Cold Exposure Rejuvenates the Metabolic Phenotype of Mice.

Pannexin1 (Panx1) ATP channels are important in adipocyte biology, potentially influencing energy storage and expenditure. We compared the metabolic phenotype of young (14 weeks old) and mature (20 weeks old) wild-type (WT) and mice exposed or not to cold (6 °C) during 28 days, a condition promoting adipocyte browning. Young mice weighed less and exhibited increased fat mass, improved glucose tolerance, and lower insulin sensitivity than WT mice.

Differential intracellular management of fatty acids impacts on metabolic stress-stimulated glucose uptake in cardiomyocytes.

Stimulation of glucose uptake in response to ischemic metabolic stress is important for cardiomyocyte function and survival. Chronic exposure of cardiomyocytes to fatty acids (FA) impairs the stimulation of glucose uptake, whereas induction of lipid droplets (LD) is associated with preserved glucose uptake. However, the mechanisms by which LD induction prevents glucose uptake impairment remain elusive.

Detecting early myocardial ischemia in rat heart by MALDI imaging mass spectrometry.

Diagnostics of myocardial infarction in human post-mortem hearts can be achieved only if ischemia persisted for at least 6-12 h when certain morphological changes appear in myocardium. The initial 4 h of ischemia is difficult to diagnose due to lack of a standardized method. Developing a panel of molecular tissue markers is a promising approach and can be accelerated by characterization of molecular changes.

Cardiac metabolism as a driver and therapeutic target of myocardial infarction.

Reducing infarct size during a cardiac ischaemic-reperfusion episode is still of paramount importance, because the extension of myocardial necrosis is an important risk factor for developing heart failure. Cardiac ischaemia-reperfusion injury (IRI) is in principle a metabolic pathology as it is caused by abruptly halted metabolism during the ischaemic episode and exacerbated by sudden restart of specific metabolic pathways at reperfusion. It should therefore not come as a surprise that therapy directed at metabolic pathways can modulate IRI.

Neuregulin-1 triggers GLUT4 translocation and enhances glucose uptake independently of insulin receptor substrate and ErbB3 in neonatal rat cardiomyocytes.

During stress conditions such as pressure overload and acute ischemia, the myocardial endothelium releases neuregulin-1β (NRG-1), which acts as a cardioprotective factor and supports recovery of the heart. Recently, we demonstrated that recombinant human (rh)NRG-1 enhances glucose uptake in neonatal rat ventricular myocytes via the ErbB2/ErbB4 heterodimer and PI3Kα. The present study aimed to further elucidate the mechanism whereby rhNRG-1 activates glucose uptake in comparison to the well-established insulin and to extend the findings to adult models.

Chronic AICAR treatment prevents metabolic changes in cardiomyocytes exposed to free fatty acids.

The stimulation of glucose transport by metabolic stress is an important determinant of myocardial susceptibility to ischemia and reperfusion injury. Stimulation of glucose transport is markedly impaired in cardiomyocytes chronically exposed to excess free fatty acids (FFA), as occurs in vivo in type 2 diabetes. To determine whether chronic low-grade activation of AMP-activated kinase (AMPK) improves substrate metabolism in cardiomyocytes exposed to FFA, isolated cultured cardiomyocytes were exposed for 7 days to FFA ± the AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR).

Pleiotropic Effects of Chronic Phorbol Ester Treatment to Improve Glucose Transport in Insulin-Resistant Cardiomyocytes.

Stimulation of glucose transport is an important determinant of myocardial susceptibility to ischemia and reperfusion. Stimulation of glucose transport is markedly impaired in cardiomyocytes exposed to free fatty acids (FFA). Deactivation of the Focal Adhesion Kinase (FAK) by FFA contributes to glucose transport impairment, and could be corrected by chronic treatment with the phorbol ester TPA.

A Role for Focal Adhesion Kinase in the Stimulation of Glucose Transport in Cardiomyocytes.

Stimulation of glucose transport is markedly impaired in cardiomyocytes exposed to free fatty acids (FFA), despite relative preservation of canonical insulin- or metabolic stress signaling. We determined whether Focal Adhesion Kinase (FAK) activity is required for stimulation of glucose transport in cardiomyocytes, and whether FAK downregulation participates in FFA-induced impairment of glucose transport stimulation. Glucose transport, measured in isolated cultured cardiomyocytes, was acutely stimulated either by insulin treatment, or by metabolic inhibition with oligomycin resulting in AMP-activated kinase (AMPK) activation.

