Cardiac Lipid Research Articles

Real-ambient particulate matter exposure-induced FGFR1 methylation contributes to cardiac dysfunction via lipid metabolism disruption

Particulate matter (PM)-induced cardiometabolic disorder contributes to the progression of cardiac diseases, but its epigenetic mechanisms are largely unknown. This study used bioinformatic analysis, in vivo and in vitro multiple models to investigate the role of PM-induced cardiac fibroblast growth factor 1 (FGFR1) methylation and its impact on cardiomyocyte lipid metabolic disruption. Bioinformatic analysis revealed that FGFR1 was associated with cardiac pathologies, mitochondrial function and metabolism, supporting the possibility that FGFR1 may play regulatory roles in PM-induced cardiac functional impairment and lipid metabolism disorders. Individually ventilated cage (IVC)-based real-ambient PM exposure system mouse models were used to expose C57/BL6 mice for six and fifteen weeks. The results showed that PM induced cardiac lipid metabolism disorder, DNA nucleotide methyltransferases (DNMTs) alterations and FGFR1 expression declines in mouse heart. Lipidomics analysis revealed that carnitines, phosphoglycerides and lysophosphoglycerides were most significantly affected by PM exposure. At the cellular level, AC16 cells treated with FGFR1 inhibitor (PD173074) led to impaired mitochondrial and metabolic functions in cardiomyocytes. Inhibition of DNA methylation in cells by 5-AZA partially restored the FGFR1 expression, ameliorated cardiomyocyte injury and mitochondrial functions. These changes involved alterations in AMP-activated protein kinase (AMPK)-peroxisome proliferator activated receptors gamma, coactivator 1 alpha (PGC1α) pathways. Bisulfite sequencing PCR (BSP) and DNA methylation specific PCR (MSP) confirmed that PM exposure induced FGFR1 gene promoter region methylation. These results suggested that, by inducing FGFR1 methylation, PM exposure would affect cardiac injury and deranged lipid metabolism. Overexpression of FGFR1 in mouse heart using adeno-associated virus 9 (AAV9) effectively alleviated PM-induced cardiac impairment and metabolic disorder. Our findings identified that FGFR1 methylation might be one of the potential indicators for PM-induced cardiac mitochondrial and metabolic dysfunction, providing novel insights into underlying PM-related cardiotoxic mechanisms.

Western Diet Causes Heart Failure With Reduced Ejection Fraction and Metabolic Shifts After Diastolic Dysfunction and Novel Cardiac Lipid Derangements

Western diet (WD) impairs glucose tolerance and cardiac lipid dynamics, preceding heart failure with reduced ejection fraction (HFrEF) in mice. Unlike diabetic db/db mice with high cardiac triglyceride (TG) and rapid TG turnover, WD mice had high TG but slowed turnover, reducing lipolytic PPAR⍺ activation. WD deranged cardiac TG dynamics by imbalancing synthesis and lipolysis, with low cardiac TG lipase (ATGL), low ATGL co-activator, and high ATGL inhibitory peptide. By 24weeks of WD, hearts shifted from diastolic dysfunction to diastolic dysfunction with HFrEF with decreases in GLUT4 and exogenous glucose oxidation and elevated β-hydroxybutyrate dehydrogenase 1 without increasing ketone oxidation.

Characterisation of the Paternal Influence on Intergenerational Offspring Cardiac and Brain Lipid Homeostasis in Mice.

There is growing evidence that poor paternal diet at the time of conception increase the risk of offspring developing a range of non-communicable metabolic diseases, such as obesity, diabetes and cardiovascular disease, in adulthood. We hypothesise that a paternal low protein-high carbohydrate diet perturbs offspring tissue lipid abundance through both sperm and seminal plasma-mediated mechanisms. To test our hypothesis, we fed male C57BL/6 mice either a control normal protein diet (NPD; 18% protein) or an isocaloric low protein diet (LPD; 9% protein) for a minimum of 8 weeks. We generated offspring through artificial insemination, in combination with vasectomised male mating. Using this approach, we derived offspring from either NPD or LPD sperm but in the presence of NPD or LPD seminal plasma. Using high resolution mass-spectrometry, we found that offspring derived from either LPD sperm or seminal fluid displayed perturbed cardiac and brain lipid abundance from just three weeks of age, typically associated with the altered abundance of tissue triglycerides. We also observed the differential sex-specific patterns of lipids between the control and experimental offspring's hearts and brains. These observations indicate that poor paternal diet at the time of conception affects offspring cardiac and brain lipid profiles in an age-, sex- and generation-specific manner.

