Role of Stearoyl-CoA Desaturase 1 in Cardiovascular Physiology.

Stearoyl-CoA desaturase is a rate-limiting enzyme in the synthesis of monounsaturated fatty acids. Monounsaturated fatty acids limit the toxicity of exogenous saturated fats. Studies have shown that stearoyl-CoA desaturase 1 is involved in the remodeling of cardiac metabolism. The loss of stearoyl-CoA desaturase 1 reduces fatty acid oxidation and increases glucose oxidation in the heart. Such a change is protective under conditions of a high-fat diet, which reduces reactive oxygen species-generating ß-oxidation. In contrast, stearoyl-CoA desaturase 1 deficiency predisposes individuals to atherosclerosis under conditions of hyperlipidemia but protects against apnea-induced atherosclerosis. Stearoyl-CoA desaturase 1 deficiency also impairs angiogenesis after myocardial infarction. Clinical data show a positive correlation between blood stearoyl-CoA Δ-9 desaturation rates and cardiovascular disease and mortality. Moreover, stearoyl-CoA desaturase inhibition is considered an attractive intervention in some obesity-associated pathologies, and the importance of stearoyl-CoA desaturase in the cardiovascular system might be a limitation for developing such therapy. This review discusses the role of stearoyl-CoA desaturase 1 in the regulation of cardiovascular homeostasis and the development of heart disease and presents markers of systemic stearoyl-CoA desaturase activity and their predictive potential in the diagnosis of cardiovascular disorders.

Interplay between Thyroid Hormones and Stearoyl-CoA Desaturase 1 in the Regulation of Lipid Metabolism in the Heart.

Stearoyl-CoA desaturase 1 (SCD1), an enzyme that is involved in the biosynthesis of monounsaturated fatty acids, induces the reprogramming of cardiomyocyte metabolism. Thyroid hormones (THs) activate both lipolysis and lipogenesis. Many genes that are involved in lipid metabolism, including Scd1, are regulated by THs. The present study used SCD1 knockout (SCD1-/-) mice to test the hypothesis that THs are important factors that mediate the anti-steatotic effect of SCD1 downregulation in the heart. SCD1 deficiency decreased plasma levels of thyroid-stimulating hormone and thyroxine and the expression of genes that regulate intracellular TH levels (i.e., Slc16a2 and Dio1-3) in cardiomyocytes. Both hypothyroidism and SCD1 deficiency affected genomic and non-genomic TH pathways in the heart. SCD1 deficiency is known to protect mice from genetic- or diet-induced obesity and decrease lipid content in the heart. Interestingly, hypothyroidism increased body adiposity and triglyceride and diacylglycerol levels in the heart in SCD1-/- mice. The accumulation of triglycerides in cardiomyocytes in SCD1-/- hypothyroid mice was caused by the activation of lipogenesis, which likely exceeded the upregulation of lipolysis and fatty acid oxidation. Lipid accumulation was also observed in the heart in wildtype hypothyroid mice compared with wildtype control mice, but this process was related to a reduction of triglyceride lipolysis and fatty acid oxidation. We also found that simultaneous SCD1 and deiodinase inhibition increased triglyceride content in HL-1 cardiomyocytes, and this process was related to the downregulation of lipolysis. Altogether, the present results suggest that THs are an important part of the mechanism of SCD1 in cardiac lipid utilization and may be involved in the upregulation of energetic metabolism that is associated with SCD1 deficiency.

Correction to: Cardiospecific deletion of αE-catenin leads to heart failure and lethality in mice.

The original version of this article unfortunately contained a mistake. The published paper presented an incorrect version of Table 1. The corrected Table is given here.

Cardiospecific deletion of αE-catenin leads to heart failure and lethality in mice.

