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Advances in Biochemistry in Health and Disease Naranjan S. Dhalla Sukhwinder K. Bhullar Anureet K. Shah Editors The Renin Angiotensin System in Cardiovascular Disease Advances in Biochemistry in Health and Disease Volume 24 SeriesEditor NaranjanS.Dhalla,InstituteofCardiovascularSciences,St.BonifaceHospital, Winnipeg,MB,Canada EditorialBoard RobertoBolli,Medicine&CardiologyDepartment,3rdFloor,Universityof Louisville,Louisville,KY,USA RameshGoyal,DelhiPharmaceuticalSciences&Research,NewDelhi,India ChandrasekharanKartha,CardiovascularDiseasesandDiabetesBiology,Kerala InstituteofMedicalSciences,Thiruvananthapuram,Kerala,India LorrieKirshenbaum,St.BonifaceGeneralHospital,Winnipeg,MB,Canada NaokiMakino,KyushuUniversity,Fukuoka,Japan JawaharL.Mehta,DivisionofCardiology,UniversityofArkansasforMedical Sciences,LittleRock,AR,USA BohuslavOstadal,InstituteofPhysiology,CzechAcademyofSciences,Prague, CzechRepublic GrantN.Pierce,St.BonifaceGeneralHospital,Winnipeg,MB,Canada JanSlezak,InstituteforHeartResearch,SlovakAcademyofSciences,Karlova Ves,Slovakia AndrasVarro,Pharmacology&Pharmacotherapy,UniversityofSzeged,Szeged, Hungary KarlWerdan,MartinLutherUniversityHalle-Wittenber,Halle(Saale), Sachsen-Anhalt,Germany WilliamB.Weglicki,SchoolofMedicineandHealthSciences,GeorgeWashington University,Washington,USA AdvancesinBiochemistryinHealthandDiseasefocusonthelatestdevelopments in biochemical research with implications for health and disease. This book series consists of original edited volumes and monographs, presented by leading experts inthefieldandprovidesanuptodateanduniquesourceofinformationforallthose interestedinthefundamental,biochemicalprocessesofthelatestandemergingtopics andtechniques. Covering a wide variety of topics, this book series is a valuable source of informationfromthoseatthelabbenchthroughtotheHealthCareworkers. · · Naranjan S. Dhalla Sukhwinder K. Bhullar Anureet K. Shah Editors The Renin Angiotensin System in Cardiovascular Disease Editors NaranjanS.Dhalla SukhwinderK.Bhullar InstituteofCardiovascularSciences InstituteofCardiovascularSciences St.BonifaceHospitalAlbrecthsen St.BonifaceHospitalAlbrecthsenResearch ResearchCentre Centre UniversityofManitoba UniversityofManitoba Winnipeg,MB,Canada Winnipeg,MB,Canada AnureetK.Shah SchoolofKinesiology,Nutritionand FoodScience CaliforniaStateUniversity LosAngeles,CA,USA ISSN 2512-2142 ISSN 2512-2150 (electronic) AdvancesinBiochemistryinHealthandDisease ISBN 978-3-031-14951-1 ISBN 978-3-031-14952-8 (eBook) https://doi.org/10.1007/978-3-031-14952-8 ©TheEditor(s)(ifapplicable)andTheAuthor(s),underexclusivelicensetoSpringerNature SwitzerlandAG2023 Thisworkissubjecttocopyright.AllrightsaresolelyandexclusivelylicensedbythePublisher,whether thewholeorpartofthematerialisconcerned,specificallytherightsoftranslation,reprinting,reuse ofillustrations,recitation,broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,and transmissionorinformationstorageandretrieval,electronicadaptation,computersoftware,orbysimilar ordissimilarmethodologynowknownorhereafterdeveloped. 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ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSwitzerlandAG Theregisteredcompanyaddressis:Gewerbestrasse11,6330Cham,Switzerland Preface Thereninangiotensinsystem(RAS)isakeyregulatorymechanisminthebodyandis knowntoplayacriticalroleincardiovascularphysiologyandpathophysiology.This systemisaccountableformaintainingarterialbloodpressureandelectrolytehome- ostasis,aswellasregulatingorganperfusion.Underpathologicalconditions,RAS elicitsitsresponsebytriggeringoxidativestress,inflammation,aswellasfunctional andstructuralremodelingofboththebloodvesselsandmyocardium.Byinducing cardiovasculardamage,itparticipatesinthepathogenesisofcardiovascularabnor- malitiessuchashypertension,ischemicheartdisease,andheartfailure.Itispointed outthatcardiovasculardiseasesarethenumberonecauseofdeathworldwide,with themorbidityandmortalityrateofmorethan36%ofalldeaths.Anin-depthstudy of the RAS, under both experimental and clinical