Agonist-Induced Hypertrophy and Diastolic Dysfunction Are Associated With Selective Reduction in Glucose Oxidation A Metabolic Contribution to Heart Failure With Normal Ejection Fraction

作者：Mori Jun; Basu Ratnadeep; McLean Brent A; Das Subhash K; Zhang Liyan; Patel Vaibhav B; Wagg Cory S; Kassiri Zamaneh; Lopaschuk Gary D; Oudit Gavin Y^*

来源：Circulation-Heart Failure, 2012, 5(4): 493-503.

DOI：10.1161/CIRCHEARTFAILURE.112.966705

• angiotensin II
• cardiac metabolism
• diastolic dysfunction
• heart failure
• phenylephrine
• pyruvate dehydrogense 4

Background-Activation of the renin-angiotensin and sympathetic nervous systems may alter the cardiac energy substrate preference, thereby contributing to the progression of heart failure with normal ejection fraction. We assessed the qualitative and quantitative effects of angiotensin II (Ang II) and the alpha-adrenergic agonist, phenylephrine (PE), on cardiac energy metabolism in experimental models of hypertrophy and diastolic dysfunction and the role of the Ang II type 1 receptor.
Methods and Results-Ang II (1.5 mg.kg(-1).day(-1)) or PE (40 mg.kg(-1).day(-1)) was administered to 9-week-old male C57/BL6 wild-type mice for 14 days via implanted microosmotic pumps. Echocardiography showed concentric hypertrophy and diastolic dysfunction, with preserved systolic function in Ang II- and PE-treated mice. Ang II induced marked reduction in cardiac glucose oxidation and lactate oxidation, with no change in glycolysis and fatty acid beta-oxidation. Tricarboxylic acid acetyl coenzyme A production and ATP production were reduced in response to Ang II. Cardiac pyruvate dehydrogenase kinase 4 expression was upregulated by Ang II and PE, resulting in a reduction in the pyruvate dehydrogenase activity, the rate-limiting step for carbohydrate oxidation. Pyruvate dehydrogenase kinase 4 upregulation correlated with the activation of the cyclin/cyclin-dependent kinase-retinoblastoma protein-E2F pathway in response to Ang II. Ang II type 1 receptor blockade normalized the activation of the cyclin/cyclin-dependent kinase-retinoblastoma protein-E2F pathway and prevented the reduction in glucose oxidation but increased fatty acid oxidation.
Conclusions-Ang II- and PE-induced hypertrophy and diastolic dysfunction is associated with reduced glucose oxidation because of the cyclin/cyclin-dependent kinase-retinoblastoma protein-E2F-induced upregulation of pyruvate dehydrogenase kinase 4, and targeting these pathways may provide novel therapy for heart failure with normal ejection fraction. (Circ Heart Fail. 2012; 5: 493-503.)

• 出版日期2012-7