Both hydrogen peroxide and transforming growth factor beta 1 contribute to endothelial Nox4 mediated angiogenesis in endothelial Nox4 transgenic mouse lines

Chen, Lili; Hou, Xiuyun; Xiao, Jennifer; Kuroda, Junya; Ago, Tetsuro; Sadoshima, Junichi; Cohen, Richard A.; Tong, Xiaoyong

doi:10.1016/j.bbadis.2014.10.007

Cited by 44 publications

(61 citation statements)

References 32 publications

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“…DDAH‐2 plays a crucial role in regulating ADMA metabolism of ECs 24, 25. We analyzed whether overexpression of DDAH‐2 protects against ADMA‐induced impairment of simvastatin‐mediated NO production and tube formation.…”

Section: Resultsmentioning

confidence: 99%

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Hsu

Zhao²,

Lin

et al. 2016

JAHA

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BackgroundAsymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered a risk factor for the pathogenesis of cardiovascular diseases. Simvastatin, a lipid‐lowering drug with other pleiotropic effects, has been widely used for treatment of cardiovascular diseases. However, little is known about the effect and underlying molecular mechanisms of ADMA on the effectiveness of simvastatin in the vascular system.Methods and ResultsWe conducted a prospective cohort study to enroll 648 consecutive patients with coronary artery disease for a follow‐up period of 8 years. In patients with plasma ADMA level ≥0.49 μmol/L (a cut‐off value from receiver operating characteristic curve), statin treatment had no significant effect on cardiovascular events. We also conducted randomized, controlled studies using in vitro and in vivo models. In endothelial cells, treatment with ADMA (≥0.5 μmol/L) impaired simvastatin‐induced nitric oxide (NO) production, endothelial NO synthase (eNOS) phosphorylation, and angiogenesis. In parallel, ADMA markedly increased the activity of NADPH oxidase (NOX) and production of reactive oxygen species (ROS). The detrimental effects of ADMA on simvastatin‐induced NO production and angiogenesis were abolished by the antioxidant, N‐acetylcysteine, NOX inhibitor, or apocynin or overexpression of dimethylarginine dimethylaminohydrolase 2 (DDAH‐2). Moreover, in vivo, ADMA administration reduced Matrigel plug angiogenesis in wild‐type mice and decreased simvastatin‐induced eNOS phosphorylation in aortas of apolipoprotein E–deficient mice, but not endothelial DDAH‐2‐overexpressed aortas.ConclusionsWe conclude that ADMA may trigger NOX‐ROS signaling, which leads to restricting the simvastatin‐conferred protection of eNOS activation, NO production, and angiogenesis as well as the clinical outcome of cardiovascular events.

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Section: Resultsmentioning

confidence: 99%

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Hsu

Zhao²,

Lin

et al. 2016

JAHA

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“…NOX4 enhances angiogenesis under ischemic conditions and is therefore protective against ischemic injury in lower limbs (35). Furthermore, Chen et al demonstrated that endothelial NOX4 mediates angiogenesis (36). Thus, the presence of NOX4 in endothelial cells may induce a difference in phenotype between cardiac-specific NOX4 KO mice and systemic NOX4 KO mice.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling

Matsushima

Kuroda

Zhai

et al. 2016

Journal of Clinical Investigation

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NADPH oxidases (Noxes) produce ROS that regulate cell growth and death. NOX4 expression in cardiomyocytes (CMs) plays an important role in cardiac remodeling and injury, but the posttranslational mechanisms that modulate this enzyme are poorly understood. Here, we determined that FYN, a Src family tyrosine kinase, interacts with the C-terminal domain of NOX4. FYN and NOX4 colocalized in perinuclear mitochondria, ER, and nuclear fractions in CMs, and FYN expression negatively regulated NOX4-induced O 2 -production and apoptosis in CMs. Mechanistically, we found that direct phosphorylation of tyrosine 566 on NOX4 was critical for this FYN-mediated negative regulation. Transverse aortic constriction activated FYN in the left ventricle (LV), and FYN-deficient mice displayed exacerbated cardiac hypertrophy and dysfunction and increased ROS production and apoptosis. Deletion of Nox4 rescued the exaggerated LV remodeling in FYN-deficient mice. Furthermore, FYN expression was markedly decreased in failing human hearts, corroborating its role as a regulator of cardiac cell death and ROS production. In conclusion, FYN is activated by oxidative stress and serves as a negative feedback regulator of NOX4 in CMs during cardiac remodeling.

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“…These differences may have caused the disparity in results. Angiogenesis is induced not only by VEGF but also by the platelet-derived growth factor [25] and transforming growth factor beta [26] . Cilostazol inhibits the activity of phosphodiesterase type 3 [27] , leading to the upregulation of the hepatocyte growth factor [28] and possible induction of angiogenesis [29] .…”

Section: Discussionmentioning

confidence: 99%

Combination of Cilostazol and <smlcap>L</smlcap>-Carnitine Improves Walking Performance in Peripheral Arterial Disease Model Rats

Shiga¹,

Sahara²,

Orito³

2015

Pharmacology

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Cilostazol and L-carnitine have been used as a first-line drug and supplement, respectively, in patients with peripheral arterial disease with intermittent claudication. In this study, the effect of the combination of cilostazol and L-carnitine has been investigated in rats with unilateral hindlimb ischemia. For 28 days, cilostazol and L-carnitine were administrated separately or as a combination. The distance walked before gait disturbance developed was measured using a treadmill for 5 days a week. The capillary density of the ischemic hindlimb was evaluated by immunohistochemical staining at days 7, 14, 21, and 28. Angiogenic gene expression was measured by real-time RT-PCR at days 7 and 28. The greatest increase in the distance was observed in the combination therapy group when compared to the other groups. The capillary density in the adductor muscles of rats treated with cilostazol alone and combination therapy increased at day 28. Angiopoietin-2/Angiopoietin-1 expression ratios were higher, suggesting the promotion of angiogenesis, with cilostazol alone and combination therapy at day 7. This is the first study to show functional improvement of the hind limb following combination therapy with cilostazol and L-carnitine in experimental animals. This study also revealed that cilostazol promotes angiogenesis, and L-carnitine additively contributes to functional improvement via a non-angiogenic mechanism.

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Both hydrogen peroxide and transforming growth factor beta 1 contribute to endothelial Nox4 mediated angiogenesis in endothelial Nox4 transgenic mouse lines

Cited by 44 publications

References 32 publications

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling

Combination of Cilostazol and <smlcap>L</smlcap>-Carnitine Improves Walking Performance in Peripheral Arterial Disease Model Rats

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