Phospholipid-Mediated Signaling and Heart Disease

Tappia, Paramjit S.; Singal, Tushi

doi:10.1007/978-1-4020-8831-5_11

Cited by 21 publications

(14 citation statements)

References 158 publications

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“…Normal cardiac function depends on FA metabolism and, to a lesser degree, on glucose metabolism as an energy source (3,25,26). In contrast, the hypertrophied heart requires alternative energy sources and tends to rely more on glucose metabolism (25,(27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Male-Specific Cardiac Dysfunction in CTP:Phosphoethanolamine Cytidylyltransferase (Pcyt2)-Deficient Mice

Basu

Alibhai

Tsimakouridze

et al. 2015

Molecular and Cellular Biology

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b Phosphatidylethanolamine (PE) is the most abundant inner membrane phospholipid. PE synthesis from ethanolamine and diacylglycerol is regulated primarily by CTP:phosphoethanolamine cytidylyltransferase (Pcyt2). Pcyt2 ؉/؊ mice have reduced PE synthesis and, as a consequence, perturbed glucose and fatty acid metabolism, which gradually leads to the development of hyperlipidemia, obesity, and insulin resistance. Glucose and fatty acid uptake and the corresponding transporters Glut4 and Cd36 are similarly impaired in male and female Pcyt2 ؉/؊ hearts. These mice also have similarly reduced phosphatidylinositol 3-kinase (PI3K)/Akt1 signaling and increased reactive oxygen species (ROS) production in the heart. However, only Pcyt2 ؉/؊ males develop hypertension and cardiac hypertrophy. Pcyt2 ؉/؊ males have upregulated heart AceI expression, heart phospholipids enriched in arachidonic acid and other n-6 polyunsaturated fatty acids, and dramatically increased ROS production in the aorta. In contrast, Pcyt2 ؉/؊ females have unmodified heart phospholipids but have reduced heart triglyceride levels and altered expression of the structural genes Acta (low) and Myh7 (high). These changes together protect Pcyt2 ؉/؊ females from cardiac dysfunction under conditions of reduced glucose and fatty acid uptake and heart insulin resistance. Our data identify Pcyt2 and membrane PE biogenesis as important determinants of gender-specific differences in cardiac lipids and heart function. The mammalian heart requires an enormous amount of energy to perform (1). The heart can use various sources of energy (2), but in a normal adult heart, lipids are the main source, and they account for ϳ70 to 80% of the total energy requirements (3). Phosphatidylethanolamine (PE) is the most important phospholipid and is located in the inner leaflet of cellular membranes. PE has many biological functions, including in membrane integrity, cell division, cytokinesis, autophagy, apoptosis, and blood coagulation, as reviewed by Bakovic et al. (4). The de novo synthesis of PE occurs through the ethanolamine Kennedy pathway. In this pathway, ethanolamine is phosphorylated by ethanolamine kinase to produce phosphoethanolamine. The CTP:phosphoethanolamine cytidylyltransferase (Pcyt2) then converts phosphoethanolamine to CDP-ethanolamine. Finally, CDP-ethanolamine:1,2-diacylglycerol phosphotransferase catalyzes the production of PE from CDP-ethanolamine and diacylglycerol (DAG). CDP-ethanolamine is also alternatively coupled with alkylacylglycerols derived in peroxisomes, to produce plasmanyl-PE, which is further modified in mitochondria to the final vinyl-ether (plasmalogen) PE. Various isoforms of kinases and phosphotransferases share substrates for the choline and ethanolamine branches of the Kennedy pathway; however, Pcyt2 is a product of a single gene (5) and therefore is highly specific for the ethanolamine branch of the pathway. The Pcyt2 gene has been cloned and characterized in human (5), Saccharomyces cerevisiae (6), rat (7), and mouse (5, 8).The total d...

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Section: Discussionmentioning

confidence: 99%

Male-Specific Cardiac Dysfunction in CTP:Phosphoethanolamine Cytidylyltransferase (Pcyt2)-Deficient Mice

Basu

Alibhai

Tsimakouridze

et al. 2015

Molecular and Cellular Biology

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“…Although we are proposing a metabolic component explaining improved function at baseline, it is also conceivable that cardiacspecific ATGL overexpression alters (lipid) signaling pathways to secondarily influence cardiac function. Given the connection between metabolism of phospholipids and TG (6,10,25,27) and emerging evidence showing that phospholipid metabolism and signaling influence cardiac function (27,41,43,44), it is also possible that altered TG metabolism in MHC-ATGL hearts modulates phospholipid homeostasis to enhance myocardial performance. Future research will help to test these possibilities.…”

Section: Discussionmentioning

confidence: 99%

Myocardial ATGL Overexpression Decreases the Reliance on Fatty Acid Oxidation and Protects against Pressure Overload-Induced Cardiac Dysfunction

