Influence of diet and carnitine palmitoyltransferase I inhibition on myosin and sarcoplasmic reticulum

Rupp, Heinz; Wahl, R. A.; Hansen, Matthias

doi:10.1152/jappl.1992.72.1.352

Cited by 38 publications

(35 citation statements)

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“…Treatment of rats with etomoxir blocks the decrease in SERCA2a in response to either pressure overload or diabetes. [91][92][93] Indeed, the promoter of SERCA2a contains both E-boxes and Sp1 binding sites, consensus sequences on which known glucose sensing transcription factors to bind. 94 Consistent with a role of glucose metabolites in the regulation of SERCA2a gene expression is a recent study which reported that perfusion of hearts with glucose lowered SERCA2a mRNA levels.…”

Section: Young Et Almentioning

confidence: 99%

Adaptation and Maladaptation of the Heart in Diabetes: Part II

2002

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T he prevailing concept of the heart's response to changes in its environment is a complex network of interconnecting signal transduction cascades. 1 In such a scheme, the focus is on communication of various cell surface receptors, heterotrimeric G-proteins, protein kinases, and transcription factors. [2][3][4] Diabetes is a disorder of metabolic dysregulation. At first glance it appears that metabolism and the metabolic consequences of diabetes do not fit into this signal-response coupling scheme. Two questions arise. First, is metabolism simply an "effect" rather than a "cause" of adaptation? Second, is metabolism only a by-product of signal transduction-induced adaptation, allowing equilibrium (and therefore maintenance of function) in the presence of the other adaptational responses?An alternative is to take a new, less restricted view of metabolism. Beyond its stereotypical function as a provider of ATP, alterations in metabolic flux within the cell create essential signals for the adaptation of the heart to situations such as diabetes. This concept is novel for the heart, but has already been considered in the liver. Like the phosphorylation events occurring in signal transduction cascades, changes in metabolic flux are extremely rapid. For example, translocation of GLUT4 to the cell surface in response to insulin occurs within a second. 5 We have previously found that increases or decreases in workload also change metabolic fluxes in seconds. 6,7 Therefore, changes in metabolites are rapid enough to allow them to act as signaling molecules.Many of these acute changes in metabolic flux are brought about by the same signal transduction cascades believed to be involved in the adaptation of the heart to changes in its environment. Phosphatidylinositol 3-kinase, Ca 2ϩ , and protein kinase C, all of which play a role in cardiac adaptation, regulate metabolism in the heart. 8,9 Metabolic signals therefore provide a new dimension to the preexisting concepts of cardiac adaptation, as illustrated in Figure 1.

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Section: Young Et Almentioning

confidence: 99%

Adaptation and Maladaptation of the Heart in Diabetes: Part II

2002

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“…It was, therefore, an unexpected finding that metabolically active compounds which increase myosin V1 are associated with an improved pump function of an overloaded heart. It turned out that an increased myosin V1 proportion can be associated with an enhanced activity of the sarco-(endo-)plasmic reticulum Ca 2+ -ATPase-2 (SERCA2) [113]. The search for drugs which increase myosin V1 has also been neglected because it has been assumed that human heart does not exhibit myosin V1.…”

Section: Metabolic Therapy For Overloaded Cardiocytesmentioning

confidence: 99%

The Use of Partial Fatty Acid Oxidation Inhibitors for Metabolic Therapy of Angina Pectoris and Heart Failure

Rupp

Zarain‐Herzberg

Maisch

2002

Herz

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Partial fatty acid oxidation inhibitors have raised great interest since they are expected to counteract a dysregulated gene expression of hypertrophied cardiocytes. Some of these compounds have been developed for treating non-insulin-dependent diabetes mellitus and stable angina pectoris. A shift from fatty acid oxidation to glucose oxidation leads to a reduced gluconeogenesis and improved economy of cardiac work. An increased glucose oxidation can be achieved with the following enzyme inhibitors: etomoxir, oxfenicine, methyl palmoxirate, S-15176, metoprolol, amiodarone, perhexiline (carnitine palmitoyltransferase-1); aminocarnitine, perhexiline (carnitine palmitoyltransferase-2); hydrazonopropionic acid (carnitine-acylcarnitine translocase); MET-88 (gamma-butyrobetaine hydroxylase); 4-bromocrotonic acid, trimetazidine, possibly ranolazine (thiolases); hypoglycin (butyryl-CoA dehydrogenase); dichloroacetate (pyruvate dehydrogenase kinase). CLINICAL TRIALS with trimetazidine and ranolazine showed that this shift in substrate oxidation has an antianginal action. Etomoxir and MET-88 improved the function of overloaded hearts by increasing the density of the Ca(2+) pump of sarcoplasmic reticulum (SERCA2). The promoters of SERCA2 and alpha-myosin heavy-chain exhibit sequences which are expected to respond to transcription factors responsive to glucose metabolites and/or peroxisome proliferator-responsive element (PPAR) agonists. Further progress in elucidating novel compounds which upregulate SERCA2 expression is closely linked to the characterization of regulatory sequences of the SERCA2 promoter.