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

The WNT/β-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/β-catenin signaling cascade is considered to be cardioprotective after infarction through the upregulation of prosurvival genes and reprogramming of metabolism. Chronically high WNT/β-catenin pathway activity causes profibrotic and hypertrophic effects in the adult heart. New data suggest more complex functions of β-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/β-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/β-catenin pathway in cardiac glucose, lipid metabolism, and mitochondrial physiology.

β2AR against myocarditis-lipid deposition depends on estrogenic environment in stress.

Cardiac lipid accumulation and inflammation have been linked to stress. There is mounting evidence that estrogen reduces lipid deposition and has anti-inflammatory properties; however, the exact mechanism is unknown. Recent studies showed that NLRP3 inflammasome is a key trigger of cardiac inflammation, and it is also involved in the progression of metabolic diseases. This study investigated the crucial role of the NLRP3 inflammasome in lipid accumulation during stress and the regulatory mechanism of estrogen in this process. Stress models were established by isoproterenol treatments in mice and H9c2 cells. With 5 mM isoproterenol, NLRP3 inflammasome activation was observed earlier at 0.5 h than that of lipid accumulation at 1 h in H9c2 cells. At 1 h after stress, the isoproterenol concentration required for NLRP3 inflammasome activation was lower compared to the concentration required for lipid deposition in mice myocardia and H9c2 cells; the former required 210 mg/kg or 10 μM for activation while the latter required 280 mg/kg or 5 mM. Knocking out or inhibiting NLRP3 inflammasome reduced myocardial lipid accumulation caused by stress in the mice myocardia and H9c2 cells. Estrogen downregulated NLRP3 inflammasome and reduced lipid accumulation in cardiomyocytes during stress. Finally, the anti-inflammatory and lipid-lowering effect of estrogen disappeared in β2ARKO mice and H9c2 cells pre-treated with ICI118,551. In conclusion, the upregulation of NLRP3 inflammasome induced by stress led to myocardial lipid accumulation, and β2AR downregulated NLRP3 inflammasome thereby reducing lipid accumulation which was dependent on the estrogenic environment.

Low-Intensity Exercise Affects Cardiac Fatty Acid Oxidation by Increasing the Nuclear Content of PPARα, FOXO1, and Lipin1 in Fructose-Fed Rats.

Background and Aim: Excessive fructose consumption along with a sedentary lifestyle provokes metabolic disorders and cardiovascular diseases. Fructose overload causes cardiac insulin resistance and increases reliance on fatty acid (FA) uptake and catabolism. The cardiometabolic benefits of exercise training have long been appreciated. The goal of the presented study is to shed a new light to the preventive role of exercise training on cardiac lipid metabolism in fructose-fed rats. Methods: Male Wistar rats were divided into control (C), sedentary fructose (F), and exercised fructose (EF) groups. Fructose was given as a 10% fructose solution in drinking water for 9 weeks. Low-intensity exercise training was applied for 9 weeks. The protein expression and subcellular localization of Lipin1, peroxisome proliferator-activated receptor α (PPARα), and peroxisome proliferator-activated receptor-γ coactivator 1 α (PGC1) were analyzed in the heart using Western blot. Cardiac forkhead box transcription factor 1 (FOXO1) and sirtuin 1 (SIRT1) protein levels were also evaluated. Gene expression of long-chain acyl-CoA dehydrogenase was analyzed by quantitative polymerase chain reaction. Results: Exercise training has augmented the expression of main regulators of FA oxidation in the heart and achieves its effect by increasing the nuclear content of PPARα, Lipin1, and FOXO1 compared with the fructose group (P = 0.0422, P = 0.000045, P = 0.00958, respectively). In addition, Lipin1, FOXO1, and SIRT1 were increased in nuclear extract after exercise compared with the control group (P = 0.000043, P = 0.0417, P = 0.0329, respectively). In cardiac lysate, low-intensity exercise caused significantly increased protein level of PPARα, PGC1, FOXO1, and SIRT1 compared with control (P = 0.0377, P = 0.0275, P = 0.0096, P = 0.0282, respectively) and PGC1 level compared with the fructose group (P = 0.0417). Conclusion: The obtained results imply that the heart with a metabolic burden additionally relies on FA as an energy substrate after low-intensity running.