Kienesberger

Pulinilkunnil

Sung

et al. 2012

Molecular and Cellular Biology

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Alterations in myocardial triacylglycerol content have been associated with poor left ventricular function, suggesting that enzymes involved in myocardial triacylglycerol metabolism play an important role in regulating contractile function. Myocardial triacylglycerol catabolism is mediated by adipose triglyceride lipase (ATGL), which is rate limiting for triacylglycerol hydrolysis. To address the influence of triacylglycerol hydrolysis on myocardial energy metabolism and function, we utilized mice with cardiomyocyte-specific ATGL overexpression (MHC-ATGL). Biochemical examination of MHC-ATGL hearts revealed chronically reduced myocardial triacylglycerol content but unchanged levels of long-chain acyl coenzyme A esters, ceramides, and diacylglycerols. Surprisingly, fatty acid oxidation rates were decreased in ex vivo perfused working hearts from MHC-ATGL mice, which was compensated by increased rates of glucose oxidation. Interestingly, reduced myocardial triacylglycerol content was associated with moderately enhanced in vivo systolic function in MHC-ATGL mice and increased isoproterenol-induced cell shortening of isolated primary cardiomyocytes. Most importantly, MHC-ATGL mice were protected from pressure overloadinduced systolic dysfunction and detrimental structural remodeling following transverse aortic constriction. Overall, this study shows that ATGL overexpression is sufficient to alter myocardial energy metabolism and improve cardiac function. Myocardial triacylglycerol (TG) is stored in cytosolic lipid droplets within cardiomyocytes and constitutes a critical fatty acid (FA) and energy reserve for the heart. Metabolism of cardiac TG is highly dynamic (2, 29), which likely evolved as a means to ensure continuous FA supply for mitochondrial oxidation independent of short-term fluctuations in plasma FA availability. Previous studies have shown that FAs released by intracellular TG hydrolysis contribute significantly to the generation of ATP necessary for contractile function (2, 34, 39), suggesting that TG hydrolysis plays a critical role in regulating cardiac function. In agreement with this finding, dysregulation of myocardial TG metabolism and either increased or reduced TG content have been associated with cardiac dysfunction and/or heart failure induced by obesity, diabetes, aging, ischemia, and hemodynamic pressure overload (3,5,8,22,26,(31)(32)(33)(34). Moreover, a clear correlation between increased myocardial TG content and decreased cardiac function has been established in rodents and humans (7,12,22,24), supporting the concept that excessive TG accumulation in the heart is detrimental. On the other hand, it has also been postulated that increasing TG content and sequestration of potentially lipotoxic FA metabolites in the myocardial TG pool can be beneficial for heart function (28, 42). As such, the physiological consequences of preventing myocardial TG accumulation with regard to normal physiology and disease remain to be elucidated.As the enzymes that control TG lipolysis may have an as yet und...

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“…Acute metabolic stress conditions such as ischemia and reperfusion may cause a change in phosphoinositide turnover (see [32]). In chronic diseases, reduced PIP 2 levels have been reported in hypertrophy, diabetic cardiomyopathy, and congestive heart failure [33]. Recent studies indicate that a loss of function of TRPM7 may underlie neurodegenerative diseases [13,18], and in the case of familial Alzheimer's diseases, 1 the underlying mechanism seems to involve an abnormal turnover of PIP 2 with decreased membrane PIP 2 levels and decreased TRPM7 current [18].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Magnesium-Sensitive TRPM7-like Channel in Cardiac Myocytes by Nonhydrolysable GTP Analogs: Involvement of Phosphoinositide Metabolism

Mačianskienė

Gwanyanya²,

Vereecke

et al. 2008

Cell Physiol Biochem

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Background/Aims: A magnesium-inhibited, transient receptor potential melastatin 7 (TRPM7)-like channel is expressed in cardiac cell membranes. The role and regulation of this channel by intracellular nucleotides and membrane components remain unclear. Methods: We used the whole-cell voltage-clamp technique in pig isolated ventricular myocytes to investigate the effect of non-hydrolysable guanine nucleotides. Results: The TRPM7-like current, induced by intracellular dialysis with low [Mg²⁺], remained stable when the intracellular solution contained GTP. Substituting GTP by GTP-γ-S or Gp-pNp, but not GDP-β-S, induced a run-down of the current. Under dialysis with GTP-γ-S, inhibiting phospholipase C by edelfosine or intracellularly adding exogenous phosphatidylinositol-4,5-bisphosphate (PIP₂) decreased run-down, whereas extracellularly applying carbachol and phenylephrine accelerated it. Pretreatment of cells with pertussis toxin did not prevent the run-down induced by GTP-γ-S. Conclusion: Guanine nucleotides can modulate cardiac TRPM7-like channels via a mechanism linked to G proteins and to PIP₂ metabolism.

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Phospholipid-Mediated Signaling and Heart Disease

Cited by 21 publications

References 158 publications

Male-Specific Cardiac Dysfunction in CTP:Phosphoethanolamine Cytidylyltransferase (Pcyt2)-Deficient Mice

Male-Specific Cardiac Dysfunction in CTP:Phosphoethanolamine Cytidylyltransferase (Pcyt2)-Deficient Mice

Myocardial ATGL Overexpression Decreases the Reliance on Fatty Acid Oxidation and Protects against Pressure Overload-Induced Cardiac Dysfunction

Inhibition of the Magnesium-Sensitive TRPM7-like Channel in Cardiac Myocytes by Nonhydrolysable GTP Analogs: Involvement of Phosphoinositide Metabolism

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