Publications by authors named "Brent A McLean"

16 Publications

  • Page 1 of 1

Revisiting the Complexity of GLP-1 Action from Sites of Synthesis to Receptor Activation.

Endocr Rev 2021 Mar;42(2):101-132

Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, Canada.

Glucagon-like peptide-1 (GLP-1) is produced in gut endocrine cells and in the brain, and acts through hormonal and neural pathways to regulate islet function, satiety, and gut motility, supporting development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. Classic notions of GLP-1 acting as a meal-stimulated hormone from the distal gut are challenged by data supporting production of GLP-1 in the endocrine pancreas, and by the importance of brain-derived GLP-1 in the control of neural activity. Moreover, attribution of direct vs indirect actions of GLP-1 is difficult, as many tissue and cellular targets of GLP-1 action do not exhibit robust or detectable GLP-1R expression. Furthermore, reliable detection of the GLP-1R is technically challenging, highly method dependent, and subject to misinterpretation. Here we revisit the actions of GLP-1, scrutinizing key concepts supporting gut vs extra-intestinal GLP-1 synthesis and secretion. We discuss new insights refining cellular localization of GLP-1R expression and integrate recent data to refine our understanding of how and where GLP-1 acts to control inflammation, cardiovascular function, islet hormone secretion, gastric emptying, appetite, and body weight. These findings update our knowledge of cell types and mechanisms linking endogenous vs pharmacological GLP-1 action to activation of the canonical GLP-1R, and the control of metabolic activity in multiple organs.
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http://dx.doi.org/10.1210/endrev/bnaa032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958144PMC
March 2021

Glucagon-Like Peptide-1 Receptor Agonists in Adult Patients With Type 2 Diabetes: Review of Cardiovascular Outcome Trials.

Can J Diabetes 2020 Feb 23;44(1):68-77. Epub 2019 Aug 23.

Sunnybrook Research Institute, Toronto, Ontario, Canada; Department of Medicine, Division of Endocrinology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada; Banting and Best Diabetes Centre, Toronto, Ontario, Canada. Electronic address:

People with type 2 diabetes are at heightened risk for developing cardiovascular (CV) events. CV disease is the leading cause of premature death among adults with type 2 diabetes. Unfortunately, historically, some antidiabetes agents were implicated in worsening CV function, despite improving glycemic and metabolic control. Accordingly, over a decade ago, health regulatory bodies modified approval requirements for novel antidiabetes pharmacotherapies, requiring prospective evaluation of CV safety through cardiovascular outcome trials (CVOTs). To meet regulatory requirements, CVOTs were primarily designed around establishing CV safety by demonstrating noninferiority to placebo in addition to standard of care, without significant differences in blood glucose. If appropriately designed and powered, however, these CVOTs could also determine superiority, and hence CV protection. Although many of these CVOTs were initiated several years ago, the recent reporting of the results for these CVOTs has been pivotal and practice-changing. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are one such class of antidiabetes therapies, wherein multiple GLP-1RA CVOTs, but interestingly, not all, have demonstrated CV benefits. In this review, we provide a comprehensive summary of all the reported CVOTs completed with GLP-1RAs to date. Although it remains unclear why some GLP-1RAs are associated with reducing CV events, whereas others have been consistent with CV safety alone, we highlight and provide an overview of some key differences between the various GLP-1RAs and their respective CVOTs and possible implications of study design differences. We also speculate on potential mechanisms of action for glucagon-like peptide-1 receptor signalling in the CV system.
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http://dx.doi.org/10.1016/j.jcjd.2019.08.011DOI Listing
February 2020

PI3Kα Pathway Inhibition With Doxorubicin Treatment Results in Distinct Biventricular Atrophy and Remodeling With Right Ventricular Dysfunction.

