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Inhibition of Endothelial Notch Signaling Impairs Fatty Acid Transport and Leads to Metabolic and Vascular Remodeling of the Adult Heart Markus Jabs, Adam J

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Inhibition of Endothelial Notch Signaling Impairs Fatty Acid Transport and Leads to Metabolic and Vascular Remodeling of the Adult Heart Markus Jabs, Adam J 10.1161/CIRCULATIONAHA.117.029733 Inhibition of Endothelial Notch Signaling Impairs Fatty Acid Transport and Leads to Metabolic and Vascular Remodeling of the Adult Heart Running Title: Jabs et al.; Heart failure After Endothelial Notch Inhibition Markus Jabs, PhD, et al. The full author list is available on page 19. Downloaded from Address for Correspondence: AAndreasndreas FischerFischer,, MMDD http://circ.ahajournals.org/ GGermanerman CCancerancer Research CCenterenter VVascularascular Signaling and Cancer (A270) Imm NNeuenheimereuenheimer FFeldeld 282800 6692109210 Heidelberg,Heidelberg, GermanyGermany TeTel:l: +4+499 62622121 42 414415050 FFax:axx: ++4+499 626221211 4422 414415959 by guest on March 20, 2018 Email:Emmail: [email protected]@@ddkfzz.de 1 10.1161/CIRCULATIONAHA.117.029733 Abstract Background—Nutrients are transported through endothelial cells before being metabolized in muscle cells. However, little is known about the regulation of endothelial transport processes. Notch signaling is a critical regulator of metabolism and angiogenesis during development. Here, we studied how genetic and pharmacological manipulation of endothelial Notch signaling in adult mice affects endothelial fatty acid transport, cardiac angiogenesis, and heart function. Methods—Endothelial-specific Notch inhibition was achieved by conditional genetic inactivation of Rbp-jκ in adult mice to analyze fatty acid metabolism and heart function. Wild- type mice were treated with neutralizing antibodies against the Notch ligand Dll4. Fatty acid transport was studied in cultured endothelial cells and transgenic mice. Results—Treatment of wild-type mice with Dll4 neutralizing antibodies for eight weeks impaired fractional shortening and ejection fraction in the majority of mice. Inhibition of Notch signaling specifically in the endothelium of adult mice by genetic ablation of Rbp-jκ caused heart Downloaded from hypertrophy and failure. Impaired heart function was preceded by alterations in fatty acid metabolism and an increase in cardiac blood vessel density. Endothelial Notch signaling controlled the expression of endothelial lipase, Angptl4, CD36 and Fabp4, which are all needed for fattyfatty acid transporttransport across the vessel wall.wall. In endothelial-specificendothelial specific RRbp-bp jκ-mutantmutant mmiceice lipaselipase activityactivity and transendothelial transport of lonlong-chaing-chain fatty acids to muscle cellcellss wa wasas imimpaired.pairi ed. IIn http://circ.ahajournals.org/ turn,urn, therethere wwasas a accumulationccumulation ooff llipidsipids in plasma andand liver.liver. TheThe aattenuatedttenuated supply ooff cardiomyocytescardiomyocytes with long-chainlong-chain fatty acids was accompanied by hhigherigher glucose uptakuptake,e, increasedncreased concentration of glycolysis intermediateintermediatess an andd m mTOR-S6KTOR-S6K signaling. TreatTreatmentment wwithith thehe mTORmTOR inhibitorinhibitor rapamycinrapamycin or displacing glucose as cardiac substrate by feeding a ketogenic dietdiet prolongedproolonggede ssurvivalurrvvival of eendothelial-specificndothelial-specific RRbp-bbpp-jκ-deficient-deficient mice.miice. ConclusionsConcllusions—ThisThiss studysttuddy identifiesidi enntit fies NotchNootct h signalingsignala inng ass a novelnovvele regulatorregegullattoro ofof fattyfattty acidaca id tr transportrana spport by guest on March 20, 2018 acrossacrrosss ththee eendotheliumndotheeliumm andaand asa an esessentialssesenntiial rerepressorpreessor of angiogenesisanggiooggeneessis inn tthehee aadultdult hheart.eartt. TTh Thee ddadatatta implympply thatt thehe enendotheliumndod theeliium cocontrolsontrols c cardiomyocytearddiomyoccyte memmetabolismtaabolismm aandnnd ffunction.ununcttion. KeyKey WoWords:rds: endothelialendothelial cecell;ll; ananimalimal mmodelodel cardiovascularcardiovascular didisease;sease; aangiogenesis;ngiogenesis; mmetabolismetabolism 2 10.1161/CIRCULATIONAHA.117.029733 Clinical Perspective What is new? x This work shows that Notch signaling in the endothelium controls blood vessel formation and fatty acid transport in the adult mouse heart. x Inhibition of Notch signaling in the vasculature leads to expansion of the cardiac vasculature and impairment of fatty acid transport to cardiomyocytes. x This results in metabolic reprogramming and heart failure. What are clinical implications? Downloaded from x Notch signaling is a promising target in oncology. x Pharmacologicalgg inhibition of Notch signalingg could lead to heart failure due to vascular http://circ.ahajournals.org/ and metabolic remodeliremodelingng