αE-catenin is a component of adherens junctions that link the cadherin-catenin complex to the actin cytoskeleton. The signaling function of this protein was recently revealed. In the present study, we investigated the role of αE-catenin in the pathogenesis of heart failure. We mated αE-catenin conditional knockout mice with αMHC-Cre mice and evaluated their mutant offspring. We found that αE-catenin knockout caused enlargement of the heart and atria, fibrosis, the upregulation of hypertrophic genes, and the dysregulation of fatty acid metabolism via the transcriptional activity of Yap and ß-catenin. The activation of canonical Wnt and Yap decreased the activity of main regulators of energy metabolism (i.e., adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor α) and dysregulated hypertrophic pathway activity (i.e., phosphatidylinositide 3-kinase/Akt, cyclic adenosine monophosphate/protein kinase A, and MEK1/extracellular signal regulated kinase 1/2). The loss of αE-catenin also negatively affected cardio-hemodynamic function via the protein kinase A pathway. Overall, we found that the embryonic heart-specific ablation of αE-catenin leads to the development of heart failure with age and premature death in mice. Thus, αE-catenin appears to have a crucial signaling function in the postnatal heart, and the dysfunction of this gene causes heart failure through canonical Wnt and Yap activation.

SCD1-related epigenetic modifications affect hormone-sensitive lipase (Lipe) gene expression in cardiomyocytes.

Stearoyl-CoA desaturase 1 (SCD1) is an enzyme that is involved in the regulation of lipolysis in the heart. SCD1 also affects epigenetic mechanisms, such as DNA and histone modifications, in various tissues. Both epigenetic modifications and changes in lipid metabolism are involved in the heart's response to hypoxia. The present study tested the hypothesis that SCD1 and epigenetic modifications interact to control lipolysis in cardiomyocytes under normoxic and hypoxic conditions. We found that the inhibition of SCD1 activity and loss of SCD1 expression reduced global DNA methylation levels, DNA methyltransferase (DNMT) activity, and DNMT1 expression in HL-1 cardiomyocytes and the mouse heart. We also found that the inhibition of adipose triglyceride lipase is involved in the control of global DNA methylation levels in cardiomyocytes in an SCD1-independent manner. Additionally, SCD1 inhibition reduced expression of the hormone-sensitive lipase (Lipe) gene through an increase in methylation of the Lipe gene promoter. Under hypoxic conditions, SCD1 inhibition abolished hypoxia-inducible transcription factor 1α, likely through decreases in histone deacetylase, protein kinase A, and abhydrolase domain containing 5 protein levels, leading to the attenuation of DNA hypomethylation by DNMT1. Hypoxia led to demethylation of the Lipe promoter in cardiomyocytes with SCD1 inhibition, which increased Lipe expression. These results indicate that SCD1 is involved in the control of epigenetic mechanisms in the heart and may affect Lipe expression through changes in methylation in its promoter region. Therefore, SCD1 may be considered a key player in the epigenetic response to normoxia and hypoxia in cardiomyocytes.

WNT/ß-catenin pathway is a key regulator of cardiac function and energetic metabolism.

The WNT/ß-catenin pathway is a master regulator of cardiac development and growth, and its activity is low in healthy adult hearts. However, even this low activity is essential for maintaining normal heart function. Acute activation of the WNT/ß-catenin signaling cascade is considered to be cardioprotective after infarction through the upregulation of prosurvival genes and reprogramming of metabolism. Chronically high WNT/ß-catenin pathway activity causes profibrotic and hypertrophic effects in the adult heart. New data suggest more complex functions of ß-catenin in metabolic maturation of the perinatal heart, establishing an adult pattern of glucose and fatty acid utilization. Additionally, low basal activity of the WNT/ß-catenin cascade maintains oxidative metabolism in the adult heart, and this pathway is reactivated by physiological or pathological stimuli to meet the higher energy needs of the heart. This review summarizes the current state of knowledge of the organization of canonical WNT signaling and its function in cardiogenesis, heart maturation, adult heart function, and remodeling. We also discuss the role of the WNT/ß-catenin pathway in cardiac glucose, lipid metabolism, and mitochondrial physiology.

Induction of Glutathione Synthesis Provides Cardioprotection Regulating NO, AMPK and PPARa Signaling in Ischemic Rat Hearts.