settings, has revealed the thera- peuticefficacyoftheblockadeofthissystembyvariouspharmacologicalagentsin reducingcardiovascularandrelatedevents.Treatmentofthepatientshavingcardio- vascular abnormalities with angiotensin-converting enzyme (ACE) inhibitors and angiotensinIItype1receptor(AT R)blockers,aloneorincombination,hassignif- 1 icantlyimprovedtheglobalmortalityandmorbidity.Itisalsowellknownthatthe RASispresentinboththeperipheralsystemanddifferenttissuesandisinvolvedin theformationofangiotensinII(AngII)duetotheparticipationofvariouscompo- nents, including ACE. The circulating Ang II affects different organs in the body upon binding to its receptor Ang II type 1, located at the plasma membrane. It then activates signal transduction mechanisms in the cell leading to a variety of biological effects such as vasoconstriction, sodium retention, hypertension, aldos- teroneandvasopressinproduction,plateletactivation,endothelialdysfunction,cell growth, connective tissue formation, as well as inflammatory, fibrotic, and oxida- tive stress activities. On the other hand, the activation of the angiotensin II type 2 receptormitigatesthegrowth-promotingandothereffectsoftheangiotensinIItype 1receptorstimulation.Thus,RAScanbeseentoexertmultifactorial(bothharmful andbeneficial)effectsinthebody. v vi Preface Sinceseveralstudiesunderlyingphysiological,pathologicalaswellaspharmaco- logicalaspectsofRAScomponentshaveremainedafocusofcardiovascularhealth anddiseaseoverthepastdecades,thepresentbookintendstosummarizethecurrent status regarding the role of RAS in cardiovascular diseases. Due to a direct link to neurohormonal dysregulation and cellular dysfunction, excessive activation of RASanditsinteractionwithdifferenthormonesareconsideredessentialmodulatory mechanisms,whichareinvolvedininducingcardiovascularabnormalities.Thisbook describestheroleofRASinthepathophysiologyofhypertension,atherosclerosis, and ischemic heart disease with particular focus on vascular remodeling, cardiac dysfunction, arrhythmias, and heart failure under various stressfulconditions such as pressure and volume overload as well as myocardial infarction. In this context, the molecular and biochemical regulation, genetic and mechanistic approaches, as well as signaling transduction pathways in the pathogenesis of these diseases are discussed. Despite the progress and achievements, in the area of neurohormonal treatments,thegrowingglobalburdenimposedbythesediseasesisemphasized.A frameworkofcurrentandfuturistictreatmentoptionstargetingRASforthepreven- tionorreversalofcardiovascularandinfectiousdiseases,aswellasthetranslational successforcontrollingtheexpressionofRAS,isaddressed.Inviewofthefactthat prolongedactivationofRASisknowntoinduceinflammation,metabolicalterations, oxidativestress,andCa2+-handlingabnormalities,someinformationonthesemech- anismsofdefectswithorwithoutACEinhibitorsandAT Rantagoniststreatments 1 ofdiseasedsubjectsisincluded. This book is assembled to contain 25 chapters by international experts in the fieldofRASincardiovascularhealthanddisease.Overall,thismonographprovides recent developments in our understanding of alterations in RAS due to different risk factors for cardiovascular disease, as well as highlighting the potential phar- macological approaches for targeting RAS to improve cardiac function in clinical situations. The 25 chapters of this book are arranged in three different parts, namely:PartI–ModulatoryAspectsofReninAngiotensinSystem(9chapters),Part II–Pathophysiological Aspects of the Renin Angiotensin System (9 chapters), and Part III–Pharmacotherapeutic Aspects of Renin Angiotensin System (7 chapters). Allthesethreepartsofthebookareinterrelatedbecauseeachchapterwillhopefully motivate investigators to develop innovative approaches to prevent cardiovascular diseasesduetotheinvolvementofRAS.Thisbookwillalsobeparticularlyuseful formedicalstudents,fellows,residents,graduatestudents,andhealthprofessionals. It is our contention that the state-of-the-art information about the involvement of RAS in the pathogenesis of cardiovascular