期刊
FRONTIERS IN CARDIOVASCULAR MEDICINE
卷 5, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fcvm.2018.00017
关键词
pyruvate dehydrogenase; glucose oxidation; diabetic cardiomyopathy; cardiac function; diastolic dysfunction
资金
- Heart and Stroke Foundation of Canada
- Saudi Arabian Ministry of Higher Education
Obesity and type 2 diabetes (T2D) increase the risk for cardiomyopathy, which is the presence of ventricular dysfunction in the absence of underlying coronary artery disease and/or hypertension. As myocardial energy metabolism is altered during obesity/T2D (increased fatty acid oxidation and decreased glucose oxidation), we hypothesized that restricting myocardial glucose oxidation in lean mice devoid of the perturbed metabolic milieu observed in obesity/T2D would produce a cardiomyopathy phenotype, characterized via diastolic dysfunction. We tested our hypothesis via producing mice with a cardiac-specific gene knockout for pyruvate dehydrogenase (PDH, gene name Pdha1), the rate-limiting enzyme for glucose oxidation. Cardiac-specific Pdha1 deficient (Pdha1(Cardiac-/-)) mice were generated via crossing a tamoxifen-inducible Cre expressing mouse under the control of the alpha-myosin heavy chain (alpha MHC-MerCreMer) promoter with a floxed Pdha1 mouse. Energy metabolism and cardiac function were assessed via isolated working heart perfusions and ultrasound echocardiography, respectively. Tamoxifen administration produced an similar to 85% reduction in PDH protein expression in Pdha1(Cardiac-/-) mice versus their control littermates, which resulted in a marked reduction in myocardial glucose oxidation and a corresponding increase in palmitate oxidation. This myocardial metabolism profile did not impair systolic function in Pdha1(Cardiac-/-) mice, which had comparable left ventricular ejection fractions and fractional shortenings as their aMHC-MerCreMer control littermates, but did produce diastolic dysfunction as seen via the reduced mitral E/A ratio. Therefore, it does appear that forced restriction of glucose oxidation in the hearts of Pdha1(Cardiac-/-) mice is sufficient to produce a cardiomyopathy-like phenotype, independent of the perturbed metabolic milieu observed in obesity and/or T2D.
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