2024
Update in genetic and epigenetic causes of hypertension
Mani A. Update in genetic and epigenetic causes of hypertension. Cellular And Molecular Life Sciences 2024, 81: 201. PMID: 38691164, PMCID: PMC11062952, DOI: 10.1007/s00018-024-05220-4.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesProtein-coding sequencesGWAS-identified lociGWAS-identified genesHuman Genome ProjectEpigenetic mechanism of actionActual genesGenome ProjectAssociation studiesGenetic variationPolygenic formsGenetic basisGenetic variantsEpigenetic mechanismsHeritable diseaseEpigenetic causesPolygenic causeGenesLociPotential targetMechanism of actionManagement of blood pressurePRDM6SequenceVariants
2023
From mouse to human
Mani A. From mouse to human. ELife 2023, 12: e94382. PMID: 38060304, PMCID: PMC10703438, DOI: 10.7554/elife.94382.Peer-Reviewed Original ResearchA systems biology approach identifies the role of dysregulated PRDM6 in the development of hypertension
Gunawardhana K, Hong L, Rugira T, Uebbing S, Kucharczak J, Mehta S, Karunamuni D, Cabera-Mendoza B, Gandotra N, Scharfe C, Polimanti R, Noonan J, Mani A. A systems biology approach identifies the role of dysregulated PRDM6 in the development of hypertension. Journal Of Clinical Investigation 2023, 133: e160036. PMID: 36602864, PMCID: PMC9927944, DOI: 10.1172/jci160036.Peer-Reviewed Original ResearchConceptsDevelopment of hypertensionParallel reporter assaysRenin inhibitor aliskirenNeural crest-derived cellsRenin-producing cellsSystems biology approachRNA-seq analysisCell-specific disruptionCrest-derived cellsSmooth muscle cellsMuscle cell proteinsSystemic hypertensionBlood pressureWT miceAntihypertensive drugsBiology approachSuper enhancersFine mappingWT littermatesThird intronMultiple GWASCollagen depositionMouse aortaReporter assaysFate mapping
2022
TCF7L2 transcriptionally regulates Fgf15 to maintain bile acid and lipid homeostasis through gut‐liver crosstalk
Bhat N, Esteghamat F, Chaube BK, Gunawardhana K, Mani M, Thames C, Jain D, Ginsberg HN, Fernandes‐Hernando C, Mani A. TCF7L2 transcriptionally regulates Fgf15 to maintain bile acid and lipid homeostasis through gut‐liver crosstalk. The FASEB Journal 2022, 36: e22185. PMID: 35133032, PMCID: PMC9624374, DOI: 10.1096/fj.202101607r.Peer-Reviewed Original ResearchConceptsGut-liver crosstalkBile synthesisDiet-induced fatty liver diseaseSmall intestineHepatic bile saltIntestinal lipid uptakePlasma bile saltsFatty liver diseaseTreatment of NASHColorectal cancer cellsBile saltsConditional knockout modelHuman NASHFatty liverLiver diseaseFXR activationClinical trialsEnterohepatic circulationTranscription factor TCF4Fl/Hepatic levelsBile acidsEndocrine regulatorLipid uptakeIntestinal epitheliumPrdm6 controls heart development by regulating neural crest cell differentiation and migration
Hong L, Li N, Gasque V, Mehta S, Ye L, Wu Y, Li J, Gewies A, Ruland J, Hirschi KK, Eichmann A, Hendry C, van Dijk D, Mani A. Prdm6 controls heart development by regulating neural crest cell differentiation and migration. JCI Insight 2022, 7: e156046. PMID: 35108221, PMCID: PMC8876496, DOI: 10.1172/jci.insight.156046.Peer-Reviewed Original ResearchConceptsCardiac NCCNeural crest cell fateNeural crest cell differentiationSingle-cell RNA-seq analysisRNA-seq analysisDorsal neural tubeG1-S progressionFate-mapping approachCNCC migrationSpecification genesH4K20 monomethylationCell fateTranscriptomic analysisEpigenetic modifiersHeart developmentRegulated networkTranscript levelsKey regulatorMolecular mechanismsCell differentiationNeural tubePRDM6Ductus arteriosusPotential targetDifferentiationDyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice
Bhat N, Narayanan A, Fathzadeh M, Kahn M, Zhang D, Goedeke L, Neogi A, Cardone RL, Kibbey RG, Fernandez-Hernando C, Ginsberg HN, Jain D, Shulman G, Mani A. Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice. Journal Of Clinical Investigation 2022, 132: e153724. PMID: 34855620, PMCID: PMC8803348, DOI: 10.1172/jci153724.Peer-Reviewed Original ResearchConceptsDe novo lipogenesisNonalcoholic steatohepatitisInsulin resistanceHepatic lipogenesisElevated de novo lipogenesisNonalcoholic fatty liver diseaseFatty liver diseaseLiver of patientsHepatic glycogen storageHigh-sucrose dietHepatic insulin resistanceFatty acid uptakeMetabolic syndromeLiver diseaseHepatic steatosisTriacylglycerol secretionNovo lipogenesisHepatic insulinTherapeutic targetImpaired activationAcid uptakeGlycogen storageMouse liverLiverLipogenesis
2021
Dyrk1b promotes autophagy during skeletal muscle differentiation by upregulating 4e-bp1
Bhat N, Narayanan A, Fathzadeh M, Shah K, Dianatpour M, Abou Ziki MD, Mani A. Dyrk1b promotes autophagy during skeletal muscle differentiation by upregulating 4e-bp1. Cellular Signalling 2021, 90: 110186. PMID: 34752933, PMCID: PMC8712395, DOI: 10.1016/j.cellsig.2021.110186.Peer-Reviewed Original ResearchConceptsSkeletal muscle differentiationMuscle differentiationC2C12 cellsHuman skeletal muscle developmentSkeletal muscle developmentGlobal gene networksPost-transcriptional targetEmbryonic lethalGene networksZebrafish embryosMyofiber differentiationOverexpression approachesMuscle developmentCRISPR/DYRK1BRare gainDownstream targetsTranslational inhibitorKey regulatorUntargeted proteomicsFunction mutationsAutophagic fluxEnhances AutophagyDifferentiationAutophagy
2020
The role of Wnt signalling in development of coronary artery disease and its risk factors
Liu Y, Neogi A, Mani A. The role of Wnt signalling in development of coronary artery disease and its risk factors. Open Biology 2020, 10: 200128. PMID: 33081636, PMCID: PMC7653355, DOI: 10.1098/rsob.200128.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisBiomarkersCarrier ProteinsCell DifferentiationCell MovementCoronary Artery DiseaseDisease SusceptibilityEndotheliumGene Expression RegulationHumansLipid MetabolismMacrophage ActivationMacrophagesMyocytes, Smooth MuscleProtein BindingRisk FactorsWnt ProteinsWnt Signaling PathwayConceptsCoronary artery diseaseArtery diseaseRole of WntVascular smooth muscle cellsEndothelial cell dysfunctionReduced blood flowLow-density lipoproteinModified low-density lipoproteinWnt pathwaySmooth muscle cellsNon-canonical Wnt/CaAggregation of monocytesTissue-resident macrophagesChest painEndothelial dysfunctionWnt/CaHeart failureLuminal narrowingCascade of eventsPathophysiological mechanismsMyocardial infarctionRisk factorsHeart diseaseCell dysfunctionInflammatory reaction
2018
TCF7L2 (Transcription Factor 7-Like 2) Regulation of GATA6 (GATA-Binding Protein 6)-Dependent and -Independent Vascular Smooth Muscle Cell Plasticity and Intimal Hyperplasia