of the heartheart.. by guest on March 20, 2018 3 10.1161/CIRCULATIONAHA.117.029733 Introduction Endothelial cells (EC) form tubes for the transport of blood, but in addition, ECs regulate organogenesis, tissue regeneration, stem cell differentiation, or tumor progression in a paracrine (angiocrine) fashion.1, 2 Given that ECs are in close proximity to almost every other cell type, they are ideally suited to control homeostasis. Even though this may also be important for controlling distribution of nutrients to parenchymal cells, little is known about this. Located at the interface between plasma and parenchymal cells, EC heterogeneity 1 Downloaded from provides organ-specific vascular beds. For instance, sinusoidal liver ECs form gaps and do not provide a physical barrier for nutrient transport, whereas the continuous endothelium, in muscle, heart,heart, lung or braibrainn r requiresequires transcellular transport ooff nnutrients.utrients. EC fatty acid trtransportannsport is http://circ.ahajournals.org/ fafacilitatedcilitated by PPARγ and Meox2/Tcf1Meox2/Tcf155,3,3, 4 andand it isis discusseddiscussed howhow VEGF-BVEGF-B secsecretedreted frfromom cardiomyocytescardiomyyocytes stimulates EC fatty acid transporttransport..5-75-7 TheThe acactivityctiivvityt ooff NoNotchtct h sisignalinggnnalini g ini varvariousioousu ccellell tytypesypes iniincludingcllududing ECEECss iss iinfluencednfluene ceed byb llevelsevels by guest on March 20, 2018 ofof plasmaplaasma glglucoseuccoose8-118-11 andannd ininflammatorynflammatoryy lipidlipids,s,,122 suggestingsuugggese tiinng a linklink betweenbbetwweeen thtthee memetabolictaabololic sstatustattuus andand NoNotchtch sisignalingignaling acactivity.tivity. NoNotchtch sisignalinggnaling is aann inintercellulartercellular cocommunicationmmunication sysystem.stem. BiBindingnding of ligands (Delta-like (Dll) and Jagged) triggers cleavage of Notch receptors to release the intracellular domain (Notch-ICD) that enters the nucleus, interacts with Mastermind like-1 (MAML1) and the Rbp-jκ complex to act as a transcription factor. In the developing vasculature and in solid tumors, Dll4/Notch signaling restrains angiogenesis,13 while in the adult, quiescent endothelium the role of Notch signaling is not yet understood. Notch signaling is an interesting target for therapeutic interventions in oncology. However, severe congestive heart failure occurred in a substantial proportion of patients treated 4 10.1161/CIRCULATIONAHA.117.029733 with different DLL4-blocking antibodies in phase-I studies,14, 15 that target Notch signaling predominantly in ECs and a few other cell types. The reason for this remains elusive. Methods The authors declare that all supporting data are available within the article and its online supplementary files. Please refer to the Expanded Methods in the Online Data Supplements for experimental details. Downloaded from Animal Studies The study was approved by Institutional and Regional Animal Research Committees. All animal proceduresprocedures were in accordance with ininstitutionalstitutional guidelines and performed accoaccordingrdding to ttheheh http://circ.ahajournals.org/ guidelinesguidelines of the local institution and the local government ((RegierungspräsidiumRegierungspräsidium Karlsruhe).Karlsruhe). RbpjRbpjiΔEC micemice ((Cdh5-CreERT2,RbpjCdh5-CreERT2,Rbpjlox/loxlox/lox) were obtained by crossing CdhCdh5-CreERT25-CreERT2 mice with RbpjRbpjlox/loxloox/lox mice,micee,161 andana d in injectednjectc edd wiw withtht 1.1 1.55 mgm ttamoxifenammoxo ifeen ii.p..pp. foforr 5 coconsecutiveonsn ece utivi e dadays.ys. TATTAG,G, ttotalotal by guest on March 20, 2018 ketoneketoonne bodies anandd NENEFAEFFA wwereerre memeasuredasuredd usiusingngg kkitsitts frfromrom SSigmaigmma aandnnd WWakoaako DiDDiagnostics.agnoostticcs. GluGlucose-cocose- 6-phosphate6-phosphate wawass dedeterminedtermined wwithith a kikitt frfromom CCaymanayman ChemicalChemical CCompany.ompany. Acyl-CoAsAcyl-CoAs werewere extracted from tissues and measured as described.17, 18 Mice were not anesthetized during transthoracic echocardiography.19 Long-chain FA organ uptake was assessed as described.20 Dll4 blocking antibodies were from Genentech.21 Statistical Analysis The results are presented as mean and SEM. SigmaPlot 12.5 (Systat Software) was used for statistical analysis. Unpaired two-tailed Student’s t-test was used for comparisons of two groups (most of the presented experiments). Significance between more than two groups was tested by 5 10.1161/CIRCULATIONAHA.117.029733 Two Way ANOVA using Holm-Sidak method as post-hoc test. The log-rank test was used to compare survival of mouse cohorts (Fig. 8B). p<0.05 was considered as statistically significant. Results Neutralizing DLL4 antibodies impair heart function in mice Notch1 is expressed in variable amounts in ECs and several other cell types.22 We observed Notch1 expression in ECs of heart, skeletal muscle, liver and white
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