Excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies afterload-induced diastolic dysfunction in the type 2 diabetic heart. (March 2015)

• Record Type: Journal Article
• Authors: Kouzu, Hidemichi; Miki, Takayuki; Tanno, Masaya; Kuno, Atsushi; Yano, Toshiyuki; Itoh, Takahito; Sato, Tatsuya; Sunaga, Daisuke; Murase, Hiromichi; Tobisawa, Toshiyuki; Ogasawara, Makoto; Ishikawa, Satoko; Miura, Tetsuji
• Is Part Of: Journal of molecular and cellular cardiology. Volume 80(2015:Mar.)
• Page Start: 136
• Page End: 145
• Publication Date: 2015-03
• Subjects: Diabetes mellitus -- Heart failure -- Diastolic function -- Metabolism; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.01.004
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Type 2 diabetes mellitus (T2DM) is often complicated with diastolic heart failure, which decompensates under increased afterload. Focusing on cardiac metabolomes, we examined mechanisms by which T2DM augments ventricular diastolic stiffness in response to pressure overloading. Pressure–volume relationships (PVRs) and myocardial metabolomes were determined at baseline and during elevation of aortic pressure by phenylephrine infusion in a model of T2DM, OLETF, and its non-diabetic control, LETO. Pressure overloading augmented diastolic stiffness without change in systolic reserve in OLETF as indicated by a left-upward shift of end-diastolic PVR. In contrast, PVRs under cardioplegic arrest in buffer-perfused isolated hearts were similar in OLETF and LETO, indicating that extracellular matrix or titin remodeling does not contribute to the afterload-induced increase in stiffness of the beating ventricle of OLETF. Metabolome analyses revealed impaired glycolysis and facilitation of the pentose phosphate pathway in OLETF. Pressure overloading significantly reduced ATP and total adenine nucleotides by 34% and 40%, respectively, in OLETF but not in LETO, while NADH-to-NAD + ratios were similar in the two groups. The decline in ATP by pressure overloading in OLETF was associated with increased inosine 5-monophosphate and decreased adenosine levels, being consistent with the 2.5-times higher activity of cardiac AMP deaminase in OLETF. Tissue ATP level was negatively correlated with tau of LV pressure and LVEDP. These results suggest that ATP depletion due to excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies ventricular stiffening during acute pressure overloading in T2DM hearts. Highlights: Pressure overloading increased diastolic ventricular stiffness in type 2 diabetes. Augmented diastolic stiffness in diabetes was undetected under cardioplegic arrest. Pressure overloading reduced adenine nucleotides in diabetic hearts. AMP deaminase activity was up-regulated in diabetic hearts. Diastolic dysfunction was correlated with ATP depletion.