Diabetic Rat Hearts Research Articles

Effects of omega-3 fatty acids and metformin combination on diabetic cardiomyopathy in rats through autophagic pathway

Diabetic cardiomyopathy is a primary cause of increased morbidity and mortality in diabetics. Evidence has suggested a pivotal role for interrupted mitochondrial dynamics and quality control machinery in the onset and development of diabetic cardiomyopathy. Sequestosome 1 (SQSTM1) is a major reporter of selective autophagic activity. Other than controlling the expression of genes involved in mitochondrial biogenesis, recently peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) was reported to directly affect SQSTM1 gene expression. Calcineurin, a pivotal mediator of cardiac hypertrophy, has been also linked to enhanced expression of SQSTM1. This study aimed to test the cardioprotective effects of adding ω-3 polyunsaturated fatty acids (PUFAs) to metformin in a rat model of type 2 diabetes mellitus and to evaluate the molecular mechanisms underlying their effects on mitochondrial quality. Diabetes was induced in male Sprague Dawley rats by a high-fat diet for 6 weeks, followed by a low-dose streptozotocin (35 mg/kg). Diabetic rats were either treated with metformin (150 mg/kg/d), ω-3 PUFAs (300 mg/kg/d), or their combination in the same doses for further 8 weeks. Along with metabolic and pathological derangements, we report that correlating with electron microscopic evidence of mitochondrial degeneration, gene expression of the autophagic indicators SQSTM1, PGC-1α, and calcineurin were decreased in the hearts of diabetic rats. Independent of its anti-hyperglycemic effects, metformin successfully preserved mitochondrial integrity and upregulated myocardial PGC-1α, calcineurin, and SQSTM1 gene expression. ω-3 PUFAs possess synergistic cardioprotection when added to metformin, suggested by improvements in myocardial ultrastructure, autophagic activity, and SQSTM1 gene expression.

Mechanical effects of ranolazine on normal and diabetic-isolated rat heart

Background and purpose:Diabetic cardiomyopathy is a complication of diabetes defined as cardiac dysfunction without the involvement of pericardial vessels, hypertension, or cardiac valve disorders. Ranolazine, an antianginal drug, acts through blocking of cardiac late sodium channels and/or inhibiting beta-oxidation of fatty acids. With regard to its mechanism of action, the present work has been carried out to investigate the potential useful effects of ranolazine on the systolic and diastolic dysfunctions in an experimental rat model of diabetic cardiomyopathy. Lidocaine, as a sodium channel blocker, was used to have a clearer image of the involved mechanisms.Experimental approach:Diabetes was induced by streptozocin. After 8 weeks, the effects of cumulative concentrations of ranolazine and lidocaine were evaluated on diabetic and normal hearts by the Langendorff method. Finally, the hearts were isolated from the Langendorff system and adenosine three phosphates (ATP) and adenosine diphosphate (ADP) concentrations were measured to assay the metabolic effect of ranolazine.Findings/Results:Ranolazine significantly decreased the velocity of systolic contraction (+dP/dt) and the velocity of diastolic relaxation (-dP/dt) and developed pressure in normal and diabetic rat hearts. However, this negative effect was greater in normal hearts compared to diabetics. Ranolazine (100 μM) decreased the ATP level only in normal hearts and the ATP/ADP ratio decreased significantly (P < 0.05) in both groups. This reduction was more prominent in normal hearts.Conclusion and implications:It is concluded that in the isolated rat heart preparation, ranolazine has no benefit on diabetic cardiomyopathy and may even worsen it. It seems that these effects are related to the metabolic effects of ranolazine.

