HFD-induced Cardiac Dysfunction Research Articles

Aerobic exercise mitigates high-fat diet-induced cardiac dysfunction, pyroptosis, and inflammation by inhibiting STING-NLRP3 signaling pathway.

Obesity has been identified as an independent risk factor for cardiovascular disease. Recent reports have highlighted the significance of stimulator of interferon genes (STING)-NOD-like receptor protein 3 (NLRP3) signaling pathway mediated pyroptosis, and inflammation in cardiovascular disease. Previous studies have demonstrated that exercise training effectively prevents cardiac pyroptosis and inflammation in high-fat diet (HFD)-fed mice. However, it is currently unknown whether exercise reduces pyroptosis and inflammation in obese hearts by targeting the STING-NLRP3 signaling pathway. We investigated the impact of an 8-week aerobic exercise regimen on cardiac function, pyroptosis, inflammation, and the STING-NLRP3 signaling pathway in HFD-induced obese mice. Additionally, to explore the underlying mechanism of STING in exercise-mediated cardioprotection, we administered intraperitoneal injections of the STING agonist diABZI to the mice. Furthermore, to investigate the role of the STING-NLRP3 signaling pathway in HFD-induced cardiac dysfunction, we administered adeno-associated virus 9 (AAV9) encoding shRNA targeting STING (shRNA-STING) via tail vein injection to knockdown STING expression specifically in mouse hearts. After one week of AAV9 injection, we intraperitoneally injected nigericin as an NLRP3 agonist. We first found that aerobic exercise effectively suppressed HFD-mediated upregulation of STING and NLRP3 in the hearts. Moreover, we demonstrated that the protective effect of aerobic exercise in HFD-induced cardiac dysfunction, pyroptosis, and inflammation was impaired by stimulating the STING pathway using diABZI. Additionally, activation of the NLRP3 with nigericin abolished the ameliorative effect of STING deficiency in HFD-induced cardiac dysfunction, pyroptosis, and inflammation. Based on these findings, we concluded that 8-week aerobic exercise alleviates HFD-induced cardiac dysfunction, pyroptosis, and inflammation by targeting STING-NLRP3 signaling pathway. Inhibition of STING-NLRP3 signaling pathway may serve as a promising therapeutic strategy against obesity-induced cardiomyopathy.

Angiotensin II type 1a receptor knockout ameliorates high-fat diet-induced cardiac dysfunction by regulating glucose and lipid metabolism.

Obesity-related cardiovascular diseases are associated with overactivation of the renin-angiotensin system (RAS). However, the underlying mechanisms remain elusive. In this study, we investigate the role of angiotensin II (Ang II) in high-fat diet (HFD)-induced cardiac dysfunction by focusing on cardiac glucose and lipid metabolism and energy supply. Ang II plays a role in cardiovascular regulation mainly by stimulating angiotensin II type 1 receptor (AT1R), among which AT1aR is the most important subtype in regulating the function of the cardiovascular system. AT1aR gene knockout (AT1aR ‒/‒) rats and wild-type (WT) rats are randomly divided into four groups and fed with either a normal diet (ND) or a HFD for 12 weeks. The myocardial lipid content, Ang II level and cardiac function are then evaluated. The expressions of a number of genes involved in glucose and fatty acid oxidation and mitochondrial dynamics are measured by quantitative polymerase chain reaction and western blot analysis. Our results demonstrate that AT1aR knockout improves HFD-induced insulin resistance and dyslipidemia as well as lipid deposition and left ventricular dysfunction compared with WT rats fed a HFD. In addition, after feeding with HFD, AT1aR ‒/‒ rats not only show further improvement in glucose and fatty acid oxidation but also have a reverse effect on increased mitochondrial fission proteins. In conclusion, AT1aR deficiency ameliorates HFD-induced cardiac dysfunction by enhancing glucose and fatty acid oxidation, regulating mitochondrial dynamics-related protein changes, and further promoting cardiac energy supply.