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“…It has been thought that the antiarrhythmogenic effects of EPA and DHA arise from their incorporation into membrane phospholipids thereby altering the membrane fluidity. However, in the context of studies on effects of ω-3 fatty acids on sarcoplasmic reticulum Ca 2+ uptake [68], cardiac hypertrophy and dilatation [5,32] and reperfusion-induced arrhythmias [4], no significant alterations in the Na + channel activity of papillary muscles of fish oil-fed rats was found by the loose patch clamp technique [17]. It was at that time not known that free fatty acids of EPA and DHA were involved in the antiarrhythmogenic action.…”

Section: Mechanisms Of Antiarrhythmogenic Action Of Epa and Dha Free mentioning

confidence: 99%

“…Although serum triacylglycerols are reduced approximately in parallel with the unsaturation index of fatty acids [68], a more specific action has been described for EPA. An important mechanism relates to the inhibitory effects on the triacylglycerol synthesis from diacylglycerols and stimulation of fatty acid oxidation [7].…”

Section: Mechanisms Of Antiarrhythmogenic Action Of Epa and Dha Free mentioning

confidence: 99%

Risk Stratification by the ?EPA+DHA Level? and the ?EPA/AA Ratio?

Rupp

Wagner

Rupp

et al. 2004

Herz

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The identification of risks associated with sudden cardiac death requires further investigations. The question was addressed whether parameters can be established which not only describe an increased risk for an enhanced electrical instability of the heart but also of inflammatory events underlying plaque rupture. Emphasis is placed on dose-dependent effects of the long-chain omega-(omega-)3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Since free acids of EPA and DHA are required for most of their biological effects, it appears essential not only to build up stores in the body for release of these fatty acids, but also to provide a sustained uptake of EPA and DHA in the form of ethyl esters. In contrast to rapidly absorbed triacylglycerols from fish, ethyl esters are taken up more slowly within 24 h. For the administration of 1 g/day highly purified EPA+DHA ethyl esters (Omacor) to healthy volunteers, it is shown that EPA is increased from 0.6% to 1.4% within 10 days, while DHA is increased from 2.9% to 4.3%. After withdrawal, EPA and DHA approach baseline values within 10 days. A gas chromatographic procedure was established which requires only 10 microl of whole blood for the identification of more than 35 fatty acids. Evidence is summarized strengthening the concept that a low "EPA+DHA level" presents a risk for sudden cardiac death and that the administration of 840 mg/day of EPA+DHA ethyl esters raises the "EPA+DHA level" to approximately 6% that is associated with a marked protection from sudden cardiac death. For reducing pro-inflammatory eicosanoids and cytokines, a higher "EPA+DHA level" is required which can be achieved with an intake of 2-4 g/day of 84% EPA+DHA ethyl esters. For assessing influences from pro-inflammatory eicosanoids and cytokines, the EPA/arachidonic acid ratio ("EPA/AA ratio") was identified as diagnostic parameter. To assess the dietary EPA+DHA intake, fatty acids were determined in fish dishes of the cafeteria of the Philipps University Hospital Marburg, Germany. The EPA+DHA content of the popular Alaska Pollock was 125 +/- 70 mg/100 g. A once daily fish dish can thus not provide the 840 mg/day EPA+DHA administered in the GISSI Prevention Study in the form of ethyl ester which markedly reduced the risk of sudden cardiac death in postmyocardial infarction patients. Nonetheless, at least two preferably oily fish meals per week should be consumed as preventive measure by persons without coronary artery disease. With documented coronary heart disease, it was advised to consume approximately 1 g/day of EPA+DHA.

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Influence of diet and carnitine palmitoyltransferase I inhibition on myosin and sarcoplasmic reticulum

Cited by 38 publications

References 0 publications

Adaptation and Maladaptation of the Heart in Diabetes: Part II

Adaptation and Maladaptation of the Heart in Diabetes: Part II

The Use of Partial Fatty Acid Oxidation Inhibitors for Metabolic Therapy of Angina Pectoris and Heart Failure

Risk Stratification by the ?EPA+DHA Level? and the ?EPA/AA Ratio?

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