The effect of dapagliflozin on myocardial ischemia–reperfusion injury in diabetic rats

The incidence of ischemic heart disease is 2-3 times higher in diabetic patients. However, the effect of dapagliflozin on ischemia-reperfusion myocardial injury in diabetic rats has not been studied. We examined the effects of dapagliflozin on myocardial IR injury in streptozotocin-nicotinamide-induced diabetic rats. Rats were divided into four groups (n = 7 in each group): control, control-dapagliflozin, diabetes, and diabetes-dapagliflozin. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water for 2 months. The hearts were perfused in a Langendorff's apparatus at 2 months and assessed before (baseline) and after myocardial IR for the following parameters: left ventricular developed pressure (LVDP), minimum and maximum rates of pressure change in the left ventricle (±dP/dt), endothelial nitric oxide (NO) synthase (eNOS) and inducible NO synthase (iNOS) mRNA expressions, creatine kinase MB (CK-MB) and troponin imyocardial enzyme extravasation, and lactate dehydrogenase. The recovery of LVDP and±dP/dt in diabetic rats was lower than that in controls but near normal after dapagliflozin treatment. Diabetic rats had decreased eNOS expression and increased iNOS expression at baseline and after IR, whereas dapagliflozin normalized these parameters after IR. Compared with controls, cardiac NOx levels were initially lower in diabetic patients but higher after IR. Baseline MDA levels were higher in diabetic rats after IR, whereas cardiac NOx levels decreased after treatment with dapagliflozin. Dapagliflozin protects the diabetic rat heart from ischemia-reperfusion myocardial injury by regulating the expression of eNOS and iNOS and inhibiting cardiac lipid peroxidation.

PS-B11-1: ACETATE RESTORES CARDIAC METABOLIC FLEXIBILITY IN HIGH FAT DIET-INDUCED OBESITY THROUGH HDAC MODULATION

Objectives: Obesity remains a global epidemic and an independent risk factor for cardiovascular disease. Histone deacetylase (HDAC) activity has been implicated to increase adipogenic differentiation and consequent increase in adiposity, which are crucial features of obesity. Short chain fatty acids (SCFAs), which are potential HDAC inhibitors have been shown to be effective for glycemic/immune modulation. However, the involvement of HDAC or ANP/BNP in obesity-associated cardiac metabolic events is inconclusive. The present study hypothesized that cardiac metabolic inflexibility is dependent on cardiac ANP/BNP alteration and HDAC activity. We further sought to investigate the therapeutic potential of SCFA, acetate in high fat diet (HFD)-induced obese rat model. Methods: Adult male Wistar rats were assigned into groups (n = 6/group): Control, Obese, Sodium acetate (NaAc)-treated and Obese+ NaAc-treated groups received distilled water once daily (oral gavage), 40% HFD ad libitum, 200 mg/kg NaAc once daily (oral gavage) and 40% HFD+NaAc respectively. Results: The treatments lasted for 12 weeks. HFD resulted in increased food intake, body weight and cardiac mass. It also caused insulin resistance and enhanced Beta-cell function, increased fasting insulin, lactate, plasma and cardiac triglyceride, total cholesterol, glycogen content, lipid peroxidation, TNF-alpha, IL-6, HDAC and cardiac troponin T and gamma-glutamyl transferase and decreased plasma and cardiac GSH with unaltered cardiac ANP and BNP. However, these alterations were averted when treated with acetate. Conclusions: Taken together, these results indicate that obesity induces defective cardiac metabolic flexibility, which is accompanied by elevated level of HDAC and not ANP/BNP alteration. The results also suggest that acetate ameliorates obesity-induced cardiac metabolic inflexibility by suppression of HDAC and independent of ANP/BNP modulation.

