pressure, and other physiological changes consistent with clinical PPHN (33, 52). Ductal ligation initially induces a large increase in pulmonary blood flow followed by a return to baseline flow while PA pressure remains high (1). In vivo experiments s...

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Section: Discussionmentioning

confidence: 95%

Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells

Wedgwood

Lakshminrusimha

Schumacker

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In ECs, cyclic stretch enhanced p22phox expression, and ROS production was sensitive to NOX inhibition with diphenyl iodonium (84). In contrast, physiological levels of cyclic strain down-regulated Nox4 expression and superoxide anion formation, accompanied by an increase in NO release and eNOS expression (46).…”

Section: Cyclic Stretchmentioning

confidence: 93%

Hemodynamic Regulation of Reactive Oxygen Species: Implications for Vascular Diseases

Raaz

Toh

Maegdefessel

et al. 2014

Antioxidants & Redox Signaling

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Significance: Arterial blood vessels functionally and structurally adapt to altering hemodynamic forces in order to accommodate changing needs and to provide stress homeostasis. This ability is achieved at the cellular level by converting mechanical stimulation into biochemical signals (i.e., mechanotransduction). Physiological mechanical stress helps maintain vascular structure and function, whereas pathologic or aberrant stress may impair cellular mechano-signaling, and initiate or augment cellular processes that drive disease. Recent Advances: Reactive oxygen species (ROS) may represent an intriguing class of mechanically regulated second messengers. Chronically enhanced ROS generation may be induced by adverse mechanical stresses, and is associated with a multitude of vascular diseases. Although a causal relationship has clearly been demonstrated in large numbers of animal studies, an effective ROS-modulating therapy still remains to be established by clinical studies. Critical Issues and Future Directions: This review article focuses on the role of various mechanical forces (in the form of laminar shear stress, oscillatory shear stress, or cyclic stretch) as modulators of ROS-driven signaling, and their subsequent effects on vascular biology and homeostasis, as well as on specific diseases such as arteriosclerosis, hypertension, and abdominal aortic aneurysms. Specifically, it highlights the significance of the various NADPH oxidase (NOX) isoforms as critical ROS generators in the vasculature. Directed targeting of defined components in the complex network of ROS (mechano-)signaling may represent a key for successful translation of experimental findings into clinical practice. Antioxid. Redox Signal. 20,[914][915][916][917][918][919][920][921][922][923][924][925][926][927][928]

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“…Indeed, in the heart, stretch-induced ROS production was absent in Nox2 knockout mice (97), but Nox4 knockout mice have not been studied in this context. In human umbilical vein endothelial cells (HUVECs) studied in the Flexcell system applying 12% elongation, Nox4 mRNA expression decreased to 50%, which was, in part, sensitive to NO synthase inhibition (38). Nevertheless, cell swelling-induced ROS production in NIH3T3 mouse fibroblasts was attenuated by Nox4 siRNA, whereas downregulation of p47phox or p67phox did not affect this response (33).…”

Section: Stretch and Nox-dependent Ros Productionmentioning

confidence: 99%

Nox Family NADPH Oxidases in Mechano-Transduction: Mechanisms and Consequences

Brandes

Weißmann

Schröder

2014

Antioxidants & Redox Signaling

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Significance: The majority of cells in a multi-cellular organism are continuously exposed to ever-changing physical forces. Mechano-transduction links these events to appropriate reactions of the cells involving stimulation of signaling cascades, reorganization of the cytoskeleton and alteration of gene expression. Recent Advances: Mechano-transduction alters the cellular redox balance and the formation of reactive oxygen species (ROS). Nicotine amide adenine dinucleotide reduced form (NADPH) oxidases of the Nox family are prominent ROS generators and thus, contribute to this stress-induced ROS formation. Critical Issues: Different types and patterns of mechano-stress lead to Nox-dependent ROS formation and Nox-mediated ROS formation contributes to cellular responses and adaptation to physical forces. Thereby, Nox enzymes can mediate vascular protection during physiological mechano-stress. Despite this, over-activation and induction of Nox enzymes and a subsequent substantial increase in ROS formation also promotes oxidative stress in pathological situations like disturbed blood flow or extensive stretch. Future Directions: Individual protein targets of Nox-mediated redoxsignaling will be identified to better understand the specificity of Nox-dependent ROS signaling in mechanotransduction. Nox-inhibitors will be tested to reduce cellular activation in response to mechano-stimuli. Antioxid. Redox Signal. 20, 887-898.

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Long-Term Cyclic Strain Downregulates Endothelial Nox4

Cited by 36 publications

References 61 publications

Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells

Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells

Hemodynamic Regulation of Reactive Oxygen Species: Implications for Vascular Diseases

Nox Family NADPH Oxidases in Mechano-Transduction: Mechanisms and Consequences

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