Impaired stimulation of glucose transport in cardiac myocytes exposed to very low-density lipoproteins.

We recently observed that free fatty acids impair the stimulation of glucose transport into cardiomyocytes in response to either insulin or metabolic stress. In vivo, fatty acids for the myocardium are mostly obtained from triglyceride-rich lipoproteins (chylomicrons and Very Low-Density Lipoproteins). We therefore determined whether exposure of cardiac myocytes to VLDL resulted in impaired basal and stimulated glucose transport.

Free Fatty Acids Impair FGF21 Action in HepG2 Cells.

Background/aims: Fibroblast growth factor 21 (FGF21) is a key mediator of glucose and lipid metabolism. However, the beneficial effects of exogenous FGF21 administration are attenuated in obese animals and humans with elevated levels of circulating free fatty acids (FFA).

Methods: We investigated in vitro how FFA impact FGF21 effects on hepatic lipid metabolism.

JAK-STAT signaling and myocardial glucose metabolism.

JAK-STAT signaling occurs in virtually every tissue of the body, and so does glucose metabolism. In this review, we summarize the regulation of glucose metabolism in the myocardium and ponder whether JAK-STAT signaling participates in this regulation. Despite a paucity of data directly pertaining to cardiac myocytes, we conclude that JAK-STAT signaling may contribute to the development of insulin resistance in the myocardium in response to various hormones and cytokines.

Role of NADPH oxidase isoforms NOX1, NOX2 and NOX4 in myocardial ischemia/reperfusion injury.

Myocardial reperfusion injury is mediated by several processes including increase of reactive oxygen species (ROS). The aim of the study is to identify potential sources of ROS contributing to myocardial ischemia-reperfusion injury. For this purpose, we investigated myocardial ischemia/reperfusion pathology in mice deficient in various NADPH oxidase isoforms (Nox1, Nox2, Nox4, as well as Nox1/2 double knockout).

Dual effect of the heart-targeting cytokine cardiotrophin-1 on glucose transport in cardiomyocytes.

Cardiotrophin-1 (CT-1) is a heart-targeting cytokine that is increased in the metabolic syndrome due to overexpression in the adipocytes. The effects of CT-1 on cardiomyocyte substrate metabolism remain unknown. We therefore determined the effects of CT-1 on basal and stimulated glucose transport in cardiomyocytes exposed to a low dose (1nM) or a high dose (10nM).

Regulation and dysregulation of glucose transport in cardiomyocytes.

The ability of the heart muscle to derive energy from a wide variety of substrates provides the myocardium with remarkable capacity to adapt to the ever-changing metabolic environment depending on factors including nutritional state and physical activity. There is increasing evidence that loss of metabolic flexibility of the myocardium contributes to cardiac dysfunction in disease conditions such as diabetes, ischemic heart disease and heart failure. At the level of glucose metabolism reduced metabolic adaptation in most cases is characterized by impaired stimulation of transarcolemmal glucose transport in the cardiomyocytes in response to insulin, referred to as insulin resistance, or to other stimuli such as energy deficiency.

Inhibition of nicotinamide phosphoribosyltransferase reduces neutrophil-mediated injury in myocardial infarction.

Aims: Nicotinamide phosphoribosyltransferase (Nampt) is a key enzyme for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, and recent evidence indicates its role in inflammatory processes. Here, we investigated the potential effects of pharmacological Nampt inhibition with FK866 in a mouse myocardial ischemia/reperfusion model. In vivo and ex vivo mouse myocardial ischemia/reperfusion procedures were performed.

Differential effects of high-fat diet on myocardial lipid metabolism in failing and nonfailing hearts with angiotensin II-mediated cardiac remodeling in mice.

Normal myocardium adapts to increase of nutritional fatty acid supply by upregulation of regulatory proteins of the fatty acid oxidation pathway. Because advanced heart failure is associated with reduction of regulatory proteins of fatty acid oxidation, we hypothesized that failing myocardium may not be able to adapt to increased fatty acid intake and therefore undergo lipid accumulation, potentially aggravating myocardial dysfunction. We determined the effect of high-fat diet in transgenic mice with overexpression of angiotensinogen in the myocardium (TG1306/R1).

Differential regulation of stimulated glucose transport by free fatty acids and PPARα or -δ agonists in cardiac myocytes.

Stimulation of glucose transport in response to insulin or metabolic stress is an important determinant of cardiac myocyte function and survival, particularly during ischemia-reperfusion episodes. The impact of dyslipidemia and its consequence PPAR activation on stimulated glucose transport in cardiac myocytes remains unknown. Isolated adult rat cardiac myocytes were chronically exposed to free fatty acids (FFA) or PPAR agonists.

