Agonist-induced hypertrophy and diastolic dysfunction are associated with selective reduction in glucose oxidation: a metabolic contribution to heart failure with normal ejection fraction.
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 α-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.


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 β-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.
Department of Pediatrics and Pharmacology, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada.
Jun
J
Mori
Ratnadeep
R
Basu
Brent A
BA
McLean
Subhash K
SK
Das
Liyan
L
Zhang
Vaibhav B
VB
Patel
Cory S
CS
Wagg
Zamaneh
Z
Kassiri
Gary D
GD
Lopaschuk
Gavin Y
GY
Oudit
D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D050684:E2F Transcription Factors / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006333:Heart Failure / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010656:Phenylephrine; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D014463:Ultrasonography; D016276:Ventricular Function / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D050684:E2F Transcription Factors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D044140:Receptor, Angiotensin, Type 1; D011942:Receptors, Adrenergic, alpha; D016160:Retinoblastoma Protein; D000804:Angiotensin II; D010656:Phenylephrine; D017346:Protein Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases; D005947:Glucose