Glabridin from licorice alleviates vascular inflammation and promotes vascular remodeling of the left anterior descending coronary artery in diabetic rat heart

IntroductionThe aim of this study was to investigate the effects of glabridin on vascular inflammation and vascular remodeling of the left anterior descending artery (LAD) in diabetic rat heart.Material and methodsEighty male Wistar rats were divided into five groups: (1) control rats; (2) glabridin control rats that received diet supplemented with glabridin (CGB); (3) diabetic rats (STZ); (4) diabetic rats that received a supplemented with glabridin (STZ + GB) 40 mg/kg BW; and (5) diabetic rats treated with glyburide (STZ + GR) 4 mg/kg BW. Diabetic animals were rendered diabetic by injection of a single dose (60 mg/kg BW) of streptozotocin (STZ). After 8 weeks, the biochemical markers of oxidative stress were assessed. The three-dimensional morphology of LAD was examined by vascular corrosion casting. Enzyme-linked immunosorbent assay was applied to determine the expression of TNF-α and IL-1β proteins. Western blot and immunofluorescence analysis were used to detect the expression of VEGF and TGF-β1 secretions.ResultsThe lumen diameter of the LAD was notably smaller and stenotic. LAD analysis revealed arterial notch and evolved irregular caliber. Moreover, neovascularization appeared and was extensive. The Trolox equivalent antioxidant capacities and Trolox equivalent antioxidant capacity levels of heart tissue were significantly decreased and levels of malondialdehyde were found to be elevated in STZ rats whereas they were improved in the STZ + GB group. Increased expression levels of VEGF, TGF-β1, TNF-α, and IL-1β proteins in heart tissues were observed in the STZ group. The inflammation cytokine levels were decreased in the STZ + GB group.ConclusionsThese results revealed that glabridin was able to reduce LAD and heart tissue damage. Glabridin can be an antioxidant and can reduce the pathology of the LAD in terms of reducing inflammation and restoring condition of the LAD. It would be beneficial in examining the role of glabridin as a therapeutic aim in diabetes treatment research in coronary artery disease.

SHORT-TERM CRIZOTINIB TREATMENT REVERSES GLUT4 GLUCOSE TRANSPORTER DOWNREGULATION IN DIABETIC RAT HEART

Objective: Crizotinib is a multitarget ALK/c-MET/ROS1/RON inhibitor that can potentially inhibit non-intended receptor tyrosine kinases (RTKs) which play a role in cardiac development, function and/or metabolism. Tyrosine kinase inhibitors (TKIs) studies in diabetic patients showed antidiabetic effects of some TKIs and several potential mechanisms were suggested including mechanisms via RTKs. We examined RTKs after short-term crizotinib treatment in diabetic heart. Design and method: To induce diabetes, male Wistar rats were injected with streptozotocin (STZ; 80 mg/kg, i.p.), controls received vehicle (CON). After 3 days, diabetic rats were treated with crizotinib in a dose 25 mg/kg/day p.o. (STZ+CRI) or vehicle p.o. for 7 days (STZ). mRNA expression of selected RTKs were assessed by RT-qPCR method in rat left ventricle samples. Blood glucose, c-peptide and glucagon in plasma samples and expression of cardiac glucose transporters Glut1 and Glut4 were assessed to determine impact on glucose homeostasis. Results: Intriguingly, crizotinib had a hypoglycaemic effect in diabetic animals (plasma glucose in STZ: 19.2 mmol/L vs. STZ+CRI: 14.5 mmol/L., P&lt;0.05). STZ animals had lower c-peptide and unaltered glucagon plasma levels. However, plasma levels of c-peptide and glucagon were not changed after crizotinib treatment suggesting altered glucose utilization in tissues. In STZ rats, we detected downregulation of insulin dependent glucose transporter Glut4 (by 40% as compared to CON, P &lt; 0.05). Interestingly, crizotinib prevented this downregulation. Insulin non-dependent Glut1 glucose transporter remained stable across all groups. Diabetes upregulated cardiac insulin receptor and Igf-1 receptor without significant crizotinib impact. Regarding RTKs, we observed unaltered c-Met, Flt1 and Erbb2 expressions in diabetic hearts without influence of crizotinib. Conclusions: Crizotinib had a hypoglycaemic effect in diabetic animals after short-term treatment. This was independent of insulin and glucagon levels. Crizotinib prevented cardiac insulin-dependent Glut4 decrease. Downregulation of cardiac insulin receptor family RTKs expression remains stable under crizotinib suggesting modulation of alternative pathways responsible for crizotinib action in diabetic rat heart.

