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Pathophysiology of Heart Failure with Reduced Ejection Fraction
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Jacob Cao, John O'Sullivan, Sean Lal
Etomoxir is an inhibitor of carnitine palmitoyl transferase 1 (CPT-1), which normally transports fatty acids across the mitochondrial membrane for oxidation. In vitro studies of etomoxir have demonstrated improved cardiomyocyte calcium handling via upregulation of SERCA expression. An initial trial of etomoxir in moderate-severity HF patients demonstrated up to 27% increase in ejection fraction after three months of treatment.24 The subsequent randomized trial was ceased prematurely due to associated liver function derangement, and, at time of cessation, there was no echocardiographic improvement in the treatment groups, although the power was limited.25
Mitochondrial Dysfunction and DNA Methylation in Atherosclerosis
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Subsequent work suggested that the mitochondria could participate in shaping the DNA methylome of the atherosclerotic artery. Arachidonic acid (AA) induces DNA hypermethylation in cultured THP-1 monocytes and HEK-293 cells (Silva-Martínez et al. 2016). The response to AA is greatly reduced by etomoxir, an inhibitor of FA import into mitochondria, and by PPARα inhibitors. Furthermore, a comparison of AA-induced DNA methylation profiles with published data in a variety of diseases and normal tissues, revealed significant clustering with atherosclerosis-specific and the proinflammatory PA-induced profiles. Thus, the data suggest that increased mitochondrial FAO results in DNA hypermethylation, possibly by generating incomplete oxidation products, some of which can act as PPAR ligands (Figure 1) (Forman et al. 1997). Accordingly, PA increases mitochondrial mass as outlined above (Dymkowska et al. 2017). Also, enhanced long-chain FA oxidation has been reported in atherosclerosis (Gillies and Bell 1979). Interestingly, the dynamic DNA hypermethylation followed by demethylation observed in the previously discussed human study, mirrors a corresponding biphasic increase/decrease trend of mitochondrial abundance in a rabbit model of atherosclerosis (Rosnowski and Kujawa 1977).
Noninsulin-Dependent Animal Models of Diabetes Mellitus
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Christopher H. S. McIntosh, Raymond A. Pederson
Psammomys obesus is a small rodent (gerbil), indigenous to desert regions of the Middle East where access to food and water is limited. They normally eat saltbush, a succulent halophilic plant with high salt and water content, and under these conditions they are lean and normoglycemic.134 However, sand rats exhibit a genetic predisposition to the development of NIDDM and cataracts, when fed a standard high-calorie laboratory diet ad libitum.336 The mode of inheritance is complex: some rats develop hyperinsulinemia but remain relatively normoglycemic, others develop NIDDM, whereas some remain normal.337,338 In the hyperglycemic group, fatty acid oxidation has been shown to play an important role since administration of the oxidation inhibitor etomoxir reduced tissue uptake of glucose and circulating levels of glucose and insulin.337
Inhibition of fatty acid metabolism by etomoxir or TOFA suppresses murine dendritic cell activation without affecting viability
Published in Immunopharmacology and Immunotoxicology, 2019
Connie C. Qiu, Atilio E. Atencio, Stefania Gallucci
Among the current pharmacologic tools used to manipulate cell metabolism, we investigated etomoxir, an irreversible inhibitor of carnitine palmitoyltransferase-1 (CPT-1), a key enzyme in FAO, critical transporter of long chain FAs into mitochondria for oxidation [27]. In addition, we investigated the effects of 5-tetradecyloxy-2-furoic acid (TOFA), an inhibitor of acetyl-CoA carboxylase-α (ACC), targeting the rate-limiting enzyme in long-chain FAS. DC dysfunction in cancer has been associated with lipid accumulation, and administration of TOFA has been found to normalize DC functional activity [28,29]. We explored how FA metabolism may be essential for DC activation and production of proinflammatory cytokines. We show that inhibiting FA metabolism by etomoxir and TOFA suppresses both pDC and cDC activation, suggesting these drugs as novel therapeutics for affecting DCs.
Glucose metabolism and metabolic flexibility in cultured skeletal muscle cells is related to exercise status in young male subjects
Published in Archives of Physiology and Biochemistry, 2018
Jenny Lund, Daniel S. Tangen, Håvard Wiig, Hans K. Stadheim, Siw A. Helle, Jesper B. Birk, Thorsten Ingemann-Hansen, Arild C. Rustan, G. Hege Thoresen, Jørgen F. P. Wojtaszewski, Eili T. Kase, Jørgen Jensen
Myotubes from the trained subjects showed significantly higher suppression of glucose oxidation by oleic acid (Figure 6(A)). Overall the highest rate of carbohydrate oxidation in vivo correlated positively with oleic acid-induced suppression of glucose oxidation in vitro (r = 0.61, p = .04, n = 12 [combination of trained and untrained], Figure 6(B)). Etomoxir, which inhibits fatty acid oxidation by targeting the mitochondrial carnitine palmitoyltransferase 1 (CPT1, reviewed in (Rupp et al.2002)) reversed the oleic acid-induced suppression of fractional glucose oxidation and quenched the difference in glucose oxidation between the two donor groups (Figure 6(C)). There were no differences in mRNA expression of CPT1A and CPT1B (data not shown), and neither mRNA nor protein expression of PDK4, a key enzyme in regulating switching of fuel between glucose and fatty acids (Badin et al.2012), were significantly differently expressed (Figure 6(D–F)). mRNA expression of the mitochondrial gene CYC1 as well as expression of proteins involved in oxidative phosphorylation, complex III and ATP synthase, were also similar between myotubes from the two groups (Figure 6(D–F)). AMPK phosphorylation after oleic acid stimulation did not differ between the groups (Figure 6(G, H)).
α1-Adrenergic receptors increase glucose oxidation under normal and ischemic conditions in adult mouse cardiomyocytes
Published in Journal of Receptors and Signal Transduction, 2021
Robert S. Papay, Dianne M. Perez
Several studies previously demonstrated that glucose oxidation in the heart is altered in many cardiovascular diseases, including ischemia, heart failure, and diabetic cardiomyopathy [17,18,27]. During episodes of ischemia, the reduction in glucose and oxygen to feed oxidative phosphorylation accelerates the uptake of glucose to provide a needed source of ATP to maintain cardiac function. Etomoxir and other inhibitors show beneficial effects in patients with heart failure by inhibiting fatty acid oxidation, resulting in increased glucose oxidation in the heart [28–30]. Drugs that directly enhance glucose oxidation such as dichloroacetate improve the coupling between glycolysis and glucose oxidation in the heart and benefited patients with coronary artery disease [31].