Inflammation and metabolic dysregulation in diabetic cardiomyopathy

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/67430Diabetic cardiomyopathy is characterized by structural and functional alterations in the heart muscle of people with diabetes that finally lead to heart failure. Metabolic disturbances characterized by increased lipid oxidation, intramyocardial triglyceride accumulation and reduced glucose utilization have all been involved in the pathogenesis of diabetic cardiomyopathy. On the other hand, evidences arisen in the recent years point to a potential link between chronic low-grade inflammation in the heart and metabolic dysregulation. Interestingly, the progression of heart failure and cardiac hypertrophy usually entails the activation of pro-inflammatory pathways. Therefore, in this chapter we summarize novel insights into the crosstalk between inflammatory processes and metabolic dysregulation in the failing heart during diabetes

Emerging Actors in Diabetic Cardiomyopathy: Heartbreaker Biomarkers or Therapeutic Targets?

The diabetic heart is characterized by metabolic disturbances that are often accompanied by local inflammation, oxidative stress, myocardial fibrosis, and cardiomyocyte apoptosis. Overall changes result in contractile dysfunction, concentric left ventricular (LV) hypertrophy, and dilated cardiomyopathy, that together affect cardiac output and eventually lead to heart failure, the foremost cause of death in diabetic patients. There are currently several validated biomarkers for the diagnosis and risk assessment of cardiac diseases, but none is capable of discriminating patients with diabetic cardiomyopathy (DCM). In this review we point to several novel candidate biomarkers from new activated molecular pathways (including microRNAs) with the potential to detect or prevent DCM in its early stages, or even to treat it once established. The prospective use of selected biomarkers that integrate inflammation, oxidative stress, fibrosis, and metabolic dysregulation is widely discussed

Recent advances in pharmaceutical sciences IV

Reproducció del llibre publicat a: http://www.trnres.com/ebookcontents.php?id=234Like in the three previous editions, this E-book compiles a series of contributions in the multidisciplinary research arena of Pharmaceutical Sciences. The E-book has been organized in 12 chapters, whose main topics belong to the fields of pharmacology, physical chemistry, plant physiology, microbiology, physiology, preventive medicine and public health, food science, botany, clinical pharmacy and pharmacotherapy, organic chemistry, biochemistry and molecular biology, and parasitology..

The PPARβ/δ-AMPK Connection in the Treatment of Insulin Resistance

The current treatment options for type 2 diabetes mellitus do not adequately control the disease in many patients. Consequently, there is a need for new drugs to prevent and treat type 2 diabetes mellitus. Among the new potential pharmacological strategies, activators of peroxisome proliferator-activated receptor (PPAR)β/δ show promise. Remarkably, most of the antidiabetic effects of PPARβ/δ agonists involve AMP-activated protein kinase (AMPK) activation. This review summarizes the recent mechanistic insights into the antidiabetic effects of the PPARβ/δ-AMPK pathway, including the upregulation of glucose uptake, muscle remodeling, enhanced fatty acid oxidation, and autophagy, as well as the inhibition of endoplasmic reticulum stress and inflammation. A better understanding of the mechanisms underlying the effects resulting from the PPARβ/δ-AMPK pathway may provide the basis for the development of new therapies in the prevention and treatment of insulin resistance and type 2 diabetes mellitus

Peroxisome Proliferator-Activated Receptor β/δ (PPAR β/δ) as a Potential Therapeutic Target for Dyslipidemia

Dyslipidemia is a powerful predictor of cardiovascular disease in patients at high risk (Turner et al., 1998), such as type 2 diabetic patients. Lowering of LDL-C is the prime target for treatment (2002), but even with intensification of statin therapy, a substantial residual cardiovascular risk remains (Barter et al., 2007; Miller et al., 2008; Fruchart et al., 2008; Shepherd et al., 2006). This may partly be due to atherogenic dyslipidemia. This term is commonly used to describe a condition of abnormally elevated plasma triglycerides and low high-density lipoprotein cholesterol (HDL-C), irrespective of the levels of LDL-C (Grundy, 1995). In addition to these key components, increased levels of small, dense LDL-C particles are also present, which in conjunction with the former components conform the also called “lipid triad” (Shepherd et al., 2005). Other abnormalities include accumulation in plasma of triglyceride-rich lipoproteins (TLRs), including chylomicron and very-low-density lipoprotein (VLDL) remnants. This is reflected by elevated plasma concentrations of non- HDL-C and apolipoprotein B-100 (apoB). Postprandially, there is also accumulation in plasma of TLRs and their remnants, as well as qualitative alterations in LDL and HDL particles. Thus, hypertriglyceridemia is associated with a wide spectrum of atherogenic lipoproteins not measured routinely (Taskinen, 2003). The presence of this lipid plasma profile with high triglyceride and low HDL-C levels have been shown to increase the risk of cardiovascular events independent of conventional risk factors (Bansal et al., 2007; Barter et al., 2007; deGoma et al., 2008). In fact, guidelines recommend modifying high triglyceride and low HDL-C as secondary therapeutic targets to provide additional vascular protection (2002). The presence of atherogenic dyslipidemia is seen in almost all patients with triglycerides > 2.2 mmol/l and HDL-C < 1.0 mmol/l, virtually all of whom have type 2 diabetes or abdominal obesity and insulin resistance (Taskinen, 2003)..