PS-B06-1: LOW DOSE SPIRONOLACTONE ALLEVIATES CARDIO-RENAL DISORDER IN EXPERIMENTAL PCOS RAT MODEL BY REDUCTION OF BAX/INFLAMMASOME IMMUNOHISTOCHEMICAL EXPRESSION

Objectives: Polycystic ovarian syndrome (PCOS) is the most common endocrine and metabolic disorders among women of reproductive age. It has been associated with cardio-renal disturbance. In fact, cardiovascular disease and chronic kidney disease remain the major cause of disease burden worldwide. Mineralocorticoid receptor activation has been demonstrated in various pathological conditions, including cardiovascular and renal dysfunction. Spironolactone is a mineralocorticoid receptor blocker that regulates metabolic-related functions. However, the impact of spironolactone (LSPL), on PCOS associated cardio-renal disorder is unknown. Therefore, the present study hypothesized that LSPL would ameliorate cardio-renal disorders in experimental PCOS animal. Materials and Methods: Female Wistar rats that were eight-week-old were allotted into three groups. The control group received vehicle (distilled water; p.o.), LET-treated group designated as PCOS group received letrozole (1 mg/kg; p.o.), while PCOS+LSPL received a combination of letrozole and LSPL (0.25 mg/kg, p.o.). The treatment was done once daily for 21 days uninterrupted. Results: The experimental PCOS rats were characterized with insulin resistance as well as, elevated testosterone and LH/FSH with a significant increase in cardiac and renal lipid profile, oxidative stress, inflammatory biomarkers (NF-kappaB and TNF-alpha), LDH and lactate content, and decrease in cardiac and renal antioxidant system (GPX and GSH) compared with the control rats. There was also a significant increase in cardiac GGT but not renal GGT activity in PCOS animals. In addition, immunohistochemical assessment of cardiac and renal tissue showed severe expression of inflammasome and moderate expression of BAX in animals with PCOS. Nevertheless, these perturbations were attenuated following the administration of LSPL. Conclusion: Collectively, the present results suggests that low dose spironolactone attenuates PCOS-associated cardio-renal disorders by reduction of oxidative stress and BAX/Inflammasome expression.

Rutin and Hesperidin Alleviate Paclitaxel-Induced Nephrocardiotoxicity in Wistar Rats via Suppressing the Oxidative Stress and Enhancing the Antioxidant Defense Mechanisms.

Paclitaxel is a primary chemotherapy agent that displays antitumor activity against a variety of solid tumors. However, the clinical effectiveness of the drug is hampered by its nephrotoxic and cardiotoxic side effects. Thus, this investigation aimed at assessing the protective effects of rutin, hesperidin, and their combination to alleviate nephrotoxicity caused by paclitaxel (Taxol), cardiotoxicity in male Wistar rats, as well as oxidative stress. Rutin (10 mg/kg body weight), hesperidin (10 mg/kg body weight), and their mixture were given orally every other day for six weeks. Rats received intraperitoneal injections of paclitaxel twice weekly, on the second and fifth days of the week, at a dose of 2 mg/kg body weight. In paclitaxel-treated rats, the treatment of rutin and hesperidin decreased the elevated serum levels of creatinine, urea, and uric acid, indicating a recovery of kidney functions. The cardiac dysfunction in paclitaxel-treated rats that got rutin and hesperidin treatment also diminished, as shown by a substantial reduction in elevated CK-MB and LDH activity. Following paclitaxel administration, the severity of the kidney and the heart's histopathological findings and lesion scores were markedly decreased by rutin and hesperidin administration. Moreover, these treatments significantly reduced renal and cardiac lipid peroxidation while markedly increased GSH content and SOD and GPx activities. Thus, paclitaxel likely induces toxicity in the kidney and the heart by producing oxidative stress. The treatments likely countered renal and cardiac dysfunction and histopathological changes by suppressing oxidative stress and augmenting the antioxidant defenses. Rutin and hesperidin combination was most efficacious in rescuing renal and cardiac function as well as histological integrity in paclitaxel-administered rats.