Srivastava R, Rolyan H, Xie Y, Li N, Bhat N, Hong L, Esteghamat F, Adeniran A, Geirsson A, Zhang J, Ge G, Nobrega M, Martin KA, Mani A. TCF7L2 (Transcription Factor 7-Like 2) Regulation of GATA6 (GATA-Binding Protein 6)-Dependent and -Independent Vascular Smooth Muscle Cell Plasticity and Intimal Hyperplasia. Arteriosclerosis Thrombosis And Vascular Biology 2018, 39: 250-262. PMID: 30567484, PMCID: PMC6365015, DOI: 10.1161/atvbaha.118.311830.Peer-Reviewed Original ResearchConceptsInjury-induced intimal hyperplasiaIntimal hyperplasiaObstructive coronary artery diseaseVascular smooth muscle cell dedifferentiationSmooth muscle cell dedifferentiationVascular Smooth Muscle Cell PlasticityLRP6 mutant miceOverexpression of TCF7L2Coronary artery diseaseVascular smooth muscle cellsMultiple mouse modelsMuscle cell dedifferentiationWild-type littermatesSmooth muscle cellsRole of TCF7L2Smooth Muscle Cell PlasticityVascular smooth muscle cell differentiationMuscle cell plasticitySmooth muscle cell differentiationArtery diseaseSM-MHCMouse modelCell cycle inhibitorsHaploinsufficient miceHyperplasiaThe interplay of canonical and noncanonical Wnt signaling in metabolic syndrome
Abou Ziki M, Mani A. The interplay of canonical and noncanonical Wnt signaling in metabolic syndrome. Nutrition Research 2018, 70: 18-25. PMID: 30049588, PMCID: PMC6320319, DOI: 10.1016/j.nutres.2018.06.009.Peer-Reviewed Original ResearchConceptsMetabolic syndromeLow density lipoprotein clearanceVascular smooth muscle proliferationEnd-organ complicationsCanonical WntSmooth muscle proliferationLow-density lipoproteinDe novo lipogenesisInsulin receptor expressionTranscription factor 7Growth factor βRas homolog gene family member AExtracellular matrix depositionCardiometabolic abnormalitiesLiver inflammationFamily member AInsulin resistanceLipoprotein clearanceLiver fatHepatic fibrosisSevere manifestationsLDL receptor-related protein 6Receptor expressionCardiovascular diseaseMuscle proliferation
2017
Addition of Estradiol to Cross-Sex Testosterone Therapy Reduces Atherosclerosis Plaque Formation in Female ApoE−/− Mice
Goetz TG, Mamillapalli R, Sahin C, Majidi-Zolbin M, Ge G, Mani A, Taylor HS. Addition of Estradiol to Cross-Sex Testosterone Therapy Reduces Atherosclerosis Plaque Formation in Female ApoE−/− Mice. Endocrinology 2017, 159: 754-762. PMID: 29253190, PMCID: PMC5774248, DOI: 10.1210/en.2017-00884.Peer-Reviewed Original ResearchConceptsAtherosclerosis plaque formationLow-dose estradiolPlaque formationTestosterone therapyLesion progressionCross-sex hormone therapyEstradiol-treated miceLow-dose estrogenAtherosclerotic lesion progressionEffects of estrogenContribution of estradiolOil Red O stainAtherosclerosis lesion progressionAddition of estradiolWeeks of ageEstradiol therapyCardiovascular outcomesHormone therapyAortic sinusFemale ApoEAtherosclerosis progressionReduced atherosclerosisCombined therapyAortic archAtherosclerosis RiskEndothelial APLNR regulates tissue fatty acid uptake and is essential for apelin’s glucose-lowering effects
