Alterations in Cardiac Metabolism

Insulin resistance is viewed as an insufficiency in insulin action, with glucocorticoids being recognized to play a key role in its pathogenesis. With insulin resistance, metabolism in multiple organ systems such as skeletal muscle, liver, and adipose tissue is altered. These metabolic alterations are widely believed to be important factors in the morbidity and mortality of cardiovascular disease. More importantly, clinical and experimental studies have established that metabolic abnormalities in the heart per se also play a crucial role in the development of heart failure. Following glucocorticoids, glucose utilization is compromised in the heart. This attenuated glucose metabolism is associated with altered fatty acid supply, composition, and utilization. In the heart, elevated fatty acid use has been implicated in a number of metabolic, morphological, and mechanical changes and, more recently, in “lipotoxicity”. In the present article, we review the action of glucocorticoids, their role in insulin resistance, and their influence in modulating peripheral and cardiac metabolism and heart disease.

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Cardiac Metabolism

Physiological Reviews ◽

10.1152/physrev.1965.45.2.171 ◽

1965 ◽

Vol 45 (2) ◽

pp. 171-213 ◽

Cited By ~ 245

Author(s):

Richard J. Bing

Keyword(s):

Cardiac Metabolism

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Hypoxic Regulation of Hand1 Controls the Fetal-Neonatal Switch in Cardiac Metabolism

PLoS Biology ◽

10.1371/journal.pbio.1001666 ◽

2013 ◽

Vol 11 (9) ◽

pp. e1001666 ◽

Cited By ~ 32

Author(s):

Ross A. Breckenridge ◽

Izabela Piotrowska ◽

Keat-Eng Ng ◽

Timothy J. Ragan ◽

James A. West ◽

...

Keyword(s):

Cardiac Metabolism

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Disruption of TRPV1-mediated coupling of coronary blood flow to cardiac metabolism in diabetic mice: role of nitric oxide and BK channels

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00011.2012 ◽

2012 ◽

Vol 303 (2) ◽

pp. H216-H223 ◽

Cited By ~ 32

Author(s):

Giacinta Guarini ◽

Vahagn A. Ohanyan ◽

John G. Kmetz ◽

Daniel J. DelloStritto ◽

Roslin J. Thoppil ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Coronary Blood Flow ◽

Cardiac Metabolism ◽

Bk Channels ◽

Bk Channel ◽

Transient Receptor Potential Vanilloid ◽

Trpv1 Channels ◽

Channel Dependent

We have previously shown transient receptor potential vanilloid subtype 1 (TRPV1) channel-dependent coronary function is compromised in pigs with metabolic syndrome (MetS). However, the mechanisms through which TRPV1 channels couple coronary blood flow to metabolism are not fully understood. We employed mice lacking TRPV1 [TRPV1(−/−)], db/db diabetic, and control C57BKS/J mice to determine the extent to which TRPV1 channels modulate coronary function and contribute to vascular dysfunction in diabetic cardiomyopathy. Animals were subjected to in vivo infusion of the TRPV1 agonist capsaicin to examine the hemodynamic actions of TRPV1 activation. Capsaicin (1–100 μg·kg−1·min−1) dose dependently increased coronary blood flow in control mice, which was inhibited by the TRPV1 antagonist capsazepine or the nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (l-NAME). In addition, the capsaicin-mediated increase in blood flow was attenuated in db/db mice. TRPV1(−/−) mice exhibited no changes in coronary blood flow in response to capsaicin. Vasoreactivity studies in isolated pressurized mouse coronary microvessels revealed a capsaicin-dependent relaxation that was inhibited by the TRPV1 inhibitor SB366791 l-NAME and to the large conductance calcium-sensitive potassium channel (BK) inhibitors iberiotoxin and Penetrim A. Similar to in vivo responses, capsaicin-mediated relaxation was impaired in db/db mice compared with controls. Changes in pH (pH 7.4–6.0) relaxed coronary vessels contracted to the thromboxane mimetic U46619 in all three groups of mice; however, pH-mediated relaxation was blunted in vessels obtained from TRPV1(−/−) and db/db mice compared with controls. Western blot analysis revealed decreased myocardial TRPV1 protein expression in db/db mice compared with controls. Our data reveal TRPV1 channels mediate coupling of myocardial blood flow to cardiac metabolism via a nitric oxide-dependent, BK channel-dependent pathway that is corrupted in diabetes.

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The new cardiac metabolism

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2012.12.019 ◽

2013 ◽

Vol 55 ◽

pp. 1 ◽

Cited By ~ 3

Author(s):

Heinrich Taegtmeyer

Keyword(s):

Cardiac Metabolism

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Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.91501.2007 ◽

2008 ◽

Vol 294 (6) ◽

pp. H2889-H2897 ◽

Cited By ~ 24

Author(s):

Qianwen Wang ◽

Rajakumar V. Donthi ◽

Jianxun Wang ◽

Alex J. Lange ◽

Lewis J. Watson ◽

...

Keyword(s):

Transgenic Mice ◽

Cardiac Fibrosis ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Weight Ratio ◽

Cardiac Metabolism ◽

Heart Weight ◽

Acid Oxidation ◽

Important Regulator

During ischemia and heart failure, there is an increase in cardiac glycolysis. To understand if this is beneficial or detrimental to the heart, we chronically elevated glycolysis by cardiac-specific overexpression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) in transgenic mice. PFK-2 controls the level of fructose-2,6-bisphosphate (Fru-2,6-P2), an important regulator of phosphofructokinase and glycolysis. Transgenic mice had over a threefold elevation in levels of Fru-2,6-P2. Cardiac metabolites upstream of phosphofructokinase were significantly reduced, as would be expected by the activation of phosphofructokinase. In perfused hearts, the transgene caused a significant increase in glycolysis that was less sensitive to inhibition by palmitate. Conversely, oxidation of palmitate was reduced by close to 50%. The elevation in glycolysis made isolated cardiomyocytes highly resistant to contractile inhibition by hypoxia, but in vivo the transgene had no effect on ischemia-reperfusion injury. Transgenic hearts exhibited pathology: the heart weight-to-body weight ratio was increased 17%, cardiomyocyte length was greater, and cardiac fibrosis was increased. However, the transgene did not change insulin sensitivity. These results show that the elevation in glycolysis provides acute benefits against hypoxia, but the chronic increase in glycolysis or reduction in fatty acid oxidation interferes with normal cardiac metabolism, which may be detrimental to the heart.

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