The impact of obesity and chronic PPAR Alpha agonist treatment on cardiac function, metabolism and ischaemic tolerance

Smith, Wayne (2012-03)

Thesis (PhD)--Stellenbosch University, 2012.


ENGLISH ABSTRACT: Background: Myocardial oxidative fuel supply is increased in obese conditions. How this metabolic environment and altered cardiometabolic phenotype associated with prediabetic obesity impacts on cardiac function and tolerance to ischaemia/reperfusion injury remains uncertain. While obese individuals are likely to be treated with PPARα agonists, controversy exists as to how activation of the PPARα receptor influences cardiovascular function and post-ischaemic recovery. Aims: To determine in a model of hyperphagia-induced obesity 1) whether protracted obesity is associated with left ventricular (LV) mechanical dysfunction; 2) the responsiveness of these hearts to insulin stimulation; 3) whether insulin can afford cardioprotection against ischaemia/reperfusion damage; and 4) how obesity and chronic PPARα agonist (K-111) treatment influences myocardial function, substrate metabolism, mitochondrial function and post-ischaemic outcomes. Methods: Male Wistar rats were fed standard rat chow or a high caloric diet. 1) In vivo LV mechanical function was assessed echocardiographically in 32 week fed animals. Ex vivo LV function was measured in the presence of glucose, insulin and/or fatty acid (FA); 2) Ex vivo myocardial insulin sensitivity was assessed by measuring insulin stimulated glycolytic flux in 16 week fed rats. Insulin was also administered prior to and during regional ischaemia to determine its effect on post-ischaemic function and infarct size; 3) K-111 was added to the drinking water during the last 10 weeks of feeding (feeding period of 18 weeks); a) Ventricular mitochondrial function was determined polarographically in the presence of either glutamate or palmitoyl-L-carnitine as substrates; b) Myocardial carbohydrate and lipid metabolism, and in a separate series of perfusions, myocardial infarct size were determined in the presence of physiological or high insulin (30 or 50μIU/ml) and FA (0.7 or 1.5mM) concentrations. Results: 1) Obese animals maintained normal in vivo LV mechanical function. Glucose perfused hearts from obese animals had depressed aortic outputs compared to the control group (32.58±1.2 vs. 46.17±0.91 ml/min; p<0.001) which was abolished by the presence of FA; 2) Hearts from obese animals had reduced insulin stimulated glycolytic flux rates (1.54±0.42 vs. 2.16±0.57 μmol/g ww/min, p<0.01). Although insulin reduced infarct size in the obese group (20.94±1.60 vs. 41.67±2.09 %, p<0.001), its cardioprotective effect was attenuated in the presence of FA; 3) By simulating the in vivo metabolic environment of control and obese animals in ex vivo perfusions, elevated insulin and FA levels associated with obesity increased infarct sizes in the obese group compared to the control group (47.44±3.13 vs. 37.17±2.63 %, p<0.05); 4) While chronic K-111 treatment reversed systemic metabolic abnormalities associated with obesity, neither obesity nor the drug influenced myocardial and mitochondrial function or postischaemic outcomes. K-111 was able to reduce palmitate oxidation in the obese group. Conclusion: Elevated levels of circulating FFA may be important in maintaining normal LV mechanical function in the obese condition. While obesity had no impact on myocardial mitochondrial function and post-ischaemic outcomes during comparable perfusion conditions, the specific metabolic environment associated with obesity may augment post-ischaemic injury. K-111 is effective in reducing obesity related metabolic abnormalities, but has no effects on myocardial function, mitochondrial function or ischaemic tolerance.