Reactivation of PPARα alleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acid β-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM), a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes, accounts for 20% of sudden cardiac death and lacks effective treatment. It is often caused by mutations in desmosome proteins, with Desmoglein-2 (DSG2) mutations as a common etiology. However, the mechanism underlying the accumulation of fibrofatty in ACM remains unknown, which impedes the development of curative treatment. Here we investigated the fat accumulation and the underlying mechanism in a mouse model of ACM induced by cardiac-specific knockout of Dsg2 (CS-Dsg2 -/-). Heart failure and cardiac lipid accumulation were observed in CS-Dsg2 -/- mice. We demonstrated that these phenotypes were caused by decline of fatty acid (FA) β-oxidation resulted from impaired mammalian target of rapamycin (mTOR) signaling. Rapamycin worsened while overexpression of mTOR and 4EBP1 rescued the FA β-oxidation pathway in CS-Dsg2 -/- mice. Reactivation of PPARα by fenofibrate or AAV9-Pparα significantly alleviated the lipid accumulation and restored cardiac function. Our results suggest that impaired mTOR-4EBP1-PPARα-dependent FA β-oxidation contributes to myocardial lipid accumulation in ACM and PPARα may be a potential target for curative treatment of ACM.

Dynamic Evolution of Cardiac Function and Glucose and Lipid Metabolism in Ovariectomized Rats and the Intervention Effect of Erxian Decoction.

Abnormal changes in cardiac function have been reported in menopausal women, but there are few clinical studies on this topic. Erxian decoction (EXD) is a classic prescription that is widely used in the treatment of female menopausal diseases. The purpose of this study was to investigate the dynamic evolution of cardiac function and glucose and lipid metabolism in ovariectomized (OVX) rats and the intervention effect of EXD. The OVX climacteric rat model was established by bilateral ovariectomy. After successful modeling, the rats were randomly divided into four groups: the sham operation (SHAM) group (equal volumes of purified water), OVX group (equal volumes of purified water), estradiol (E2) group (1.8 × 10-4 g/kg), and EXD group (9 g/kg). Each group of rats was treated for 16 weeks. At the 4th, 8th, 12th, and 16th weeks after treatment, the cardiac function of the rats in each group was evaluated by ultrasound. The coaxial method was used to measure blood pressure (BP). Serum endothelin-1 (ET-1) and angiotensin-2 (Ang II) levels were determined by the enzyme-linked immunosorbent assay (ELISA). The strip method was used to measure fasting blood glucose (FBG). The serum total cholesterol (TC) and triglyceride (TG) levels of rats were measured with the oxidase method. Direct methods were used to measure serum high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) levels. At week 16 of dosing, serum E2 levels were determined by E2 radioimmunoassay. The myocardium and uterus of the rats in each group were stained with HE (hematoxylin-eosin). The ultrastructure of the rat myocardium was observed by electron microscopy. After the 16th week of treatment, the serum E2 level decreased (P < 0.05), and the uterus was atrophied in OVX rats. The cardiac ejection fraction (EF%) decreased at 4 weeks after treatment, and systolic and diastolic function decreased after 12 weeks. After the 16th week, the EF%, which reflects the "pump" function of the heart, decreased significantly (P < 0.05 or P < 0.01). At the 4th, 8th, 12th, and 16th weeks of treatment, the systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean pressure (MBP) of the rats in the OVX group increased with time (P < 0.05 or P < 0.01). The serum ET-1 and Ang II levels of rats in the OVX group increased (P < 0.05 or P < 0.01). In the OVX group, FBG was increased (P < 0.05 or P < 0.01), and blood lipids, especially LDL-C, were significantly increased (P < 0.05 or P < 0.01). After the 16th week of treatment, the myocardial tissue of OVX rats showed obvious pathological changes. EXD significantly increased serum E2 levels (P < 0.01), decreased ET-1 and Ang II levels (P < 0.01), reduced the cardiac function risk factors BP, FBG, and blood lipids, and significantly improved cardiac function and structural changes in OVX rats (P < 0.05 or P < 0.01). EXD can improve abnormal cardiac structure and function in OVX rats.

