Coronary vasculature patterning requires a novel endothelial ErbB2 holoreceptor

Aghajanian, Haig; Cho, Young Kuk; Manderfield, Lauren J.; Herling, Madison R.; Gupta, Mudit; Ho, Vivienne C.; Li, Li; Degenhardt, Karl; Aharonov, Alla; Tzahor, Eldad; Epstein, Jonathan A.

doi:10.1038/ncomms12038

Cited by 34 publications

(31 citation statements)

References 41 publications

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“…In vitro and in vivo findings suggest that increases in oxidative stress and endothelial dysfunction with doxorubicin could be further worsened with trastuzumab (10,12,13), corroborating the notion of a 2-hit hypothesis (40). However, this study is underpowered to formally examine interactions between biomarker level and treatment group, and testing this hypothesis in clinical data remains an important area for further research.…”

Section: Discussionsupporting

confidence: 54%

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Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction in Patients With Breast Cancer

Finkelman

Putt

Wang

et al. 2017

Journal of the American College of Cardiology

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Background Oxidative/nitrosative stress and endothelial dysfunction are hypothesized to be central to cancer therapeutics-related cardiac dysfunction (CTRCD). However, the relationship between circulating arginine-nitric oxide (NO) metabolites and CTRCD remains unstudied. Objectives To examine the relationship between arginine-NO metabolites and CTRCD in a prospective cohort of 170 breast cancer patients treated with doxorubicin ± trastuzumab. Methods Plasma levels of arginine, citrulline, ornithine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and N-monomethylarginine (MMA) were quantified at baseline, 1 month, and 2 months following doxorubicin initiation. Determinants of baseline biomarker levels were identified using multivariable linear regression, and Cox regression defined the association between baseline levels and 1- or 2-month biomarker changes and CTRCD rate in 139 participants with quantitated echocardiograms at all time points. Results Age, hypertension, body mass index, and African American race were independently associated with ≥1 baseline citrulline, ADMA, SDMA, and MMA levels. Decreases in arginine and citrulline, and increases in ADMA were observed at 1 and 2 months (all P<0.05). Overall, 32 participants experienced CTRCD over a maximum follow-up of 5.4 years. Hazard ratios for ADMA and MMA at 2 months were 3.33 (95% confidence interval [CI] 1.12, 9.96) and 2.70 (95%CI 1.35, 5.41), respectively, and 0.78 (95%CI 0.64, 0.97) for arginine at 1 month. Conclusions In breast cancer patients undergoing doxorubicin therapy, early alterations in arginine-NO metabolite levels occurred, and early biomarker changes were associated with a greater CTRCD rate. Our findings highlight the potential mechanistic and translational relevance of this pathway to CTRCD.

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Section: Discussionsupporting

confidence: 54%

“…ErbB2 inhibition from trastuzumab may exacerbate these effects, resulting in worse oxidative stress and cardiomyocyte and endothelial cell dysfunction (10,12,13). …”

Section: Introductionmentioning

confidence: 99%

Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction in Patients With Breast Cancer

Finkelman

Putt

Wang

et al. 2017

Journal of the American College of Cardiology

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“…The immunoblot was developed with enhanced chemiluminescence (Fisher Scientific). Membranes were then stripped, blocked, and reprobed with antibodies against GluA1 (0.5 µg/ml; Thermo Fisher Scientific, PA1-37776) (40) or β-actin (1:2000; Cell Signaling Technology, #4967) (41). Levels of phosphorylation, expressed as the ratio of phosphospecific intensity divided by total protein intensity and computed with ImageJ, were used for statistical analysis.…”

Section: Methodsmentioning

confidence: 99%

Essential roles of AMPA receptor GluA1 phosphorylation and presynaptic HCN channels in fast-acting antidepressant responses of ketamine

Zhang

Yuan

et al. 2016

Sci. Signal.

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Although the molecular mechanism is not clear, the clinically tested drug ketamine has rapid antidepressant action that does not require the multiple weeks of treatment needed for other antidepressant drugs to have an effect. We showed that ketamine potentiated Schaffer collateral–CA1 cell excitatory synaptic transmission in hippocampal slice preparations from rodents and enhanced the phosphorylation of the GluA1 subunit on Ser845 of the AMPA-type glutamate receptor in the hippocampal area CA1. These effects persisted when γ-aminobutyric acid (GABA) receptors were pharmacologically blocked. Ketamine reduced behavioral despair in wild-type mice but had no effect in GluA1 S845A knock-in mutant mice. Presynaptic (CA3 pyramidal cell), but not postsynaptic (CA1 pyramidal cell), deletion of N-methyl-d-aspartate (NMDA)–type glutamate receptors eliminated the ketamine-induced enhancement of excitatory synaptic transmission in hippocampal slices and the antidepressant actions of ketamine in mice. The synaptic and behavioral actions of ketamine were completely occluded by inhibition or deletion of the hyperpolarization-activated cyclic nucleotide–gated channel 1 (HCN1). Our results implicate presynaptic NMDA receptor inhibition followed by reduced activity of presynaptic HCN1 channels, which would result in an increase in glutamate release and postsynaptic glutamate receptor activity, as a mechanism of ketamine action. These data provide a mechanism for changes in synaptic activity that could explain the fast-acting antidepressant effects of this drug.

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“…SEMA3D F602L binding to Nrp1 and ability to repel the migration of cultured ECs is significantly reduced 88 . Sema3D was recently reported to be expressed in the left anterior atrioventricular groove to repel venous ECs from aberrantly connecting with the left atrium 89 . It appears that in venous ECs the inhibitory Sema3D signals are conveyed through a Nrp1-ErbB2 holoreceptor complex 89 …”

Section: Other Sema3 Proteinsmentioning

confidence: 99%

Class 3 semaphorins in cardiovascular development

Valdembri

Regano

Maione

et al. 2016

Cell Adhesion & Migration

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Secreted class 3 semaphorins (Sema3), which signal through holoreceptor complexes that are formed by different subunits, such as neuropilins (Nrps), proteoglycans, and plexins, were initially characterized as fundamental regulators of axon guidance during embryogenesis. Subsequently, Sema3A, Sema3C, Sema3D, and Sema3E were discovered to play crucial roles in cardiovascular development, mainly acting through Nrp1 and Plexin D1, which funnels the signal of multiple Sema3 in vascular endothelial cells. Mechanistically, Sema3 proteins control cardiovascular patterning through the enzymatic GTPase-activating-protein activity of the cytodomain of Plexin D1, which negatively regulates the function of Rap1, a small GTPase that is well-known for its ability to drive vascular morphogenesis and to elicit the conformational activation of integrin adhesion receptors.

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Coronary vasculature patterning requires a novel endothelial ErbB2 holoreceptor

Cited by 34 publications

References 41 publications

Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction in Patients With Breast Cancer

Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction in Patients With Breast Cancer

Essential roles of AMPA receptor GluA1 phosphorylation and presynaptic HCN channels in fast-acting antidepressant responses of ketamine

Class 3 semaphorins in cardiovascular development

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