J Am Heart Assoc 2019 05;8(9):e010961

1 Department of Physiology University of Alberta Edmonton Canada.

Background Cancer therapies inhibiting PI 3Kα (phosphoinositide 3-kinase-α)-dependent growth factor signaling, including trastuzumab inhibition of HER 2 (Human Epidermal Growth Factor Receptor 2), can cause adverse effects on the heart. Direct inhibition of PI 3Kα is now in clinical trials, but the effects of PI 3Kα pathway inhibition on heart atrophy, remodeling, and function in the context of cancer therapy are not well understood. Method and Results Pharmacological PI 3Kα inhibition and heart-specific genetic deletion of p110α, the catalytic subunit of PI 3Kα, was characterized in conjunction with anthracycline (doxorubicin) treatment in female murine models. Biventricular changes in heart morphological characteristics and function were analyzed, with molecular characterization of signaling pathways. Both PI 3Kα inhibition and anthracycline therapy promoted heart atrophy and a combined effect of distinct right ventricular dilation, dysfunction, and cardiomyocyte remodeling in the absence of pulmonary arterial hypertension. Congruent findings of right ventricular dilation and dysfunction were seen with pharmacological and genetic suppression of PI 3Kα signaling when combined with doxorubicin treatment. Increased p38 mitogen-activated protein kinase activation was mechanistically linked to heart atrophy and correlated with right ventricular dysfunction in explanted failing human hearts. Conclusions PI 3Kα pathway inhibition promotes heart atrophy in mice. The right ventricle is specifically at risk for dilation and dysfunction in the setting of PI 3K inhibition in conjunction with chemotherapy. Inhibition of p38 mitogen-activated protein kinase is a proposed therapeutic target to minimize this mode of cardiotoxicity.
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http://dx.doi.org/10.1161/JAHA.118.010961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512135PMC
May 2019

PI3Kα-regulated gelsolin activity is a critical determinant of cardiac cytoskeletal remodeling and heart disease.

Nat Commun 2018 12 19;9(1):5390. Epub 2018 Dec 19.

Division of Cardiology, Department of Medicine, 2C2, 8440-112 St, Edmonton, AB T6G 2B7, Canada.

Biomechanical stress and cytoskeletal remodeling are key determinants of cellular homeostasis and tissue responses to mechanical stimuli and injury. Here we document the increased activity of gelsolin, an actin filament severing and capping protein, in failing human hearts. Deletion of gelsolin prevents biomechanical stress-induced adverse cytoskeletal remodeling and heart failure in mice. We show that phosphatidylinositol (3,4,5)-triphosphate (PIP3) lipid suppresses gelsolin actin-severing and capping activities. Accordingly, loss of PI3Kα, the key PIP3-producing enzyme in the heart, increases gelsolin-mediated actin-severing activities in the myocardium in vivo, resulting in dilated cardiomyopathy in response to pressure-overload. Mechanical stretching of adult PI3Kα-deficient cardiomyocytes disrupts the actin cytoskeleton, which is prevented by reconstituting cells with PIP3. The actin severing and capping activities of recombinant gelsolin are effectively suppressed by PIP3. Our data identify the role of gelsolin-driven cytoskeletal remodeling in heart failure in which PI3Kα/PIP3 act as negative regulators of gelsolin activity.
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http://dx.doi.org/10.1038/s41467-018-07812-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300608PMC
December 2018

Inactivation of the Glucose-Dependent Insulinotropic Polypeptide Receptor Improves Outcomes following Experimental Myocardial Infarction.

Cell Metab 2018 02 21;27(2):450-460.e6. Epub 2017 Dec 21.

Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada. Electronic address:

Incretin hormones exert pleiotropic metabolic actions beyond the pancreas. Although the heart expresses both incretin receptors, the cardiac biology of GIP receptor (GIPR) action remains incompletely understood. Here we show that GIPR agonism did not impair the response to cardiac ischemia. In contrast, genetic elimination of the Gipr reduced myocardial infarction (MI)-induced ventricular injury and enhanced survival associated with reduced hormone sensitive lipase (HSL) phosphorylation; it also increased myocardial triacylglycerol (TAG) stores. Conversely, direct GIPR agonism in the isolated heart reduced myocardial TAG stores and increased fatty acid oxidation. The cardioprotective phenotype in Gipr mice was partially reversed by pharmacological activation or genetic overexpression of HSL. Selective Gipr inactivation in cardiomyocytes phenocopied Gipr mice, resulting in improved survival and reduced adverse remodeling following experimental MI. Hence, the cardiomyocyte GIPR regulates fatty acid metabolism and the adaptive response to ischemic cardiac injury. These findings have translational relevance for developing GIPR-based therapeutics.
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http://dx.doi.org/10.1016/j.cmet.2017.11.003DOI Listing
February 2018

The autonomic nervous system and cardiac GLP-1 receptors control heart rate in mice.

Mol Metab 2017 11 1;6(11):1339-1349. Epub 2017 Sep 1.

Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Canada. Electronic address:

Objectives: Glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine cells and exerts a broad number of metabolic actions through activation of a single GLP-1 receptor (GLP-1R). The cardiovascular actions of GLP-1 have garnered increasing attention as GLP-1R agonists are used to treat human subjects with diabetes and obesity that may be at increased risk for development of heart disease. Here we studied mechanisms linking GLP-1R activation to control of heart rate (HR) in mice.

Methods: The actions of GLP-1R agonists were examined on the control of HR in wild type mice (WT) and in mice with cardiomyocyte-selective disruption of the GLP-1R (Glp1r). Complimentary studies examined the effects of GLP-1R agonists in mice co-administered propranolol or atropine. The direct effects of GLP-1R agonism on HR and ventricular developed pressure were examined in isolated perfused mouse hearts ex vivo, and atrial depolarization was quantified in mouse hearts following direct application of liraglutide to perfused atrial preparations ex vivo.

Results: Doses of liraglutide and lixisenatide that were equipotent for acute glucose control rapidly increased HR in WT and Glp1r mice in vivo. The actions of liraglutide to increase HR were more sustained relative to lixisenatide, and diminished in Glp1r mice. The acute chronotropic actions of GLP-1R agonists were attenuated by propranolol but not atropine. Neither native GLP-1 nor lixisenatide increased HR or developed pressure in perfused hearts ex vivo. Moreover, liraglutide had no direct effect on sinoatrial node firing rate in mouse atrial preparations ex vivo. Despite co-localization of HCN4 and GLP-1R in primate hearts, HCN4-directed Cre expression did not attenuate levels of Glp1r mRNA transcripts, but did reduce atrial Gcgr expression in the mouse heart.

Conclusions: GLP-1R agonists increase HR through multiple mechanisms, including regulation of autonomic nervous system function, and activation of the atrial GLP-1R. Surprisingly, the isolated atrial GLP-1R does not transduce a direct chronotropic effect following exposure to GLP-1R agonists in the intact heart, or isolated atrium, ex vivo. Hence, cardiac GLP-1R circuits controlling HR require neural inputs and do not function in a heart-autonomous manner.
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http://dx.doi.org/10.1016/j.molmet.2017.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681270PMC
November 2017

Regulators of G-Protein Signaling 10 and Heart Failure: The Importance of Negative Regulators of Heart Disease.

Hypertension 2016 Jan 16;67(1):38-40. Epub 2015 Nov 16.

From the Division of Cardiology, Department of Medicine (V.B.P., X.C., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., B.A.M., X.C., G.Y.O.), and Department of Physiology (B.A.M., G.Y.O.), University of Alberta, Edmonton, Alberta, Canada.

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.06109DOI Listing
January 2016

ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity.

Diabetes 2016 Jan 29;65(1):85-95. Epub 2015 Jul 29.

Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada Department of Physiology, University of Alberta, Edmonton, Alberta, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada

Obesity is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and studied at 6 months of age. Loss of ACE2 resulted in decreased weight gain but increased glucose intolerance, epicardial adipose tissue (EAT) inflammation, and polarization of macrophages into a proinflammatory phenotype in response to HFD. Similarly, human EAT in patients with obesity and heart failure displayed a proinflammatory macrophage phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was associated with decreased myocardial adiponectin, decreased phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity, and myocardial insulin resistance, which worsened heart function. Ang 1-7 (24 µg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated EAT inflammation and reduced cardiac steatosis and lipotoxicity, resulting in normalization of heart failure. In conclusion, ACE2 plays a novel role in heart disease associated with obesity wherein ACE2 negatively regulates obesity-induced EAT inflammation and cardiac insulin resistance.
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http://dx.doi.org/10.2337/db15-0399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4686955PMC
January 2016

Letter by McLean and Oudit regarding article, "myostatin regulates energy homeostasis in the heart and prevents heart failure".

Circ Res 2015 Mar;116(7):e51-2

Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

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http://dx.doi.org/10.1161/CIRCRESAHA.115.306124DOI Listing
March 2015

PI3Kα is essential for the recovery from Cre/tamoxifen cardiotoxicity and in myocardial insulin signalling but is not required for normal myocardial contractility in the adult heart.

Cardiovasc Res 2015 Mar 24;105(3):292-303. Epub 2015 Jan 24.

Department of Physiology, University of Alberta, Edmonton, Alberta, Canada Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada Division of Cardiology, Department of Medicine, University of Alberta, Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada

Aims: Genetic mouse models have yielded conflicting conclusions about the role of PI3Kα in heart physiology: specifically, the question of whether PI3Kα has a direct role in regulating myocardial contractility. This has led to concerns that PI3K inhibitors currently in clinical trials for cancer may potentiate cardiotoxicity. Here we seek to clarify the role of PI3Kα in normal heart physiology and investigate changes in related signalling pathways.

Methods And Results: Targeted deletion of PI3Kα and PI3Kβ in the heart with a tamoxifen-dependent Cre recombinase transgene caused transient heart dysfunction in all genotypes, but only PI3Kα deletion prevented functional recovery. Reduction in tamoxifen dosing allowed for maintained gene deletion without any cardiomyopathy, possibly through activation of survival signalling through the related ERK pathway. Similarly, mice with PI3Kα deletion induced by constitutively active Cre recombinase had normal heart function. Insulin-mediated activation of Akt, a marker of PI3Kα activity, was impaired with increased ERK1/2 activation in PI3Kα mutant hearts. Pharmacological inhibition of PI3Kα with BYL-719 also caused impaired insulin signalling in murine and human cardiomyocytes as well as in vivo in mice, with increased fasting blood glucose levels, but did not affect myocardial contractility as determined by echocardiography and invasive pressure-volume loop analysis.

Conclusion: Our results show that PI3Kα does not directly regulate myocardial contractility, but is required for recovery from tamoxifen/Cre toxicity. The important role for PI3Kα in insulin signalling and recovery from tamoxifen/Cre toxicity justifies caution when using PI3Kα inhibitors in combination with other cardiovascular comorbidities and cardiotoxic compounds in cancer patients.
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http://dx.doi.org/10.1093/cvr/cvv016DOI Listing
March 2015

Hydrogen sulfide: an old gas with new cardioprotective effects.

Clin Sci (Lond) 2015 Mar;128(5):321-3

Diabetic cardiovascular complications are reaching epidemic proportions and the risk of HF (heart failure) is increased 2-3-fold by diabetes mellitus. H2S (hydrogen sulfide) is emerging as a new gaseous signalling molecule in the cardiovascular system which possesses multifactorial effects on various intracellular signalling pathways. The proven cardioprotective and vasodilator activities of H2S warrant a detailed investigation into its role in diabetic cardiomyopathy. In the present issue of Clinical Science, Zhou et al. demonstrate an important therapeutic potential of the H2S pathway in diabetic cardiomyopathy.
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http://dx.doi.org/10.1042/CS20140668DOI Listing
March 2015

Role of autoimmunity in heart disease: is Chagas heart disease the definitive proof?