LncRNA ZNF593-AS alleviates diabetic cardiomyopathy via suppressing IRF3 signaling pathway

Diabetes could directly induce cardiac injury, leading to cardiomyopathy. However, treatment strategies for diabetic cardiomyopathy remain limited. ZNF593-AS knockout and cardiomyocyte-specific transgenic mice were constructed. In addition, high-fat diet (HFD)-induced diabetic mouse model and db/db mice, another classic diabetic mouse model, were employed. ZNF593-AS was silenced using GapmeR, a modified antisense oligonucleotide, while overexpressed using a recombinant adeno-associated virus serotype 9-mediated gene delivery system. Transcriptome sequencing, RNA pull-down assays, and RNA immunoprecipitation assays were also performed to investigate the underlying mechanisms. ZNF593-AS expression was decreased in diabetic hearts. ZNF593-AS attenuated the palmitic acid-induced apoptosis of cardiomyocytes invitro. In HFD-induced diabetic mice, ZNF593-AS deletion aggravated cardiac dysfunction and enhanced cardiac apoptosis and inflammation. In contrast, HFD-induced cardiac dysfunction was improved in ZNF593-AS transgenic mice. Consistently, ZNF593-AS exerted the same cardioprotective effects in db/db mice. Mechanistically, ZNF593-AS directly interacted with the functional domain of interferon regulatory factor 3 (IRF3), and suppressed fatty acid-induced phosphorylation and activation of IRF3, contributing to the amelioration of cardiac cell death and inflammation. In conclusion, our results identified the protective role of ZNF593-AS in diabetic cardiomyopathy, suggesting a novel potential therapeutic target.

Acid sphingomyelinase promotes diabetic cardiomyopathy via NADPH oxidase 4 mediated apoptosis

BackgroundIncreased acid sphingomyelinase (ASMase) activity is associated with insulin resistance and cardiac dysfunction. However, the effects of ASMase on diabetic cardiomyopathy (DCM) and the molecular mechanism(s) underlying remain to be elucidated. We here investigated whether ASMase caused DCM through NADPH oxidase 4-mediated apoptosis.Methods and resultsWe used pharmacological and genetic approaches coupled with study of murine and cell line samples to reveal the mechanisms initiated by ASMase in diabetic hearts. The protein expression and activity of ASMase were upregulated, meanwhile ceramide accumulation was increased in the myocardium of HFD mice. Inhibition of ASMase with imipramine (20 mg Kg−1 d−1) or siRNA reduced cardiomyocyte apoptosis, fibrosis, and mitigated cardiac hypertrophy and cardiac dysfunction in HFD mice. The similar effects were observed in cardiomyocytes treated with high glucose (HG, 30 mmol L−1) + palmitic acid (PA, 100 μmol L−1) or C16 ceramide (CER, 20 μmol L−1). Interestingly, the cardioprotective effect of ASMase inhibition was not accompanied by reduced ceramide accumulation, indicating a ceramide-independent manner. The mechanism may involve activated NADPH oxidase 4 (NOX4), increased ROS generation and triggered apoptosis. Suppression of NOX4 with apocynin prevented HG + PA and CER incubation induced Nppb and Myh7 pro-hypertrophic gene expression, ROS production and apoptosis in H9c2 cells. Furthermore, cardiomyocyte-specific ASMase knockout (ASMaseMyh6KO) restored HFD-induced cardiac dysfunction, remodeling, and apoptosis, whereas NOX4 protein expression was downregulated.ConclusionsThese results demonstrated that HFD-mediated activation of cardiomyocyte ASMase could increase NOX4 expression, which may stimulate oxidative stress, apoptosis, and then cause metabolic cardiomyopathy.

Exercise and/or Cold Exposure Alters the Gene Expression Profile in the Fat Body and Changes the Heart Function in Drosophila.