11β-HSD1 Inhibition Rescues SAMP8 Cognitive Impairment Induced by Metabolic Stress

Ageing and obesity have been shown to increase the risk of cognitive decline and Alzheimer's disease (AD). Besides, elevated glucocorticoid (GCs) levels cause metabolic stress and have been associated with the neurodegenerative process. Direct pieces of evidence link the reduction of GCs caused by the inhibition of 11β-HSD type 1 (11β-HSD1) with cognitive improvement. In the present study, we investigated the beneficial effects of 11β-HSD1 inhibitor (i) RL-118 after high-fat diet (HFD) treatment in the senescence-accelerated mouse prone 8 (SAMP8). We found an improvement in glucose intolerance induced by HFD in mice treated with RL-118, a significant reduction in 11β-HSD1 and glucocorticoid receptor (GR) protein levels. Furthermore, specific modifications in the FGF21 activation after treatment with 11β-HSD1i, RL-118, which induced changes in SIRT1/PGC1α/AMPKα pathway, were found. Oxidative stress (OS) and reactive oxygen species (ROS), as well as inflammatory markers and microglial activation, were significantly diminished in HFD mice treated with 11β-HSD1i. Remarkably, treatment with 11β-HSD1i altered PERK pathway in both diet groups, increasing autophagy only in HFD mice group. After RL-118 treatment, a decrease in glycogen synthase kinase 3 (GSK3β) activation, Tau hyperphosphorylation, BACE1 protein levels and the product β-CTF were found. Increases in the non-amyloidogenic secretase ADAM10 protein levels and the product sAPPα were found in both treated mice, regardless of the diet. Consequently, beneficial effects on social behaviour and cognitive performance were found in treated mice. Thus, our results support the therapeutic strategy of selective 11β-HSD1i for the treatment of age-related cognitive decline and AD

Peroxisome proliferator-activated receptor β/δ activation inhibits hypertrophy in neonatal rat cardiomyocytes

Objective: Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is the predominant PPAR subtype in cardiac cells and plays a prominent role in the regulation of cardiac lipid metabolism. However, the role of PPARβ/δ activators in cardiac hypertrophy is not yet known. Methods and Results: In cultured neonatal rat cardiomyocytes, the selective PPARβ/δ activator L-165041 (10 μmol/L) inhibited phenylephrine (PE)-induced protein synthesis ([3H]leucine uptake), induction of the fetal-type gene atrial natriuretic factor (ANF) and cardiac myocyte size. Induction of cardiac hypertrophy by PE stimulation also led to a reduction in the transcript levels of both muscle-type carnitine palmitoyltransferase (50%, P<0.05) and pyruvatedehydrogenase kinase 4 (30%, P<0.05), and these changes were reversed in the presence of the PPARβ/δ agonist L-165041. Stimulation of neonatal rat cardiomyocytes with PE and embryonic rat heart-derived H9c2 cells with lipopolysaccharide (LPS) enhanced the expression of the nuclear factor (NF)-κB-target gene monocyte chemoattractant protein 1 (MCP-1). The induction of MCP-1 was reduced in the presence of L-165041, suggesting that this compound prevented NF-κB activation. Electrophoretic mobility shift assay (EMSA) revealed that L-165041 significantly decreased LPS-stimulated NF-κB binding activity in H9c2 myotubes. Finally, coimmunoprecipitation studies showed that L-165041 strongly enhanced the physical interaction between PPARβ/δ and the p65 subunit of NF-κB, suggesting that increased association between these two proteins is the mechanism responsible for antagonizing NF-κB activation by PPARβ/δ activators. Conclusion: These results suggest that PPARβ/δ activation inhibits PE-induced cardiac hypertrophy and LPS-induced NF-κB activatio