Hwangbo C, Wu J, Papangeli I, Adachi T, Sharma B, Park S, Zhao L, Ju H, Go GW, Cui G, Inayathullah M, Job JK, Rajadas J, Kwei SL, Li MO, Morrison AR, Quertermous T, Mani A, Red-Horse K, Chun HJ. Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin’s glucose-lowering effects. Science Translational Medicine 2017, 9 PMID: 28904225, PMCID: PMC5703224, DOI: 10.1126/scitranslmed.aad4000.Peer-Reviewed Original ResearchConceptsGlucose-lowering effectImpaired glucose utilizationForkhead box protein O1Glucose utilizationType 2 diabetes mellitusEndothelial cellsApelin/APLNRSkeletal muscleTissue fatty acid uptakeType 2 diabetesImportant clinical challengeFatty acid uptakeEndothelial-specific deletionBox protein O1FABP4 inhibitionCardiovascular outcomesPeptide apelinDiabetes mellitusGlucose loweringFatty acidsInsulin sensitivityEndothelial expressionClinical challengeFABP4 expressionMetabolic disordersWnt signaling, a novel pathway regulating blood pressure? State of the art review
Ziki M, Mani A. Wnt signaling, a novel pathway regulating blood pressure? State of the art review. Atherosclerosis 2017, 262: 171-178. PMID: 28522145, PMCID: PMC5508596, DOI: 10.1016/j.atherosclerosis.2017.05.001.Peer-Reviewed Original ResearchConceptsBP regulationType 2 diabetes mellitusBlood pressure targetsPathogenesis of hypertensionTight BP controlTherapy of hypertensionField of hypertensionReview of PubMedDrug developmentNovel drug developmentAntihypertensive TrialBP controlDifferent metabolic profilesUnique molecular pathwaysPressure targetsBlood pressureDiabetes mellitusMetabolic syndromePatient populationHypertensionStudy populationHeterogeneous diseaseReference listsPrecision Medicine InitiativeContribution of Wnt
2016
Metabolic syndrome
Ziki M, Mani A. Metabolic syndrome. Current Opinion In Lipidology 2016, 27: 162-171. PMID: 26825138, PMCID: PMC5141383, DOI: 10.1097/mol.0000000000000276.Peer-Reviewed Original ResearchConceptsMetabolic traitsGenome-wide association studiesCognate pathwaysDiverse traitsMultifactorial heritabilityDisease genesAssociation studiesGenetic studiesTraitsGenetic investigationsCommon variantsDisease mechanismsGenetic causeGenetic risk factorsHomogenous populationDisease pathophysiologyQuantitative distributionGenesVariantsHeritabilityExtreme endsSubstantial progressKindredsPathwayLarge effect
2015
Impaired LRP6-TCF7L2 Activity Enhances Smooth Muscle Cell Plasticity and Causes Coronary Artery Disease
Srivastava R, Zhang J, Go GW, Narayanan A, Nottoli TP, Mani A. Impaired LRP6-TCF7L2 Activity Enhances Smooth Muscle Cell Plasticity and Causes Coronary Artery Disease. Cell Reports 2015, 13: 746-759. PMID: 26489464, PMCID: PMC4626307, DOI: 10.1016/j.celrep.2015.09.028.Peer-Reviewed Original ResearchConceptsCoronary artery diseaseLRP6 activityArtery diseaseObstructive coronary artery diseaseHigh-fat dietVascular smooth muscle cell differentiationMuscle cell plasticitySmooth muscle cell differentiationAtherosclerotic burdenMedial hyperplasiaCarotid injuryArterial diseaseVascular obstructionNeointima formationTherapeutic targetWnt3a administrationIntact WntVSMC differentiationKnockout backgroundDiseaseMiceVessel wallNon-canonical WntCoreceptor LRP6Cell plasticityNew targets to treat obesity and the metabolic syndrome