The major reason of human morbidity and mortality is obesity and related diseases. Brown adipose tissue (BAT) is associated with low total adipose tissue content and a lower risk of type 2 diabetes mellitus. Studies have shown that exercise and cold expose may induce browning. In this study, we verified (1) whether exercise and/or cold exposure can improve the expression level of ucp4c, serca, ampkα, camkII, sirt1, octβ3r, and hamlet; (2) if these interventions can save cardiac dysfunction induced by a high-fat diet (HFD) in Drosophila. w1118 (wild-type) virgin female flies collected within 8 h after eclosion were divided into eight groups: the normal feed control group (NFD-C), the normal feed exercise group (NFD-E), the normal feed cold exposure group (NFD-CA), the normal feed exercise/cold exposure group (NFD-EC), the HFD control group (HFD-C), the HFD exercise group (HFD-E), the HFD cold exposure group (HFD-CA), and the HFD exercise/cold exposure group (HFD-EC). After exercise and/or cold exposure for 7 days, the mRNA expression levels of ucp4c, serca, ampkα, camk II, sirt1, octβ3r, and hamlet were tested by qRT-PCR, and m-mode was used to assess cardiac function. In addition, we assessed the triacylglycerol (TAG) levels, motor ability, fat mass (by Oil Red O [ORO] staining), and morphological features. The results of TAG, ORO staining, and morphological features all indicate that after interventions, body size of Drosophila was smaller compared with the control group, irrespective of the feeding patterns. The mRNA expression levels of ucp4c, serca, octβ3r, hamlet, ampkα, camkII, and sirt1 were changed to varying degrees under different intervention states (exercise and/or cold exposure). Cold exposure and exercise/cold exposure partly improved cardiac function and the normal fruit flies’ cardiac function and exercise ability. However, after exercise intervention, exercise ability and heart function were improved in both HFD and normal-fat diet (NFD) fruit flies. In conclusion, different intervention states (exercise and/or cold exposure) can change the mRNA expression levels of ucp4c, serca, octβ3r, hamlet, ampkα, camkII, and sirt1. Exercise is the most effective way to restore HFD-induced cardiac dysfunction.

Direct cardio-protection of Dapagliflozin against obesity-related cardiomyopathy via NHE1/MAPK signaling.

Obesity is an important independent risk factor for cardiovascular diseases, remaining an important health concern worldwide. Evidence shows that saturated fatty acid-induced inflammation in cardiomyocytes contributes to obesity-related cardiomyopathy. Dapagliflozin (Dapa), a selective SGLT2 inhibitor, exerts a favorable preventive activity in heart failure. In this study, we investigated the protective effect of Dapa against cardiomyopathy caused by high fat diet-induced obesity in vitro and in vivo. Cultured rat cardiomyocyte H9c2 cells were pretreated with Dapa (1, 2.5 μM) for 1.5 h, followed by treatment with palmitic acid (PA, 200 μM) for 24 h. We showed that Dapa pretreatment concentration-dependently attenuated PA-induced cell hypertrophy, fibrosis and apoptosis. Transcriptome analysis revealed that inhibition of PA-activated MAPK/AP-1 pathway contributed to the protective effect of Dapa in H9c2 cells, and this was confirmed by anti-p-cJUN fluorescence staining assay. Using surface plasmon resonance analysis we found the direct binding of Dapa with NHE1. Gain and loss of function experiments further demonstrated the role of NHE1 in the protection of Dapa. In vivo experiments were conducted in mice fed a high fat diet for 5 months. The mice were administered Dapa (1 mg·kg-1·d-1, i.g.) in the last 2 months. Dapa administration significantly reduced the body weight and improved the serum lipid profiles. Dapa administration also alleviated HFD-induced cardiac dysfunction and cardiac aberrant remodeling via inhibiting MAPK/AP-1 pathway and ameliorating cardiac inflammation. In conclusion, Dapa exerts a direct protective effect against saturated fatty acid-induced cardiomyocyte injury in addition to the lowering effect on serum lipids. The protective effect results from negative regulating MAPK/AP-1 pathway in a NHE1-dependent way. The current study highlights the potential of clinical use of Dapa in the prevention of obesity-related cardiac dysfunction.

Increasing Fatty Acid Oxidation Prevents High-Fat Diet-Induced Cardiomyopathy Through Regulating Parkin-Mediated Mitophagy.