Design, synthesis and preclinical evaluations of (s)-2-((s)-1-benzyl-2,5-dioxopyrrolidin-3-yl)-3-(4-isopropylphenyl)-2-methylpropanal (succ-5) as cardioprotective, hepatoprotective and lipid lowering molecule. in-vivo and in-silico approaches

In this study, the newly synthesized compound (Succ-5) was analyzed through spectral methods, seen for potential receptor targets via molecular docking, and pre-clinically evaluated for therapeutic effects and safety profile using biochemical and histopathological techniques. The biochemical analysis included assessment of cardiac biomarkers, hepatic enzymes, and lipid profiles, while histopathology included evaluation of cardiac and liver tissues. The toxic dose was determined pre-clinically, followed by dividing albino rats into five treatment groups (each having n = 6). The control group received oral saline for eight days. The 5-FU (5-Fluorouracil) group received oral saline for 8 days and 5-FU (150 mg/kg I.P.) on day 5.The atenolol group was administered with atenolol (20 mg/kg) for 8 days and 5-FU (150 mg/kg I.P.) on day 5. Two groups of rats were administered with the test compound (Succ-5) at doses of 5 mg/kg I.P and 10 mg/kg I.P (for 8-days), followed by 5-FU (150 mg/kg I.P.) on day 5. Elevated serum levels of CK-MB (creatinine kinase myocardial band), cTnI (troponin I), LDH (lactate dehydrogenase), lipid profile, and selected liver enzymes including ALP (alkaline phosphatase), ALT (alanine transaminase), AST (aspartate aminotransferase), BT (bilirubin total) and BD (direct bilirubin) were associated with 5-FU toxicity. After administration of the test compound at the mentioned doses, these biomarkers significantly decreased. Likewise, histological examination revealed 5-FU damaged the heart and hepatic tissues, which were also considerably recovered following administration of the test compound. Immunohistochemistry of heart tissue also revealed the low expression of COX-2 and TNF-α in Succ-5 treated groups compared to toxic group. Dose-response evaluation showed that a dose of 10 mg/kg provided better results than 5 mg/kg. The analysis of binding energy values computed via docking simulations showed that Succ-5 interacts with the human beta2-adrenergic G protein-coupled receptor with a slightly stronger affinity than calcium channel T-type. In conclusion, the histological and biochemical findings revealed that the test compound had significant cardioprotective, hepatoprotective, and lipolytic effects in the 5-FU-induced toxicity.

Effects of Thymoquinone Alone or in Combination with Losartan on the Cardiotoxicity Caused by Oxidative Stress and Inflammation in Hypercholesterolemia.

Dietary cholesterol accelerates oxidative and pro-inflammatory processes, causing hypercholesterolemia and cardiovascular diseases. Thus, the purpose of the current study is to compare the protective effects of thymoquinone (TQ) alone or in combination with losartan (LT) against the heart damage caused by a high-cholesterol diet (HCD). HCD-fed rat groups revealed an elevated activity of indicators of cardiac enzymes in the serum. Serum and cardiac lipids were also found to be significantly higher in HCD-fed rat groups. Cardiac pro-inflammatory and oxidative markers were also increased in HCD-fed rat groups, whereas antioxidant indicators were decreased. However, all of these biochemical, inflammatory, antioxidant, and oxidative change indicators returned to levels similar to those of normal rats after treatment with TQ alone or in combination with LT administered to HCD-fed rat groups. Hypercholesterolemia considerably induced the lipid peroxidation product, thiobarbituric acid reaction substances (TBARs), and oxidative radicals in cardiac cells, which were attenuated by QT and LT treatments, particularly when combined. Finally, QT, LT, and their combination were able to reduce the histological changes changes brought on by cholesterol excess in cardiac tissues. In conclusion, administration of TQ in a combination with LT which has a better protective effect, significantly reduced the hypercholesterolemic-induced oxidative and inflammatory changes that occurred in cardiac tissue.

Decalepis hamiltonii and its bioactive constituents mitigate isoproterenol-induced cardiotoxicity in aged rats

