Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure

Sag, Can Martin; Schnelle, Moritz; Zhang, Juqian; Murdoch, Colin E.; Kossmann, Sabine; Protti, Andrea; Santos, Célio X.C.; Sawyer, Greta J.; Zhang, Xiaohong; Mongue‐Din, Héloïse; Richards, Daniel A.; Brewer, Alison C.; Prysyazhna, Oleksandra; Maier, Lars S.; Wenzel, Philip; Eaton, Philip; Shah, Ajay M.

doi:10.1161/circulationaha.116.023877

Cited by 56 publications

(62 citation statements)

References 42 publications

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“…In fact it was previously observed that endothelial dysfunction at least in response to angiotensin II is not observed in mice lacking monocytes [26] or deletion of monocytes [27] , [28] . Moreover, a striking similarity to the present data was observed in response to myeloid-specific deletion of Nox2; the animals had have lower blood pressure and increased NO levels [29] .…”

Section: Discussionsupporting

confidence: 88%

The NADPH organizers NoxO1 and p47phox are both mediators of diabetes-induced vascular dysfunction in mice

et al. 2018

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AimNADPH oxidases are important sources of reactive oxygen species (ROS). Several Nox homologues are present together in the vascular system but whether they exhibit crosstalk at the activity level is unknown. To address this, vessel function of knockout mice for the cytosolic Nox organizer proteins p47phox, NoxO1 and a p47phox-NoxO1-double knockout were studied under normal condition and during streptozotocin-induced diabetes.ResultsIn the mouse aorta, mRNA expression for NoxO1 was predominant in smooth muscle and endothelial cells, whereas p47phox was markedly expressed in adventitial cells comprising leukocytes and tissue resident macrophages. Knockout of either NoxO1 or p47phox resulted in lower basal blood pressure. Deletion of any of the two subunits also prevented diabetes-induced vascular dysfunction. mRNA expression analysis by MACE (Massive Analysis of cDNA ends) identified substantial gene expression differences between the mouse lines and in response to diabetes. Deletion of p47phox induced inflammatory activation with increased markers of myeloid cells and cytokine and chemokine induction. In contrast, deletion of NoxO1 resulted in an attenuated interferon gamma signature and reduced expression of genes related to antigen presentation. This aspect was also reflected by a reduced number of circulating lymphocytes in NoxO1-/- mice.Innovation and conclusionROS production stimulated by NoxO1 and p47phox limit endothelium-dependent relaxation and maintain blood pressure in mice. However, NoxO1 and p47phox cannot substitute each other despite their similar effect on vascular function. Deletion of NoxO1 induced an anti-inflammatory phenotype, whereas p47phox deletion rather elicited a hyper-inflammatory response.

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Section: Discussionsupporting

confidence: 88%

The NADPH organizers NoxO1 and p47phox are both mediators of diabetes-induced vascular dysfunction in mice

et al. 2018

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“…Nox2 fl/fl mice were described recently (Sag et al, 2017) and were crossed with LysM-cre knock in mice (Jackson Laboratories 004781) to generate LysM-cre +/− Nox2 fl/fl and litter mate control Nox2 fl/fl mice . See supplemental methods for genotyping details.…”

Section: Methodsmentioning

confidence: 99%

Metabolically Activated Adipose Tissue Macrophages Perform Detrimental and Beneficial Functions during Diet-Induced Obesity

et al. 2017

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SUMMARY During obesity, adipose tissue macrophages (ATMs) adopt a ‘metabolically-activated’ (MMe) phenotype. However, the functions of MMe macrophages are poorly understood. Here we combine proteomic and functional methods to demonstrate that in addition to potentiating inflammation, MMe macrophages also promote dead adipocyte clearance through lysosomal exocytosis. We identify NADPH-oxidase-2 (NOX2) as a driver of the inflammatory and adipocyte-clearing properties of MMe macrophages, and show that compared to wild-type, Nox2−/− mice exhibit a time-dependent metabolic phenotype during diet-induced obesity. After 8-weeks of high-fat feeding, Nox2−/− mice exhibit attenuated ATM inflammation and mildly improved glucose tolerance. After 16-weeks of high-fat feeding, Nox2−/− mice develop severe insulin resistance, hepatosteatosis, and visceral lipoatrophy characterized by dead adipocyte accumulation and defective ATM lysosomal exocytosis, a phenotype reproduced in myeloid cell-specific Nox2−/− mice. Collectively, our findings suggest that MMe macrophages perform detrimental and beneficial functions, whose contribution to metabolic phenotypes during obesity is determined by disease progression.

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“…In p47 phox -deficient mice, ANG II-induced hypertension (535) and afferent arteriolar contraction response are attenuated together with renal cortical NADPH oxidase activation (532). Nox2 deletion in ECs, but not in myeloid cells, attenuates ANG II-induced hypertension in mice (898). Thus, in EC-specific Nox2 transgenic mice, ANG II-induced endothelial dysfunction, hypertension, and cardiac remodeling are augmented (68,725,726).…”

Section: Ros Nox and Sodmentioning

confidence: 99%

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

821

780

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The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (ATR) is believed to mediate most functions of ANG II in the system. ATR utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between ATR signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. ATR remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.

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Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure

Abstract: Supplemental Digital Content is available in the text.

Cited by 56 publications

References 42 publications

The NADPH organizers NoxO1 and p47phox are both mediators of diabetes-induced vascular dysfunction in mice

The NADPH organizers NoxO1 and p47phox are both mediators of diabetes-induced vascular dysfunction in mice

Metabolically Activated Adipose Tissue Macrophages Perform Detrimental and Beneficial Functions during Diet-Induced Obesity

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

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