Increased fatty acid oxidation (FAO) has long been considered a culprit in the development of obesity/diabetes mellitus-induced cardiomyopathy. However, enhancing cardiac FAO by removing the inhibitory mechanism of long-chain fatty acid transport into mitochondria via deletion of acetyl coenzyme A carboxylase 2 (ACC2) does not cause cardiomyopathy in nonobese mice, suggesting that high FAO is distinct from cardiac lipotoxicity. We hypothesize that cardiac pathology-associated obesity is attributable to the imbalance of fatty acid supply and oxidation. Thus, we here seek to determine whether further increasing FAO by inducing ACC2 deletion prevents obesity-induced cardiomyopathy, and if so, to elucidate the underlying mechanisms. We induced high FAO in adult mouse hearts by cardiac-specific deletion of ACC2 using a tamoxifen-inducible model (ACC2 iKO). Control and ACC2 iKO mice were subjected to high-fat diet (HFD) feeding for 24 weeks to induce obesity. Cardiac function, mitochondria function, and mitophagy activity were examined. Despite both control and ACC2 iKO mice exhibiting a similar obese phenotype, increasing FAO oxidation by deletion of ACC2 prevented HFD-induced cardiac dysfunction, pathological remodeling, and mitochondria dysfunction, as well. Similarly, increasing FAO by knockdown of ACC2 prevented palmitate-induced mitochondria dysfunction and cardiomyocyte death in vitro. Furthermore, HFD suppressed mitophagy activity and caused damaged mitochondria to accumulate in the heart, which was attenuated, in part, in the ACC2 iKO heart. Mechanistically, ACC2 iKO prevented HFD-induced downregulation of parkin. During stimulation for mitophagy, mitochondria-localized parkin was severely reduced in control HFD-fed mouse heart, which was restored, in part, in ACC2 iKO HFD-fed mice. These data show that increasing cardiac FAO alone does not cause cardiac dysfunction, but protects against cardiomyopathy in chronically obese mice. The beneficial effect of enhancing cardiac FAO in HFD-induced obesity is mediated, in part, by the maintenance of mitochondria function through regulating parkin-mediated mitophagy. Our findings also suggest that targeting the parkin-dependent mitophagy pathway could be an effective strategy against the development of obesity-induced cardiomyopathy.

<p>microRNA Expression Profiles in Myocardium of High-Fat Diet-Induced Obesity Rat</p>

PurposeA high-fat diet (HFD) can lead to cardiac dysfunction, hypertrophy, and fibrosis. This study aimed to explore microRNA expression profiles in the myocardium of HFD-induced obesity rat.Materials and MethodsWistar rats were randomly divided into two groups, and fed with normal chow diet (NCD) or HFD for 20 weeks. Cardiac function was evaluated by echocardiography. Left ventricular myocardium was harvested to assess the extent of myocardial morphology alteration. MicroRNA expression was analyzed using Agilent miRNA microarray and quantitative real-time PCR (qRT-PCR) was used to validate the microarray data. The mirdbV6 database was used to forecast the miRNA target genes. The role of microRNAs in palmitate-induced cardiac hypertrophy and fibrosis in primary neonatal rat cardiomyocytes was evaluated by loss- and gain-of-function experiments.ResultsSignificant changes in cardiac function, hypertrophy, fibrosis, and apoptosis were found in HFD rats as compared with NCD rats. miR-141-3p and miR-144-3p were also significantly upregulated in the myocardium of HFD-induced obesity rat. A series of genes involved in essential biological processes, including anatomical structure development and metabolic process, was targeted by these two miRNAs. These target genes were also implicated in signaling pathways involved in the PI3K-Akt signaling pathway, Wnt signaling pathway, autophagy, and protein processing in the endoplasmic reticulum. Inhibition of miR-141 or overexpression of miR-144 attenuated palmitate-induced cardiac hypertrophy and fibrosis. In contrast, overexpression of miR-141 or inhibition of miR-144 aggravated palmitate-induced cardiac hypertrophy and fibrosis.ConclusionThis study identifies that miR-141 and miR-144 are candidate miRNAs associated with the development of HFD-induced cardiac dysfunction and structure alteration.

Endurance exercise prevents high-fat-diet induced heart and mobility premature aging and dsir2 expression decline in aging Drosophila.