Aging is associated with functional decline and structural deteriorations of the myocardium and plays a crucial role in cardiovascular ailments. Decalepis hamiltonii ( Dh ) is well known medicinal plant used in traditional medicine and exhibits potent antioxidant properties. Therefore, the current study was proposed to assess the cardioprotective potential of Dh extract and its bioactive constituents [Ellagic acid (EA) and 4‑hydroxyisophthalic acid (4-HIA)] against isoproterenol (ISO)-induced region-specific myocardial damage in aging rats. Male albino Wistar rats aged 22 months were administered orally with Dh extract (100mg/kg BW), EA (50 mg/kg BW), and 4‑HIA (30 mg/kg BW) for one month before inducing MI using ISO (150 mg/kg BW) for the consecutive last two days. The ISO group exhibited a significant increase in hemodynamic parameters, cardiac marker enzymes, serum lipids, and oxidative stress markers. A significant reduction in region-specific antioxidant enzymes levels and histopathological alterations were observed in ISO-treated rats. Whereas, pretreatment of EA, 4-HIA, and Dh extract reduced the cardiac dysfunction biomarkers and mitigated oxidative stress by enhancing antioxidant enzymes and restoring histopathological changes in ISO-treated rats. The Overall findings give insights into the therapeutic applications of Dh extract and its compounds in ameliorating cardiovascular disorders through its antioxidant potential.

Serum Annexin A2 concentrations are increased in patients with diabetic cardiomyopathy and are linked to cardiac dysfunctions

BackgroundDiabetic cardiomyopathy (DbCM) is defined as the existence of abnormal myocardial structure and functions in the absence of other cardiac diseases, such as coronary artery disease, hypertension, and significant valvular disease, in individuals with diabetes. Although abundant epidemic evidence demonstrates that diabetes is independently associated with the risk of developing heart failure, DbCM is not normally diagnosed in clinical practices due to its exclusive diagnosis, and no diagnostic biomarker was applied in a clinical test. MethodsTo detect the concentrations of serum Annexin A2 in non-diabetic subjects, type 2 diabetic (T2DM) patients with or without DbCM, and analyzed its relationship to parameters of cardiac functions, glucose, lipid metabolism, and renal functions. 266 eligible participants were included and were divided into 3 groups including non-diabetic subjects (NGR), T2DM patients without DbCM (T2DM group), and the DbCM group. Echocardiography, coronary computed tomography angiography, electrocardiogram, blood pressure, thyroid function, and clinical and other biochemical parameters were measured in all participants. ResultsSerum Annexin A2 concentrations were higher in DbCM (P < 0.05) and T2DM (P < 0.05) groups compared with the NGR group, especially in DbCM patients. Correlation analysis showed that serum Annexin A2 levels were negatively associated with left ventricular (LV) ejection fraction (EF), LV fractional shortening (FS), the ratio of early (E-wave) and late (A-wave) LV diastolic filling velocities (E/A ratio), and estimated glomerular filtration rate (eGFR), and were positively correlated with age, blood urea nitrogen (BUN) and creatinine (Cr) (all P < 0.05). Multiple logistical regression analyses revealed that serum in both the second and the third tertiles of Annexin A2 concentration were significantly associated with DbCM. E/A ratio is the independent factor for Annexin A2 concentration when adjusted for LV FS%, BUN, and Cr. ConclusionsCirculating Annexin A2 concentrations might be induced in DbCM patients and were negatively associated with cardiac systolic and diastolic functions, which suggested it might be a predictor of early diagnosis in DbCM and might be a potential therapeutic target for DbCM.

HFpEF with diabetic comorbidity is linked to cardiac lipid accumulation with severe diastolic dysfunction in female but not male hearts

HFpEF with diabetic comorbidity is linked to cardiac lipid accumulation with severe diastolic dysfunction in female but not male hearts

Exercise Training Upregulates Cardiac mtp Expression in Drosophila melanogaster with HFD to Improve Cardiac Dysfunction and Abnormal Lipid Metabolism.

Current evidence suggests that the heart plays an important role in regulating systemic lipid homeostasis, and high-fat diet (HFD)-induced obesity is a major cause of cardiovascular disease, although little is known about the specific mechanisms involved. Exercise training can reportedly improve abnormal lipid metabolism and cardiac dysfunction induced by high-fat diets; however, the molecular mechanisms are not yet understood. In the present study, to explore the relationship between exercise training and cardiac mtp in HFD flies and potential mechanisms by which exercise training affects HFD flies, Drosophila was selected as a model organism, and the GAL4/UAS system was used to specifically knock down the target gene. Experiments revealed that HFD-fed Drosophila exhibited changes in body weight, increased triglycerides (TG) and dysregulated cardiac contractility, consistent with observations in mammals. Interestingly, inhibition of cardiac mtp expression reduced HFD-induced cardiac damage and mitigated the increase in triglycerides. Further studies showed that in HFD +w1118, HFD + Hand &gt; w1118, and HFD+ Hand &gt; mtpRNAi, cardiac mtp expression downregulation induced by HFD was treated by exercise training and mitochondrial β-oxidation capacity in cardiomyocytes was reversed. Overall, knocking down mtp in the heart prevented an increase in systemic TG levels and protected cardiac contractility from damage caused by HFD, similar to the findings observed after exercise training. Moreover, exercise training upregulated the decrease in cardiac mtp expression induced by HFD. Increased Had1 and Acox3 expression were observed, consistent with changes in cardiac mtp expression.

