Abstract

Vascularstiffnessisanindependentpredictorofcardiovascularmortalityindiabetesandrepresentsan understudied,butpotentiallymodifiableriskfactorfordeathinthelargeandgrowingpopulationofAmerican diabetics.However,themolecularmechanismsunderlyingdiabeticvascularstiffnessareonlyrecentlycoming tolight,andtherapeutictargetsremainelusive. Theapelin-APJsignalingaxisisapotentiallytargetablemolecularpathwaythatisdysregulatedin diabetesandactivationofwhichisassociatedwithdecreasedvascularstiffnessinhumansandmice. Importantly,preliminarydatainapelinknockoutmicesuggeststhatthisdecreasedstiffnessmayoccurinpart throughdecreasedvascularmedialfibrosis.MicroRNA-29b(MiR-29b)protectsagainstmedialfibrosisby translationalrepressionofcollagenandelastintranscripts,anditsexpressionisregulatedbycanonicalsecond messengersofapelin-APJbinding.Therefore,wehypothesizethatdiabetesdecreasesapelin/APJ signaling,leadingtoamiR-29b?dependentalterationincollagenandelastinexpressioninthe vascularmediatocauseincreasedvascularstiffness.
In SpecificAim1, Iwilluseculturedvascularsmoothmusclecellsexposedtoapelinandhyperglycemia aswellasspecificinhibitorsofcanonicalAPJsignalingtoelucidatethespecificmolecularmechanismsby whichapelinincreasesmiR-29bexpressioninthevascularmedia.
In SpecificAim2, Iwilluseamousemodelofdiabetes,theleptinknockout(db/db)mouseaswellas apelinknockoutmicetoassesstheeffectofinvivomodulationofmiR-29bexpressionandapelinondiabetic vascularstiffnessasmeasuredbyexvivopressuremyography.Specifically,IexpecttodemonstratethatmiR- 29badministrationtoapelinKOmicerescuestheirincreaseinvascularstiffness,andthatindb/dbmice,apelin administrationrescuesvascularstiffnessinamiR-29b-dependentmanner.
In SpecificAim3, Iwillexaminetheregulationofthesemolecularactorsinhumandiabetesby measuringaorticexpressionofapelin,APJ,miR-29bandmarkersofvascularmedialfibrosisindiabeticvs non-diabeticpatientswhohaveundergonecoronaryarterybypassgrafting.Thiswillconfirmthattheapelin- APJ-miR-29bpathwayisdownregulatedinhumandiabetes,makingitaviabletherapeutictargettoreduce diabeticvascularstiffness. Theproposedexperimentswillidentifymultipleputativetherapeutictargetsandprovideascaffoldon whichtostudymultiplemolecularpathwaysconvergingonvascularstiffness.Asthisrepresentsoneofthefew targetablediseaseentitiesinwhichinterventioncanpreventmortalityandimprovesymptoms,thisprojecthas thepotentialtocontributegreatlytoourtreatmentofdiabeticcardiovasculardisease.

Public Health Relevance

Diabetesisaprevalentandgrowinghealthissue,anditscardiovascularcomplicationsleadtodeadly outcomes.Vascularstiffnessisamajorriskfactorformorbidityandmortalityinthispopulation,yetno therapiesexisttoaddressit.Here,wewilldefinetheroleofaspecificmolecularpathwaythatprevents vascularstiffnessbutisdeactivatedindiabetes,thusidentifyingpotentialnoveltherapeutictargetstoprevent cardiovasculardeath.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL134233-02
Application #
9413196
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Meadows, Tawanna
Project Start
2017-02-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304