High-Fat-Diet (HFD)-induced obesity is a major contributor to heart and mobility premature aging and mortality in both Drosophila and humans. The dSir2 genes are closely related to aging, but there are few directed reports showing that whether HFD could inhibit the expression dSir2 genes. Endurance exercise can prevent fat accumulation and reverse HFD-induced cardiac dysfunction. Endurance also delays age-relate functional decline. It is unclear whether lifetime endurance exercise can combat lifetime HFD-induced heart and mobility premature aging, and relieve the harmful HFD-induced influence on the dSir2 gene and lifespan yet. In this study, flies are fed a HFD and trained from when they are 1 week old until they are 5 weeks old. Then, triacylglycerol levels, climbing index, cardiac function, lifespan, and dSir2 mRNA expressions are measured. We show that endurance exercise improves climbing capacity, cardiac contraction, and dSir2 expression, and it reduces body and heart triacylglycerol levels, heart fibrillation, and mortality in both HFD and aging flies. So, lifelong endurance exercise delays HFD-induced accelerated age-related locomotor impairment, cardiac dysfunction, death, and dSir2 expression decline, and prevents HFD-induced premature aging in Drosophila.

Improvement of cardiac dysfunction by bilateral surgical renal denervation in animals with diabetes induced by high fructose and high fat diet

AimsInsulin resistance (IR) and sympathetic over-activation play a critical role in diabetic cardiomyopathy (DCM). Percutaneous renal sympathetic denervation (RDN) was tested to treat refractory hypertension. However, the benefits of RDN for DCM and IR still remain unknown. The present study aimed to investigate the effect and associated mechanisms of bilateral surgical RDN (bsRDN) on cardiac function and glucose metabolism in animals with diabetes. MethodsThirty-two male New Zealand white rabbits were randomly assigned to Chow (n=8, normal diet) and TEST (n=24, high-fructose fat diet [HFD]) groups. At 48 weeks after HFD feeding, animals in the TEST group were randomized to the Sham, HFD, and RDN subgroups and were fed a HFD for an additional 8 weeks. Repeated measurements of cardiac function, IR, apoptosis/autophagy, and histopathological assessment were performed at 48 and 56 weeks. ResultsHFD feeding for 56 weeks induced IR and diastolic cardiac dysfunction with hypertrophy in septum but well preserved eject fraction in the animals. Impaired IR further deteriorated over the time in the RDN group, featured by a more profound reduction in GLUT4 mRNA and its translocation to the plasma membrane. Successful denervation was associated with improvement of cardiac function via preventing myocardial fibrosis and over-expression of procollagen III, mammalian target of rapamycin, and cardiac apoptosis. Cardiac autophagy, assessed by either electron microscopy or Western blot, was enhanced by bsRDN. ConclusionsRenal sympathetic denervation led to a significant improvement of HFD-induced cardiac dysfunction by shifting the cardiac apoptosis to autophagy, but worsening IR. Further study is required to identify the clinical benefits of RDN.

Hydrogen sulfide attenuates high fat diet-induced cardiac dysfunction via the suppression of endoplasmic reticulum stress

Diabetic cardiomyopathy is a significant contributor to the morbidity and mortality associated with diabetes and metabolic syndrome. However, the underlying molecular mechanisms that lead to its development have not been fully elucidated. Hydrogen sulfide (H2S) is an endogenously produced signaling molecule that is critical for the regulation of cardiovascular homeostasis. Recently, therapeutic strategies aimed at increasing its levels have proven cardioprotective in models of acute myocardial ischemia–reperfusion injury and heart failure. The precise role of H2S in the pathogenesis of diabetic cardiomyopathy has not yet been established. Therefore, the goal of the present study was to evaluate circulating and cardiac H2S levels in a murine model of high fat diet (HFD)-induced cardiomyopathy. Diabetic cardiomyopathy was produced by feeding mice HFD (60% fat) chow for 24 weeks. HFD feeding reduced both circulating and cardiac H2S and induced hallmark features of type-2 diabetes. We also observed marked cardiac dysfunction, evidence of cardiac enlargement, cardiac hypertrophy, and fibrosis. H2S therapy (SG-1002, an orally active H2S donor) restored sulfide levels, improved some of the metabolic perturbations stemming from HFD feeding, and attenuated HFD-induced cardiac dysfunction. Additional analysis revealed that H2S therapy restored adiponectin levels and suppressed cardiac ER stress stemming from HFD feeding. These results suggest that diminished circulating and cardiac H2S levels play a role in the pathophysiology of HFD-induced cardiomyopathy. Additionally, these results suggest that H2S therapy may be of clinical importance in the treatment of cardiovascular complications stemming from diabetes.

