Abstract
RationaleHigh-fat diet with obesity-associated co-morbidities triggers cardiac remodeling and renders the heart more vulnerable to ischemia/reperfusion injury. However, the effect of high-fat diet without obesity and associated co-morbidities is presently unknown.ObjectivesTo characterize a non-obese mouse model of high-fat diet, assess the vulnerability of hearts to reperfusion injury and to investigate cardiac cellular remodeling in relation to the mechanism(s) underlying reperfusion injury.Methods and ResultsFeeding C57BL/6J male mice high-fat diet for 20 weeks did not induce obesity, diabetes, cardiac hypertrophy, cardiac dysfunction, atherosclerosis or cardiac apoptosis. However, isolated perfused hearts from mice fed high-fat diet were more vulnerable to reperfusion injury than those from mice fed normal diet. In isolated cardiomyocytes, high-fat diet was associated with higher diastolic intracellular Ca2+ concentration and greater damage to isolated cardiomyocytes following simulated ischemia/reperfusion. High-fat diet was also associated with changes in mitochondrial morphology and expression of some related proteins but not mitochondrial respiration or reactive oxygen species turnover rates. Proteomics, western blot and high-performance liquid chromatography techniques revealed that high-fat diet led to less cardiac oxidative stress, higher catalase expression and significant changes in expression of putative components of the mitochondrial permeability transition pore (mPTP). Inhibition of the mPTP conferred relatively more cardio-protection in the high-fat fed mice compared to normal diet.ConclusionsThis study shows for the first time that high-fat diet, independent of obesity-induced co-morbidities, triggers changes in cardiac oxidative state, calcium handling and mitochondria which are likely to be responsible for increased vulnerability to cardiac insults.
Highlights
This study shows for the first time that high-fat diet, independent of obesity-induced co-morbidities, triggers changes in cardiac oxidative state, calcium handling and mitochondria which are likely to be responsible for increased vulnerability to cardiac insults
High-fat diet causes cardiac alterations which can be the result of direct effects on the heart or indirectly as a result of obesity and associated pathologies [1,2,3]
Feeding C57BL/6J mice high-fat diet for 20 weeks resulted in elevated blood cholesterol and triglycerides and was associated with a small (,3%) but significant increase in body weight compared to mice fed normal diet (Table 1)
Summary
High-fat diet causes cardiac alterations which can be the result of direct effects on the heart (e.g. by altering cardiac metabolism) or indirectly as a result of obesity and associated pathologies (e.g. diabetes, hypertension, cardiac hypertrophy, ischemia, fibrosis and heart failure) [1,2,3]. High-fat diet triggers cardiac mitochondrial abnormalities (functional and structural) under normal and pathological conditions [14,15] which includes an increase in mitochondrial permeability transition pore (mPTP) opening in interfibrillar mitochondria [16,17]. The latter could explain why feeding rodents an obesity-generating high-fat diet increases vulnerability of hearts to ischemia/reperfusion (I/R) [18,19,20] whilst lipid-lowering drugs reduce the incidence of ischemia-induced ventricular arrhythmias and decrease infarct size after I/R [21,22]. The vulnerability is independent of whether the perfusate contains lipids or not [25]
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