Can J Cardiol 2014 Mar 9;30(3):267-9. Epub 2013 Oct 9.

Division of Cardiology, Department of Medicine and Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.cjca.2013.10.006DOI Listing
March 2014

PI3K inhibitors as novel cancer therapies: implications for cardiovascular medicine.

J Card Fail 2013 Apr;19(4):268-82

Department of Physiology, University of Alberta, Edmonton, AB, Canada.

Background: The phosphatidylinositol 3-kinase (PI3K) signaling cascade has fundamental roles in cell growth, survival, and motility; and increased PI3K activity is an important and common contributor to tumorigenesis and cancer progression. This pathway also has a significant role in physiologic hypertrophy, myocardial contractility, and metabolism in the heart and is a central determinant of pathologic remodeling in the cardiovascular system.

Methods And Results: PI3K inhibitors are a promising class of anticancer drugs, although systemic inhibition of the PI3K pathway demands careful attention to possible adverse side effects of inhibiting these ubiquitously expressed proteins. Here we review the growing body of basic research on the role of PI3K signaling in the heart and give an overview of the different therapeutic strategies being developed for cancer using PI3K inhibitors, including pan and isoform-selective inhibitors, combination PI3K/mammalian target of rapamycin inhibitors and the use of PI3K inhibitors in combination therapies with other anticancer therapies. We focus on the clinical implications for treating patients with preexisting cardiac risk factors or comorbidities with PI3K inhibitors.

Conclusions: PI3K inhibitors are novel cancer drugs that are likely to lead to considerable toxicity to the cardiovascular system, especially in elderly patients and those with preexisting cardiovascular disease.
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http://dx.doi.org/10.1016/j.cardfail.2013.02.005DOI Listing
April 2013

Enhanced recovery from ischemia-reperfusion injury in PI3Kα dominant negative hearts: investigating the role of alternate PI3K isoforms, increased glucose oxidation and MAPK signaling.

J Mol Cell Cardiol 2013 Jan 8;54:9-18. Epub 2012 Nov 8.

Department of Physiology, Department of Medicine, University of Alberta, Edmonton, Canada.

Classical ischemia-reperfusion (IR) preconditioning relies on phosphatidylinositol 3-kinase (PI3K) for protective signaling. Surprisingly, inhibition of PI3Kα activity using a dominant negative (DN) strategy protected the murine heart from IR injury. It has been proposed that increased signaling through PI3Kγ may contribute to the improved recovery of PI3KαDN hearts following IR. To investigate the mechanism by which PI3KαDN hearts are protected from IR injury, we created a double mutant (PI3KDM) model by crossing p110γ(-/-) (PI3KγKO) with cardiac-specific PI3KαDN mice. The PI3KDM model has morphological and hemodynamic features that are characteristic of both PI3Kγ(-/-) and PI3KαDN mice. Interestingly, when subjected to IR using ex vivo Langendorff perfusion, PI3KDM hearts showed significantly enhanced functional recovery when compared to wildtype (WT) hearts. However, signaling downstream of PI3K through Akt and GSK3β, which has been associated with IR protection, was reduced in PI3KDM hearts. Using ex vivo working heart perfusion, we found no difference in functional recovery after IR between PI3KDM and PI3KαDN; also, glucose oxidation rates were significantly increased in PI3KαDN hearts when compared to WT, and this metabolic shift has been associated with enhanced IR recovery. However, we found that PI3KαDN hearts still had enhanced recovery when perfused exclusively with fatty acids (FA). We then investigated parallel signaling pathways, and found that mitogen-activated protein kinase signaling was increased in PI3KαDN hearts, possibly through the inhibition of negative feedback loops downstream of PI3Kα.
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http://dx.doi.org/10.1016/j.yjmcc.2012.10.015DOI Listing
January 2013

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

Circ Heart Fail 2012 Jul 15;5(4):493-503. Epub 2012 Jun 15.

Department of Pediatrics and Pharmacology, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada.

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.

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 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.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.112.966705DOI Listing
July 2012