AIBP Regulates Metabolism of Ketone and Lipids but Not Mitochondrial Respiration.

Accumulating evidence indicates that the APOA1 binding protein (AIBP)-a secreted protein-plays a profound role in lipid metabolism. Interestingly, AIBP also functions as an NAD(P)H-hydrate epimerase to catalyze the interconversion of NAD(P)H hydrate [NAD(P)HX] epimers and is renamed as NAXE. Thus, we call it NAXE hereafter. We investigated its role in NAD(P)H-involved metabolism in murine cardiomyocytes, focusing on the metabolism of hexose, lipids, and amino acids as well as mitochondrial redox function. Unbiased metabolite profiling of cardiac tissue shows that NAXE knockout markedly upregulates the ketone body 3-hydroxybutyric acid (3-HB) and increases or trends increasing lipid-associated metabolites cholesterol, α-linolenic acid and deoxycholic acid. Paralleling greater ketone levels, ChemRICH analysis of the NAXE-regulated metabolites shows reduced abundance of hexose despite similar glucose levels in control and NAXE-deficient blood. NAXE knockout reduces cardiac lactic acid but has no effect on the content of other NAD(P)H-regulated metabolites, including those associated with glucose metabolism, the pentose phosphate pathway, or Krebs cycle flux. Although NAXE is present in mitochondria, it has no apparent effect on mitochondrial oxidative phosphorylation. Instead, we detected more metabolites that can potentially improve cardiac function (3-HB, adenosine, and α-linolenic acid) in the Naxe-/- heart; these mice also perform better in aerobic exercise. Our data reveal a new role of NAXE in cardiac ketone and lipid metabolism.

Temporal lipid profiling in the progression from acute to chronic heart failure in mice and ischemic human hearts

Background and aimsMyocardial infarction (MI) is a leading cause of heart failure (HF). After MI, lipids undergo several phasic changes implicated in cardiac repair if inflammation resolves on time. However, if inflammation continues, that leads to end stage HF progression and development. Numerous studies have analyzed the traditional risk factors; however, temporal lipidomics data for human and animal models are limited. Thus, we aimed to obtain sequential lipid profiling from acute to chronic HF. MethodsHere, we report the comprehensive lipidome of the hearts from diseased and healthy subjects. To induce heart failure in mice, we used a non-reperfused model of coronary ligation, and MI was confirmed by echocardiography and histology, then temporal kinetics of lipids in different tissues (heart, spleen, kidney), and plasma was quantitated from heart failure mice and compared with naïve controls. For lipid analysis in mouse and human samples, untargeted liquid chromatography-linear trap quadrupole orbitrap mass spectrometry (LC-LTQ-Orbitrap MS) was performed. ResultsIn humans, multivariate analysis revealed distinct cardiac lipid profiles between healthy and ischemic subjects, with 16 lipid species significantly downregulated by 5-fold, mainly phosphatidylethanolamines (PE), in the ischemic heart. In contrast, PE levels were markedly increased in mouse tissues and plasma in chronic MI, indicating possible cardiac remodeling. Further, fold change analysis revealed site-specific lipid biomarkers for acute and chronic HF. A significant decrease in sulfatides (SHexCer (34:1; 2O)) and sphingomyelins (SM (d18:1/16:0)) was observed in mouse tissues and plasma in chronic HF. ConclusionsOverall, a significant decreased lipidome in human ischemic LV and differential lipid metabolites in the transition of acute to chronic HF with inter-organ communication could provide novel insights into targeting integrative pathways for the early diagnosis or development of novel therapeutics to delay/prevent HF.