Inhibition of Endothelial Notch Signaling Impairs Fatty Acid Transport and Leads to Metabolic and Vascular Remodeling of the Adult Heart

Jabs, Markus; Rose, Adam J.; Lehmann, Lorenz; Taylor, Jacqueline; Moll, Iris; Sijmonsma, Tjeerd P.; Herberich, Stefanie E.; Sauer, Sven W.; Poschet, Gernot; Federico, Giuseppina; Mogler, Carolin; Weis, Eva-Maria; Augustin, Hellmut G.; Yan, Minhong; Gretz, Norbert; Schmid, Roland M.; Adams, Ralf H.; Gröne, Hermann-Joseph; Hell, Rüdiger; Okun, Jürgen G.; Backs, Johannes; Nawroth, Peter P.; Herzig, Stephan; Fischer, Andreas

doi:10.1161/circulationaha.117.029733

Cited by 113 publications

(131 citation statements)

References 46 publications

(52 reference statements)

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“…13,14 Moreover, metabolic changes towards more glucose uptake were shown to be sufficient to induce cardiac dysfunction. 3 In line with findings on heart failure, two studies analysing the effects of anthracyclines on FDG uptake in a total of 113 Hodgkin's lymphoma patients found a gradual increase in FDG uptake over time while on anthracycline treatment. 15,16 This increase was associated with a decrease in left ventricular function.…”

Section: Discussionsupporting

confidence: 56%

“…Secreted 'cachexokines' can lead to detrimental cardiac metabolic changes, marked by an increased glucose metabolism, while the healthy heart metabolizes predominantly fatty acids. [2][3][4] Furthermore, in vivo animal data on colon cancer and malignant melanoma linked systemic insulin depletion to a dysregulation of the cardiac glucose metabolism, visualized by 2-deoxy-2-( 18 F)fluoro-D-glucose (FDG) positron emission tomography in combination with a low-dose computed tomography (PET-CT) scans. 5 In humans, there are currently no data available for metabolic cardiac changes in cancer patients suffering from different tumour entitites.…”

Section: Introductionmentioning

confidence: 99%

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Evidence for a cardiac metabolic switch in patients with Hodgkin's lymphoma

et al. 2019

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Aims Our aim was to investigate the glucose uptake in cancer patients suffering from different entities, using 18F‐FDG positron emission tomography–computed tomography scans. We further aimed at identifying potential variables altering cardiac and skeletal muscle glucose metabolism. Methods and results In a retrospective cohort study, we analysed cardiac and skeletal muscle 18F‐FDG uptake in onco‐positron emission tomography–computed tomography scans in adult patients suffering from Hodgkin's lymphoma, non‐Hodgkin's lymphoma, and non‐lymphatic cancer including patients suffering from thyroid cancer, bronchial carcinoma, and malignant melanoma. Univariate logistic regression models were created for increased cardiac and skeletal muscle 18F‐FDG uptake using cancer entity, sex, age, previous radiation, previous chemotherapy, diabetes, obesity, serum glucose levels, renal function, and thyroid function as parameters. Multivariate models were created by selecting variables according to Akaike's information criterion in a step‐down approach. Between 2014 and 2018, a total of 337 consecutive patients suffering from Hodgkin's lymphoma (n = 52), non‐Hodgkin's lymphoma (n = 57), and non‐lymphatic cancer (n = 228) were included in the analysis. Univariate logistic regression models showed high serum glucose levels to be associated with lower absorption rates in both cardiac and skeletal muscle (odds ratio [OR] 0.38 [0.23, 0.60, 95% confidence interval—CI], P < 0.0001, and 0.52 [0.33, 0.82, 95% CI], P < 0.005, respectively). Hodgkin's lymphoma was associated with an increase in cardiac uptake (OR 2.4 [1.3, 4.5, 95% CI], P < 0.005). Decreased skeletal muscle 18F‐FDG uptake was noted in elderly and obese patients. In our multivariate analysis, Hodgkin's lymphoma patients showed higher cardiac 18F‐FDG uptake, while non‐Hodgkin's lymphoma patients did not differ significantly from non‐lymphatic cancer patients (OR 1.6 [0.7, 3.3, 95% CI], P = 0.24). High serum glucose levels and prior chemotherapy were both associated with a significantly decreased cardiac 18F‐FDG uptake (OR 0.40 [0.24, 0.65, 95% CI], P < 0.0005, and 0.50 [0.27, 0.90, 95% CI], P < 0.05, respectively). Notably, prior chemotherapy did not influence FDG uptake in skeletal muscle to the same extent. Obesity and older age were both significantly associated with decreased gluteal 18F‐FDG uptake (OR 0.49 [0.27, 0.89, 95% CI], P < 0.05, and 0.47 [0.25, 0.87, 95% CI], P < 0.05). Conclusions Our data provide evidence for metabolic alterations in patients with Hodgkin's lymphoma related to cardiac glucose uptake in humans. This effect was independent from skeletal muscle metabolism.

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Evidence for a cardiac metabolic switch in patients with Hodgkin's lymphoma

et al. 2019

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“…Inhibition of endothelial NOTCH causes heart hypertrophy and heart failure due to impaired transport of fatty acids and altered blood vessel growth (Jabs et al, 2018) TP53, tumor protein p53 MDM2 binding to p53 limits TP53 transcriptional activity. TP53 provokes transition from cardiac hypertrophy to heart failure by promoting cardiomyocyte apoptosis and limiting angiogenesis (Sano et al, 2007;Toko et al, 2010) MDM2 ubiquitination triggers proteasomal degradation of TP53…”

Section: Growth Factor Responsive Kinasesmentioning

confidence: 99%

“…This is essential for vascular growth. An elegant study by Jabs et al (2018) recently demonstrated the role of the NOTCH pathway in the adult endothelium of the heart. Endothelial-specific downregulation of NOTCH1 signal was induced by conditional ablation of the Rbp-jκ complex in adult mice.…”

Section: Cytoplasmic Downstream Targets Of Mdm2 Mdm2 Endothelial Notmentioning

confidence: 99%

Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

Lam

Roudier

2019

Front. Cell Dev. Biol.

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The E3 ubiquitin ligase Murine double minute 2 (MDM2) is the main negative regulator of the tumor protein p53 (TP53). Extensive studies over more than two decades have confirmed MDM2 oncogenic role through mechanisms both TP53-dependent and TP53-independent oncogenic function. These studies have contributed to designate MDM2 as a therapeutic target of choice for cancer treatment and the number of patents for MDM2 antagonists has increased immensely over the last years. However, the question of the physiological functions of MDM2 has not been fully resolved yet, particularly when expressed and regulated physiologically in healthy tissue. Cardiovascular complications are almost an inescapable side-effect of anti-cancer therapies. While several MDM2 antagonists are entering phase I, II and even III of clinical trials, this review proposes to bring awareness on the physiological role of MDM2 in the cardiovascular system.

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“…Recent studies conducted in a transgenic murine model have revealed that endothelial Notch modulates the synthesis of local lipase as well as other factors such as Fabp4, Angptl4 and CD36 which may be regulating the transport of free fatty acids across the endothelium. It was shown that in mutant animals with non-functional Notch signalling there is a significant accumulation of lipids in plasma [64].…”

Section: E Notch Signallingmentioning

confidence: 99%