Martin KA, Mani MV, Mani A. New targets to treat obesity and the metabolic syndrome. European Journal Of Pharmacology 2015, 763: 64-74. PMID: 26001373, PMCID: PMC4573317, DOI: 10.1016/j.ejphar.2015.03.093.Peer-Reviewed Original ResearchConceptsMetabolic syndromeCardiovascular diseaseGlucagon-like peptide-1 receptor agonistsPancreatic lipase inhibitor orlistatSingle CVD risk factorPeptide-1 receptor agonistsCVD risk factorsEpidemic of obesityLong-term treatmentType 2 diabetesLipase inhibitor orlistatDipeptidyl peptidase IV inhibitorsAnti-diabetic drugsFuture drug developmentTruncal obesitySerotonergic drugsReceptor agonistRisk factorsMelanocortin systemObesityMetabolic traitsSyndromeMetabolic profileIV inhibitorsNew targets
2014
Wnt signaling, de novo lipogenesis, adipogenesis and ectopic fat
Song K, Wang S, Mani M, Mani A. Wnt signaling, de novo lipogenesis, adipogenesis and ectopic fat. Oncotarget 2014, 5: 11000-11003. PMID: 25526027, PMCID: PMC4294374, DOI: 10.18632/oncotarget.2769.Peer-Reviewed Original ResearchConceptsNon-alcoholic fatty liver diseaseFatty liver diseaseDe novo lipogenesisEctopic fatLiver diseaseNovo lipogenesisMesenchymal stem cellsElevated plasma lipidsHigher plasma triglyceridesMetabolic syndromePlasma lipidsCoronary arteryInsulin resistancePlasma triglyceridesLoss of functionWnt coreceptor LRP6Diverse congenitalPertinent findingsFunction mutationsAdipogenesisCoreceptor LRP6DiseaseStem cellsLipogenesisMajor regulatorThe Combined Hyperlipidemia Caused by Impaired Wnt-LRP6 Signaling Is Reversed by Wnt3a Rescue
Go GW, Srivastava R, Hernandez-Ono A, Gang G, Smith SB, Booth CJ, Ginsberg HN, Mani A. The Combined Hyperlipidemia Caused by Impaired Wnt-LRP6 Signaling Is Reversed by Wnt3a Rescue. Cell Metabolism 2014, 19: 209-220. PMID: 24506864, PMCID: PMC3920193, DOI: 10.1016/j.cmet.2013.11.023.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAtherosclerosisCells, CulturedFatty LiverHepatocytesHyperlipidemiasLow Density Lipoprotein Receptor-Related Protein-6Mechanistic Target of Rapamycin Complex 1Mechanistic Target of Rapamycin Complex 2MiceModels, BiologicalMultiprotein ComplexesMutationNon-alcoholic Fatty Liver DiseaseTOR Serine-Threonine KinasesWnt3A ProteinConceptsHepatic de novo lipogenesisFatty liver diseaseElevated plasma LDLTreatment of hyperlipidemiaSp1-dependent activationCholesterol biosynthesisDe novo lipogenesisAtherogenic lipid disordersMolecular genetic basisLiver diseaseFatty liverLDL levelsPlasma lipidsTG levelsLipid disordersPlasma TGPlasma LDLNovo lipogenesisHyperlipidemiaCombined HyperlipidemiaGenetic basisWnt coreceptorNonconservative mutationsAltered expressionPrimary hepatocytes
1994
Mechanism of desensitization of the cloned vasopressin V1a receptor expressed in Xenopus oocytes
Nathanson MH, Burgstahler AD, Orloff JJ, Mani A, Moyer MS. Mechanism of desensitization of the cloned vasopressin V1a receptor expressed in Xenopus oocytes. American Journal Of Physiology 1994, 267: c94-c103. PMID: 8048495, DOI: 10.1152/ajpcell.1994.267.1.c94.Peer-Reviewed Original ResearchConceptsVasopressin V1a receptorV1a receptorReceptor desensitizationXenopus oocytesCyclic monophosphateMechanism of desensitizationG protein-mediated increasesProtein-mediated increasePretreatment of oocytesSubsequent microinjectionReceptor binding sitesMin of exposureProtein kinase C.Protein kinase CCytosolic Ca2Maximal stimulationDesensitizationReceptorsPhorbol dibutyrateKinase C.Inositol trisphosphateKinase CVasopressinOocytesConfocal microscopy