Glutathione (GSH) is essential for antioxidant defence, and its depletion is associated with tissue damage during cardiac ischemia-reperfusion (I/R). GSH is synthesized by the glutamate-cysteine ligase enzyme (GCL) from L-cysteine, which alternatively might be used for hydrogen sulfide production by cystathionine-gamma-lyase (CSE). Here, we have investigated whether in vivo treatment with L-cysteine and an inhibitor of CSE,D,L-propargylglycine (PAG), can modulate cardiac glutathione and whether this treatment can influence heart resistance to I/R in a Langendorff isolated rat hearts model. Pretreatment with PAG + L-cysteine manifested in pronounced cardioprotection, as there was complete recovery of contractile function; preserved constitutive NOS activity; and limited the production of reactive oxygen and nitrogen species in the ischemized myocardium. Cardiac GSH and GSSG levels were increased by 3.5- and 2.1-fold in PAG + L-cysteine hearts and were 3.3- and 3.6-fold higher in PAG + L-cysteine + I/R compared to I/R heart. The cardioprotective effect of PAG + L-cysteine was completely abolished by an inhibitor of GCL, DL-buthionine-(S,R)-sulfoximine. Further analysis indicated diminished fatty acid ß-oxidation, increased glucose consumption and anaerobic glycolysis, and promoted OXPHOS proteins and SERCA2 in PAG + L-cysteine + I/R compared to the I/R group. PAG + L-cysteine inhibited PPARα and up-regulated AMPK signalling in the heart. Thus, induction of glutathione synthesis provided cardioprotection regulating NO, AMPK and PPARa signaling in ischemic rat hearts.

Cardiac-specific ß-catenin deletion dysregulates energetic metabolism and mitochondrial function in perinatal cardiomyocytes.

ß-Catenin signaling pathway regulates cardiomyocytes proliferation and differentiation, though its involvement in metabolic regulation of cardiomyocytes remains unknown. We used one-day-old mice with cardiac-specific knockout of ß-catenin and neonatal rat ventricular myocytes treated with ß-catenin inhibitor to investigate the role of ß-catenin metabolism regulation in perinatal cardiomyocytes. Transcriptomics of perinatal ß-catenin-ablated hearts revealed a dramatic shift in the expression of genes involved in metabolic processes. Further analysis indicated an inhibition of lipolysis and glycolysis in both in vitro and in vivo models. Finally, we showed that ß-catenin deficiency leads to mitochondria dysfunction via the downregulation of Sirt1/PGC-1α pathway. We conclude that cardiac-specific ß-catenin ablation disrupts the energy substrate shift that is essential for postnatal heart maturation, leading to perinatal lethality of homozygous ß-catenin knockout mice.

ß-Catenin Regulates Cardiac Energy Metabolism in Sedentary and Trained Mice.

The role of canonical Wnt signaling in metabolic regulation and development of physiological cardiac hypertrophy remains largely unknown. To explore the function of ß-catenin in the regulation of cardiac metabolism and physiological cardiac hypertrophy development, we used mice heterozygous for cardiac-specific ß-catenin knockout that were subjected to a swimming training model. ß-Catenin haploinsufficient mice subjected to endurance training displayed a decreased ß-catenin transcriptional activity, attenuated cardiomyocytes hypertrophic growth, and enhanced activation of AMP-activated protein kinase (AMPK), phosphoinositide-3-kinase-Akt (Pi3K-Akt), and mitogen-activated protein kinase/extracellular signal-regulated kinases 1/2 (MAPK/Erk1/2) signaling pathways compared to trained wild type mice. We further observed an increased level of proteins involved in glucose aerobic metabolism and ß-oxidation along with perturbed activity of mitochondrial oxidative phosphorylation complexes (OXPHOS) in trained ß-catenin haploinsufficient mice. Taken together, Wnt/ß-catenin signaling appears to govern metabolic regulatory programs, sustaining metabolic plasticity in adult hearts during the adaptation to endurance training.