AFRIKAANSE OPSOMMING: Agtergrond: Miokardiale oksidatiewe substraat voorsiening is verhoog in vetsug. Hoe hierdie metaboliese omgewing en veranderde miokardiale metaboliese fenotipe in prediabetiese vetsug miokardiale funksie en iskemie/herperfusie skade beïnvloed, is onseker. Alhoewel vetsugtige individue met PPARα agoniste behandel kan word, is die resultate verkry van hierdie reseptor aktivering op miokardiale funksie en iskemiese skade teenstrydig. Doelwitte: Om te bepaal of 1) verlengde vetsug linker ventrikulêre (LV) funksie beïnvloed; 2) hierdie harte sensitief vir insulien stimulasie is; 3) insulien die hart teen iskemie/herperfusie beskadiging beskerm; en of 4) vetsug en chroniese K-111 behandeling miokardiale funksie, substraat metabolisme, mitochondriale funksie en post-iskemiese herstel in vetsugtige, insulienweerstandige rotte beïnvloed. Metodes: Manlike Wistar rotte is met gewone rotkos, of ʼn hoé kalorie dieet gevoer. 1) In vivo LV funksie in 32 week gevoerde rotte is met behulp van eggokardiografie bepaal. Ex vivo LV funksie is met of sonder insulien en/of vetsure in die perfusaat bepaal; 2) Die ex vivo insuliensensitiwiteit is in 16 weke gevoerde rotte bepaal deur miokardiale glikolise te meet. Insulien is ook voor en tydens streeksiskemie toegedien, ten einde sy effek op miokardiale beskerming te bepaal; 3) K-111 is in die drink water van rotte toegedien vir die laaste 10 weke van hul dieet (voedingsperiode van 18 weke); a) Ventrikulêre mitochondriale funksie is polarografies bepaal in die aanwesigheid van glutamaat of palmitiel-L-karnitien; b) Miokardiale koolhidraat- en lipied metabolisme, en in ʼn aparte groep rotte, infarktgrootte, is bepaal in die teenwoordigheid van fisiologiese of hoë insulien- (30 of 50μIU/ml) en vetsuurvlakke (0.7 of 1.5mM). Resultate: 1) Vetsugtige rotte het normale in vivo LV funksie gehandhaaf. Glukose geperfuseerde harte van vet rotte se LV funksie was laer as die van kontroles (Aorta omset: 32.58±1.2 vs. 46.17±0.91 ml/min; p<0.001), maar dit het verbeter in teenwoordigheid van vetsure; 2) Harte van vetsugtige rotte het verlaagde insuliengestimuleerde glikolise getoon (1.54±0.42 vs. 2.16±0.57 μmol/g ww/min, p<0.01). Alhoewel insulien infarktgrootte in die vetsugtige groep verlaag het (20.94±1.60 vs. 41.67±2.09 %, p<0.001), is sy beskermende effekte in die teenwoordigheid van vetsure verlaag; 3) deur die in vivo metaboliese omgewing van kontrole en vetsugtige rotte in die perfusaat van die harte ex vivo te simuleer, is dit aangetoon dat die verhoogde vlakke van insulien en vetsure, geassosieer met vetsugtigheid, infarktgroottes in die vetsugtige groep teenoor die kontrole groep verhoog het (47.44±3.13 vs 37.17±2.63 %, p<0.05); 4) Hoewel chroniese gebruik van K-111 die metaboliese abnormaliteite gepaardgaande met vetsug normaliseer het, het beide vetsug en die middel geen invloed op miokardiale of mitochondriale funksie of vatbaarheid vir iskemiese beskadiging gehad nie. K-111 het miokardiale palmitaatoksidasie in die vetsugtige behandelde groep verlaag. Gevolgtrekking: Verhoogde bloed vetsuurvlakke in vetsug mag n belangrike rol in die handhawing van sistoliese funksie speel. Dit blyk dat die spesifieke in vivo omgewing geassosieer met vetsug wel tot verhoogte vatbaarheid vir iskemie/herperfusie skade mag lei. K-111 is effektief om die sistemiese metaboliese abnormaliteite gepaard met vetsugtigheid te verbeter, maar het geen effek op miokardiale funksie, mitochondriale funksie of vatbaarheid vir iskemie gehad nie.

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