Conditional Knockout of Prolyl Hydroxylase Domain Protein 2 Attenuates High Fat-Diet-Induced Cardiac Dysfunction in Mice

Oxygen sensor prolyl hydroxylases (PHDs) play important roles in the regulation of HIF-α and cell metabolisms. This study was designed to investigate the direct role of PHD2 in high fat-diet (HFD)-induced cardiac dysfunction. In HFD fed mice, PHD2 expression was increased without significant changes in PHD1 and PHD3 levels in the heart. This was accompanied by a significant upregulation of myeloid differentiation factor 88 (MYD88) and NF-κB. To explore the role of PHD2 in HFD-induced cardiac dysfunction, PHD2 conditional knockout mice were fed a HFD for 16 weeks. Intriguingly, knockout of PHD2 significantly reduced MYD88 and NF-κb expression in HFD mouse hearts. Moreover, knockout of PHD2 inhibited TNFα and ICAM-1 expression, and reduced cell apoptosis and macrophage infiltration in HFD mice. This was accompanied by a significant improvement of cardiac function. Most importantly, conditional knockout of PHD2 at late stage in HFD mice significantly improved glucose tolerance and reversed cardiac dysfunction. Our studies demonstrate that PHD2 activity is a critical contributor to the HFD-induced cardiac dysfunction. Inhibition of PHD2 attenuates HFD-induced cardiac dysfunction by a mechanism involving suppression of MYD88/NF-κb pathway and inflammation.

PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity

Diabetes is a multi-organ disease and diabetic cardiomyopathy can result in heart failure, which is a leading cause of morbidity and mortality in diabetic patients. In the liver, insulin resistance contributes to hyperglycaemia and hyperlipidaemia, which further worsens the metabolic profile. Defects in mTOR signalling are believed to contribute to metabolic dysfunctions in diabetic liver and hearts, but evidence is missing that mTOR activation is causal to the development of diabetic cardiomyopathy. This study shows that specific mTORC1 inhibition by PRAS40 prevents the development of diabetic cardiomyopathy. This phenotype was associated with improved metabolic function, blunted hypertrophic growth and preserved cardiac function. In addition PRAS40 treatment improves hepatic insulin sensitivity and reduces systemic hyperglycaemia in obese mice. Thus, unlike rapamycin, mTORC1 inhibition with PRAS40 improves metabolic profile in diabetic mice. These findings may open novel avenues for therapeutic strategies using PRAS40 directed against diabetic-related diseases.

Abstract 317: Conditional Knockout Of Phd2 Ameliorates High-fat Diet-induced Cardiac Dysfunction Via Inhibition Of Tlr4-nfκB Pathway In A Hifa-independent Manner

Oxygen sensors prolyl hydroxylases (PHDs) plays an important role in the regulation of hypoxia-inducible factor (HIFα) as well as nuclear factor-κ B (NF-κB) activity. Our previous study demonstrated that activation of vascular Toll-like receptor TLR-MyD88-IRAK4 signaling pathway contributes to vascular dysfunction in high-fat-diet (HFD)-induced diabetes. The present study investigates whether conditional knockout of prolyl hydroxylase-2 (PHD2) improves cardiac function via suppression of TLR-NF-κb signaling in a HFD-induced diabetic cardiomyopathy mouse model. Wild type (WT-Cre + ), PHD2 conditional knockout (PHD2CKO) and PHD2 +/- mice were fed with either HFD or normal chow diet (NFD) for 18 weeks. The levels of PHD1-3, HIF, angiogenic growth factors, MyD88, IRAK-4, TLR4, NF-κb and Wnt7b gene expression were measured. Cardiac hypertrophy, fibrosis and cardiac function were analyzed at 18 weeks after PHD2 deactivation . Feeding of WT-Cre + mice with HFD for 18 weeks resulted in a significant reduction of cardiac functions. The basal expression of PHD2 was significantly increased in the heart of HFD mice. The expression of PHD2 was significantly reduced in the heart of PHD2CKO and PHD2 +/- mice fed with HFD whereas PHD1 and PHD3 expression remains unchanged. Conditional knockout of PHD2 resulted in suppression of MyD88, IRAK-4, TLR4, NF-κb and Wnt7b expression. Deactivation of PHD2 had little effect on the expression of HIF1α, HIF2α and angiogenic growth factor in the hearts of HFD-induced diabetic mice. Conditional knockout of PHD2 further suppressed HFD-induced cardiac hypertrophy and significantly improved HFD-induced cardiac dysfunction. In contrast, conditional knockout of PHD2 resulted in an increase in HIFα expression and cardiac dysfunction in NFD mice. These results suggest that deactivation of PHD2 attenuates HFD-induced diabetic cardiomyopathy via suppression of TLR4-MyD88-IRAK4-NF-κb-Wnt7b signaling pathway in a HIF-independent manner.