Role of ERK1/2 activation in microtubule stabilization and glucose transport in cardiomyocytes.

We previously demonstrated that microtubule disruption impairs stimulation of glucose uptake in cardiomyocytes and that 9-cis retinoic acid (9cRA) treatment preserved both microtubule integrity and stimulated glucose transport. Herein we investigated whether 1) activation of the extracellular signal-regulated kinases (ERK1/2) is responsible for microtubule destabilization and 2) ERK1/2 inactivation may explain the positive effects of 9cRA on glucose uptake and microtubule stabilization. Adult rat cardiomyocytes in primary culture showed increased basal ERK1/2 phosphorylation.

Single administration of the CXC chemokine-binding protein Evasin-3 during ischemia prevents myocardial reperfusion injury in mice.

Objective: Evasins (chemokine-binding proteins) have been shown to selectively neutralize chemokine bioactivity. We investigated the potential benefits of Evasin-3 on mouse myocardial ischemia/reperfusion injury.

Methods And Results: In vivo and ex vivo (Langendorff model) left coronary artery ligature was performed in C57Bl/6 mice.

Chemokine CCL5/RANTES inhibition reduces myocardial reperfusion injury in atherosclerotic mice.

Although beneficial for cardiomyocyte salvage and to limit myocardial damage and cardiac dysfunction, restoration of blood flow after prolonged ischemia exacerbates myocardial injuries. Several deleterious processes that contribute to cardiomyocyte death have been proposed, including massive release of reactive oxygen species, calcium overload and hypercontracture development or leukocyte infiltration within the damaged myocardium. Chemokines are known to enhance leukocyte diapedesis at inflammatory sites.

Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy.

Development of cardiac hypertrophy and progression to heart failure entails profound changes in myocardial metabolism, characterized by a switch from fatty acid utilization to glycolysis and lipid accumulation. We report that hypoxia-inducible factor (HIF)1alpha and PPARgamma, key mediators of glycolysis and lipid anabolism, respectively, are jointly upregulated in hypertrophic cardiomyopathy and cooperate to mediate key changes in cardiac metabolism. In response to pathologic stress, HIF1alpha activates glycolytic genes and PPARgamma, whose product, in turn, activates fatty acid uptake and glycerolipid biosynthesis genes.

Angiotensin II and tumour necrosis factor alpha as mediators of ATP-dependent potassium channel remodelling in post-infarction heart failure.

Aims: Angiotensin II (Ang II) and tumour necrosis factor alpha (TNFalpha) are involved in the progression from compensated hypertrophy to heart failure. Here, we test their role in the remodelling of ATP-dependent potassium channel (K(ATP)) in heart failure, conferring increased metabolic and diazoxide sensitivity.

Methods And Results: We observed increased expression of both angiotensinogen and TNFalpha in the failing rat myocardium, with a regional gradient matching that of the K(ATP) subunit Kir6.

Angiotensin II downregulates the fatty acid oxidation pathway in adult rat cardiomyocytes via release of tumour necrosis factor-alpha.

Aims: Advanced heart failure is often associated with reduced myocardial fatty acid oxidation capacity. We have previously observed that failing hearts of mice with overexpression of angiotensinogen in the myocardium exhibit marked reduction of key regulatory proteins of fatty acid oxidation. In the present study, we determined whether exposure of adult rat cardiac (ARC) myocytes to angiotensin II (Ang II) influences expression of fatty acid translocase, muscle-type carnitine palmitoyl transferase-I, and medium-chain acyl-CoA dehydrogenase.

Forkhead transcription factors coordinate expression of myocardial KATP channel subunits and energy metabolism.

Coordinate adaptation of myocyte metabolism and function is fundamental to survival of the stressed heart, but the mechanisms for this coordination remain unclear. Bioinformatics led us to discover that Foxs are key transcription factors involved. We performed experiments on the mouse atrial cell line HL-1, neonate rat heart myocytes, and an adult rat model of myocardial infarction.

Nuclear receptor agonists improve insulin responsiveness in cultured cardiomyocytes through enhanced signaling and preserved cytoskeletal architecture.

Insulin resistance is the failure of insulin to stimulate the transport of glucose into its target cells. A highly regulatable supply of glucose is important for cardiomyocytes to cope with situations of metabolic stress. We recently observed that isolated adult rat cardiomyocytes become insulin resistant in vitro.