Endoplasmic reticulum stress downregulates PGC-1α in skeletal muscle through ATF4 and an mTOR-mediated reduction of CRTC2

Background Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) downregulation in skeletal muscle contributes to insulin resistance and type 2 diabetes mellitus. Here, we examined the effects of endoplasmic reticulum (ER) stress on PGC-1α levels in muscle and the potential mechanisms involved. Methods The human skeletal muscle cell line LHCN-M2 and mice exposed to different inducers of ER stress were used. Results Palmitate- or tunicamycin-induced ER stress resulted in PGC-1α downregulation and enhanced expression of activating transcription factor 4 (ATF4) in human myotubes and mouse skeletal muscle. Overexpression of ATF4 decreased basal PCG-1α expression, whereas ATF4 knockdown abrogated the reduction of PCG-1α caused by tunicamycin in myotubes. ER stress induction also activated mammalian target of rapamycin (mTOR) in myotubes and reduced the nuclear levels of cAMP response element-binding protein (CREB)-regulated transcription co-activator 2 (CRTC2), a positive modulator of PGC-1α transcription. The mTOR inhibitor torin 1 restored PCG-1α and CRTC2 protein levels. Moreover, siRNA against S6 kinase, an mTORC1 downstream target, prevented the reduction in the expression of CRTC2 and PGC-1α caused by the ER stressor tunicamycin. Conclusions Collectively, these findings demonstrate that ATF4 and the mTOR-CRTC2 axis regulates PGC-1α transcription under ER stress conditions in skeletal muscle, suggesting that its inhibition might be a therapeutic target for insulin resistant states

Design and Synthesis of AMPK Activators and GDF15 Inducers

Targeting growth differentiation factor 15 (GDF15) is a recent strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Here, we designed, synthesized, and pharmacologically evaluated in vitro a novel series of AMPK activators to upregulate GDF15 levels. These compounds were structurally based on the (1-dibenzylamino-3-phenoxy)propan-2-ol structure of the orphan ubiquitin E3 ligase subunit protein Fbxo48 inhibitor, BC1618. This molecule showed a better potency than metformin, increasing GDF15 mRNA levels in human Huh-7 hepatic cells. Based on BC1618, structural modifications have been performed to create a collection of diversely substituted new molecules. Of the thirty-five new compounds evaluated, compound 21 showed a higher increase in GDF15 mRNA levels compared with BC1618. Metformin, BC1618, and compound 21 increased phosphorylated AMPK, but only 21 increased GDF15 protein levels. Overall, these findings indicate that 21 has a unique capacity to increase GDF15 protein levels in human hepatic cells compared with metformin and BC1618

The Interplay between NF-kappaB and E2F1 Coordinately Regulates Inflammation and Metabolism in Human Cardiac Cells

Pyruvate dehydrogenase kinase 4 (PDK4) inhibition by nuclear factor-κB (NF-κB) is related to a shift towards increased glycolysis during cardiac pathological processes such as cardiac hypertrophy and heart failure. The transcription factors estrogen-related receptor-α (ERRα) and peroxisome proliferator-activated receptor (PPAR) regulate PDK4 expression through the potent transcriptional coactivator PPARγ coactivator-1α (PGC-1α). NF-κB activation in AC16 cardiac cells inhibit ERRα and PPARβ/δ transcriptional activity, resulting in reduced PGC-1α and PDK4 expression, and an enhanced glucose oxidation rate. However, addition of the NF-κB inhibitor parthenolide to these cells prevents the downregulation of PDK4 expression but not ERRα and PPARβ/δ DNA binding activity, thus suggesting that additional transcription factors are regulating PDK4. Interestingly, a recent study has demonstrated that the transcription factor E2F1, which is crucial for cell cycle control, may regulate PDK4 expression. Given that NF-κB may antagonize the transcriptional activity of E2F1 in cardiac myocytes, we sought to study whether inflammatory processes driven by NF-κB can downregulate PDK4 expression in human cardiac AC16 cells through E2F1 inhibition. Protein coimmunoprecipitation indicated that PDK4 downregulation entailed enhanced physical interaction between the p65 subunit of NF-κB and E2F1. Chromatin immunoprecipitation analyses demonstrated that p65 translocation into the nucleus prevented the recruitment of E2F1 to the PDK4 promoter and its subsequent E2F1-dependent gene transcription. Interestingly, the NF-κB inhibitor parthenolide prevented the inhibition of E2F1, while E2F1 overexpression reduced interleukin expression in stimulated cardiac cells. Based on these findings, we propose that NF-κB acts as a molecular switch that regulates E2F1-dependent PDK4 gene transcription