disease, as well as the molecular and cellular basis of its therapy provided in this book, could be helpful to biomedical andclinicalresearchers.Particularly,thedevelopmentofnewerandmoreeffective treatmentsthatcanhelpindecreasingthediseaseburdenwhileenhancingthequality andlifeexpectancywouldprovetobechallenging. Preface vii Firstofall,weareindebtedtoallcontributorsfortheirtimeandeffortsinpreparing articles for this book. We are grateful to the St. Boniface Hospital Albrechtsen Research Centre for providing infrastructural support for this project. We wish to thank Dr. Gonzalo Cordova most sincerely for his leadership, understanding, and efforts in promoting this project on the Role of RAS in Cardiovascular Disease. WealsoexpressourgratitudetoMr.RajanMuthuandhisteamfortheirexcellent assistanceinthedevelopmentaswellasproductionofthisbook. Winnipeg,Canada NaranjanS.Dhalla Winnipeg,Canada SukhwinderK.Bhullar LosAngeles,USA AnureetK.Shah Contents PartI ModulatoryAspectsofReninAngiotensinSystem 1 Renin–Angiotensin–Aldosterone System and LOX-1 Interaction inHypertension witha Focus on Modulation oftheImmuneSystem ......................................... 3 WeijiaCheng,FangShao,JawaharL.Mehta,andXianweiWang 2 ReninAngiotensinSystemandThyroidHormoneCrosstalk: FromExperimentalApproachestoClinicalPerspectives .......... 23 LauraSabatino,DarioGenovesi,andCristinaVassalle 3 Crosstalk Between Abnormal Electrical Activity and Angiotensin II Cell Signaling in the Hyperglycemic MammalianHeart ............................................ 39 BelmaTuran 4 CardiovascularPhysiopathologyofAngiotensinIIandIts PlasmaandNuclearEnvelopMembranes’Receptors ............. 63 DanielleJacquesandGhassanBkaily 5 Epigenetic miRNA Mediated Regulation of RAS inCardiovascularDiseases ..................................... 81 AylinCaliskan,SamanthaA.W.Crouch,andSeemaDangwal 6 EpigeneticsChangesinReninAngiotensinSystem(RAS): ApplicationofBiosensorsforMonitoringTheseChanges ......... 105 ZahraSepehri, ZohrehKiani, FarkhondeSarhaddi, MehdiSepehri, SurandiKrishnaKumariWaduMesthri, andHasanBagheri 7 GeneticPolymorphismsintheRenin-Angiotensin-Aldosterone System ....................................................... 115 TomaszRechcin´ski ix x Contents 8 Mitochondria:AKeyProtagonistoftheReninAngiotensin System ....................................................... 131 RiniVargheseandAnuradhaMajumdar 9 TheReninAngiotensinSystemattheTimeofCOVID-19 ......... 145 KarstenGrote, JulianKreutz, Ann-ChristinSchaefer, BirgitMarkus,andBernhardSchieffer PartII PathophysiologicalImplicationsofReninAngiotensin System 10 AYing-YangPerspectiveontheReninAngiotensinSystem inCardiovascularDisease ...................................... 159 SarfarazAhmadandCarlosM.Ferrario 11 Central Control of Sympathetic and Renin Angiotensin SystemintheDevelopmentofHypertension ..................... 173 PaulGanguly, AlyamanAlmiro, AhmadDawalibi, TarekAlMahayni,andKhalidSaidMohammad 12 RoleReninAngiotensinSysteminHypertension ................. 187 PrithivirajNagarajan 13 Comparing the Influence of Angiotensin II and TGFβ 1 on Cardiac Fibroblasts; Myofibroblast Plasticity andResistancetoApoptosis .................................... 201 BesherAbual’anaz,SunilG.Rattan,andIanM.C.Dixon 14 RoleofReninAngiotensinSysteminthePathophysiology of Coronary Heart Disease: Advancements in Diagnosis, TherapyandPreventiveStrategies .............................. 211 JinitK.Mehta, MeheliA.Banerjee, PriyankaH.Shah, GinpreetKaur,andHarpalS.Buttar 15 ReninAngiotensinSysteminthePathophysiologyofDiabetic CardiomyopathyinType2Diabetes ............................. 237 KarinaP.Gomes,AnshulS.Jadli,andVaibhavB.Patel 16 Renin Angiotensin System and Obesity-Related Organ Damage ...................................................... 259 IsabelGalceranandAnnaOliveras 17 ReninAngiotensinSysteminAgingandRegeneration ............ 275 NehaRawal,AnupamMittal,andMadhuKhullar 18 ReninAngiotensinSystemintheMaturationandFailure ofArterio-VenousFistula ...................................... 291 VikrantRaiandDevendraK.Agrawal