A Pathologic Role for Angiotensin Ii and Endothelin-1 in Cardiac Remodelling and Ischaemia and Reperfusion Injury in a Rat Model of the Metabolic Syndrome.
Year: 2006
Type: dissertation
Abstract: Introduction: Obesity, which is implicated in the development of the metabolic syndrome (MS) is reaching epidemic proportions worldwide.MS significantly increases the risk of developing cardiovascular disease, which includes coronary artery disease.The current absence of animal models of diet induced obesity and the MS makes the investigation of the cardiovascular consequences of MS virtually impossible.As a result the effects of the MS on cardiac function, morphology and susceptibility to ischaemia are not well understood.Aims: We set out to: 1) develop and characterize a rodent model of dietinduced obesity and the MS, 2) investigate the susceptibility of hearts from these animals to ischaemia/reperfusion induced injury and, 3) determine whether angiotensin II (Ang II) and endothelin-1 (ET-1) plays a role in cardiac remodelling and/or the severity of ischaemia and reperfusion injury in this model.Methods: Male Wistar rats were fed a standard rat chow diet or cafeteria diet (CD) for 16 weeks.After the feeding period rats were sacrificed and blood and myocardial tissue samples were collected to document biochemical changes in these animals.Hearts were perfused on the isolated working rat heart perfusion apparatus to assess myocardial mechanical function before and after ischaemia.In a separate series of experiments, hearts underwent coronary artery ligation to determine the incidence and duration of ventricular arrhythmias during ischaemia and reperfusion, using electrocardiography.To assess a iii possible link between myocardial remodelling and ischaemia/reperfusion injury and myocardial Ang II and ET-1 content, we also measured these peptides under basal conditions and during ischaemia.Two-dimensional targeted Mmode echocardiography was used to assess in vivo myocardial mechanical function in control and obese rats.Results: After 16 weeks on the CD, obese rats satisfied the World Health Organization (WHO) criteria for the MS by having visceral obesity, insulin resistance, dyslipidaemia and an elevated systolic blood pressure, compared to control rats.Circulating Ang II levels, but not ET-1 levels, were elevated in CD fed rats.Obese rats had cardiac hypertrophy and ex vivo basal myocardial mechanical function was depressed in the CD fed rat hearts compared to control rat hearts.CD fed rat hearts had poorer aortic output (AO) recoveries compared to hearts from control rats.These hearts also had a higher incidence and duration of reperfusion arrhythmias.No such functional differences were seen in the in vivo experiments.No differences in basal or ischaemic myocardial Ang II and ET-1 levels were seen in either group.Conclusion: We have developed and characterized a model of diet-induced obesity and the MS.Obesity is associated with cardiac hypertrophy and an increased myocardial susceptibility to ischaemia and reperfusion injury in our model.The hearts from obese rats were also more prone to reperfusion ventricular arrhythmias.As myocardial function was only poorer in the ex vivo obese animal experiments, our data suggests that the obesity associated changes in function observed in the ex vivo studies may be related to the iv absence of circulating substrates or factors, which are essential for their normal mechanical function.v UITTREKSEL Inleiding: Vetsug, wat as 'n aanleidende faktor in die ontwikkeling van metaboliese sindroom (MS) geimpliseer word, bereik tans wêreldwyd epidemiese afmetings.MS verhoog die risiko vir die ontwikkeling van kardiovaskulêre siektes soos korenêre hartvatsiekte.Die huidige gebrek aan dier modelle van dieet geinduseerde vetsug en MS, maak die ondersoek na die kardiovaskulêre gevolge van MS feitlik onmoontlik.Die effek van MS op hart funksie, morfologie en vatbaarheid vir isgemiese skade is dus nog grootendeels onbekend Doel: Ons het gepoog om: 1) 'n model van dieet geinduseerde vetsug en MS te ontwikkel en karakteriseer, 2) die vatbaarheid van die harte van die diere vir isgemie/herperfusie skade te bepaal en, 3) te bepaal of angiotensien II (Ang II) en endotelien-1 (ET-1) 'n rol in miokardiale hermodulering en/of isgemiese/herperfusie skade in hierdie model speel.Metodes: Manlike Wistar rotte is vir 16 weke op 'n standaard rotkos (kontrole) of kafeterie dieet (KD) geplaas.Aan die einde van die voerprogram is rotte geslag en bloed en miokardiale weefsel is versamel vir biochemiese bepalings.Harte is op die werkhart perfusie aparaat geperfuseer en meganiese funksie is voor, en na isgemie bepaal.In 'n apparte reeks eksperimente is die koronêre arterie van harte afgebind en die insidensie van aritmieë gedurende isgemie en herperfusie is met behulp van elektrokardiografie bepaal.Om 'n moontlike verband tussen miokardiale hermodulering en isgemie/reperfiesie skade te bepaal is hartspierweefsel versamel en basale en isgemiese Ang II en ET-1 vi vlakke bepaal.Twee dimensionele "M-mode" egokardiografie is gebruik om in vivo miokardiale funksie in kontrole en vetsugtige rotte te bepaal.Resultate: Na 16 weke op die KD het die vet rotte aan die kriteria van die WGO vir MS voldoen.Hulle was viseraal vetsugtig, insulien weerstandig, en het abnormale lipied profiele en verhoogde sistoliese bloeddrukke gehad.Sirkulerende Ang II vlakke was verhoog in KD gevoerde rotte terwyl ET-1 vlakke onveranderd was.Vetsugtige rotte het hipertrofiese harte gehad en basale meganiese funksie was verlaag in vergelyking met kontrole rotte.Die KD gevoerde rotte het swakker aorta uitset herstelle getoon as die kontrole diere.Die harte het ook 'n hoer insidensie van herperfusie aritmieë getoon.Daar was egter geen verskil in meganiese funksie in die in vivo eksperimente nie.Basale en isgemiese Ang II en ET-1 vlakke was vergelykbaar in die miokardium van die twee groepe diere.Gevolgtrekkings: Ons het 'n model van dieet geindieseerde vetsug en MS ontwikkel en gekarakteriseer.Vetsug word in ons model geassosieer met miokardiale hipertrofie en verhoogde vatbaarheid vir isgemie/herperfusie skade.Die harte van vetsugtige rotte was ook meer vatbaar vir herperfusie aritmieë.Die waarneeming dat meganiese funksie slegs in die ex vivo eksperimente in vetsugtige diere verlaag was, dui aan dat die verlaagde funksie dalk te wyte is aan die afwesigheid van sirkulerende substraat of faktore wat vir normale meganiese funksie van die hart noodsaaklik is.
Author: Wayne Smith
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W297652006