Macrophage Migration Inhibitory Factor Inhibition Is Deleterious for High-Fat Diet-Induced Cardiac Dysfunction

AimsDevelopment of metabolic syndrome is associated with impaired cardiac performance, mitochondrial dysfunction and pro-inflammatory cytokine increase, such as the macrophage migration inhibitory factor MIF. Depending on conditions, MIF may exert both beneficial and deleterious effects on the myocardium. Therefore, we tested whether pharmacological inhibition of MIF prevented or worsened metabolic syndrome-induced myocardial dysfunction.Methods and ResultsC57BL/6J mice were fed for ten weeks with 60% fat-enriched diet (HFD) or normal diet (ND). MIF inhibition was obtained by injecting mice twice a week with ISO-1, for three consecutive weeks. Then, triglycerides, cholesterol, fat mass, glucose intolerance, insulin resistance, ex vivo cardiac contractility, animal energetic substrate utilization assessed by indirect calorimetry and mitochondrial respiration and biogenesis were evaluated. HFD led to fat mass increase, dyslipidemia, glucose intolerance and insulin resistance. ISO-1 did not alter these parameters. However, MIF inhibition was responsible for HFD-induced cardiac dysfunction worsening. Mouse capacity to increase oxygen consumption in response to exercise was reduced in HFD compared to ND, and further diminished in ISO-1-treated HFD group. Mitochondrial respiration was reduced in HFD mice, treated or not with ISO-1. Compared to ND, mitochondrial biogenesis signaling was upregulated in the HFD as demonstrated by mitochondrial DNA amount and PGC-1α expression. However, this increase in biogenesis was blocked by ISO-1 treatment.ConclusionMIF inhibition achieved by ISO-1 was responsible for a reduction in HFD-induced mitochondrial biogenesis signaling that could explain majored cardiac dysfunction observed in HFD mice treated with MIF inhibitor.

Carbon Monoxide Improves Cardiac Function and Mitochondrial Population Quality in a Mouse Model of Metabolic Syndrome

AimsMetabolic syndrome induces cardiac dysfunction associated with mitochondria abnormalities. As low levels of carbon monoxide (CO) may improve myocardial and mitochondrial activities, we tested whether a CO-releasing molecule (CORM-3) reverses metabolic syndrome-induced cardiac alteration through changes in mitochondrial biogenesis, dynamics and autophagy.Methods and ResultsMice were fed with normal diet (ND) or high-fat diet (HFD) for twelve weeks. Then, mice received two intraperitoneal injections of CORM-3 (10 mg.kg−1), with the second one given 16 hours after the first. Contractile function in isolated hearts and mitochondrial parameters were evaluated 24 hours after the last injection. Mitochondrial population was explored by electron microscopy. Changes in mitochondrial dynamics, biogenesis and autophagy were assessed by western-blot and RT-qPCR. Left ventricular developed pressure was reduced in HFD hearts. Mitochondria from HFD hearts presented reduced membrane potential and diminished ADP-coupled respiration. CORM-3 restored both cardiac and mitochondrial functions. Size and number of mitochondria increased in the HFD hearts but not in the CORM-3–treated HFD group. CORM-3 modulated HFD-activated mitochondrial fusion and biogenesis signalling. While autophagy was not activated in the HFD group, CORM-3 increased the autophagy marker LC3-II. Finally, ex vivo experiments demonstrated that autophagy inhibition by 3-methyladenine abolished the cardioprotective effects of CORM-3.ConclusionCORM-3 may modulate pathways controlling mitochondrial quality, thus leading to improvements of mitochondrial efficiency and HFD-induced cardiac dysfunction.