Galangin attenuates diabetic cardiomyopathy through modulating oxidative stress, inflammation and apoptosis in rats

Cardiovascular complications are the leading cause of morbidity in diabetes. Oxidative stress and inflammation are implicated in the development and progression of diabetic cardiomyopathy (DCM). This study explored the cardioprotective effect of galangin (Gal), a natural flavonoid with radical-scavenging and anti-inflammatory activities, in diabetic rats. An experimental diabetic rat model was achieved by a single injection of 50 mg/kg streptozotocin. Gal (15 mg/kg) was administered daily for six weeks and the samples were then collected. Diabetic rats exhibited hyperglycemia, increased glycosylated hemoglobin, triglycerides and cholesterol levels and reduced serum insulin. Serum troponin I, CK-MB and LDH were increased in diabetic rats. Furthermore, hearts of diabetic rats were characterized by elevated malondialdehyde, protein carbonyl, NF-κB p65, TNF-α, IL-1β, iNOS, IL-6, Bax, caspase-3 and 8-Oxo-dG, and decreased superoxide dismutase, catalase, reduced GSH, and Bcl-2. Gal ameliorated hyperglycemia, dyslipidemia, and heart function markers, and prevented histopathological alterations in diabetic rats. In addition, Gal attenuated cardiac oxidative injury, inflammation and apoptosis, and boosted antioxidant defenses. In conclusion, Gal has a protective effect on cardiomyopathy by attenuating hyperglycemia, dyslipidemia, oxidative stress and inflammation in diabetic rats.

FoxO1 is required for high glucose-dependent cardiac fibroblasts into myofibroblast phenoconversion

In the normal heart, cardiac fibroblasts (CFs) maintain extracellular matrix (ECM) homeostasis, whereas in pathological conditions, such as diabetes mellitus (DM), CFs converse into cardiac myofibroblasts (CMFs) and this CFs phenoconversion increase the synthesis and secretion of ECM proteins, promoting cardiac fibrosis and heart dysfunction. High glucose (HG) conditions increase TGF-β1 expression and FoxO1 activity, whereas FoxO1 is crucial to CFs phenoconversion induced by TGF-β1. In addition, FoxO1 increases CTGF expression, whereas CTGF plays an active role in the fibrotic process induced by hyperglycemia. However, the role of FoxO1 and CTGF in CFs phenoconversion induced by HG is not clear. In this study, we investigated the effects of FoxO1 pharmacological inhibition on CFs phenoconversion in both in vitro and ex vivo models of DM. Our results demonstrate that HG induces CFs phenoconversion and FoxO1 activation. Moreover, AS1842856, a pharmacological inhibitor of FoxO1 activity, prevents CFs phenoconversion and CTGF expression increase induced by HG, whereas these results were corroborated by FoxO1 silencing. Additionally, K252a, a pharmacological blocker of CTGF receptor, prevents HG-induced CFs phenoconversion, which was corroborated with CTGF expression knockdown. Furthermore, through CFs isolation from heart of diabetic rats, we showed that hyperglycemia induces FoxO1 activation, the increase of CTGF expression and CFs phenoconversion, whereas the FoxO1 activity inhibition reverses the effects induced by hyperglycemia on CFs. Altogether, our results demonstrate that FoxO1 and CTGF are necessary for CFs phenoconversion induced by HG and suggest that both proteins are likely to become a potential targeted drug for fibrotic response induced by hyperglycemic conditions.

The Protective Role of Bmal1-Regulated Autophagy Mediated by HDAC3/SIRT1 Pathway in Myocardial Ischemia/Reperfusion Injury of Diabetic Rats

Histone deacetylase 3 (HDAC3) and silent information regulator 1 (SIRT1) are histone deacetylases that regulate important metabolic pathways and play important roles in diabetes and myocardial ischemia/reperfusion (IR) injury. In this study, we explored the protective mechanism of Bmal1-regulated autophagy mediated by the HDAC3/SIRT1 pathway in myocardial IR injury of diabetic rats. Type 1 diabetes was established by administering an intraperitoneal injection of streptozotocin. After 8 weeks, the left anterior descending coronary artery was ligated for 30 min and reperfused for 120 min to establish a myocardial IR injury model in diabetic rats. H9c2 cardiomyocytes were exposed to high glucose concentration (30 mM) and hypoxia/reoxygenation (H/R) stimulation in vitro. The myocardial infarct size and levels of serum cTn-I, CK-MB, and LDH in diabetic rats subjected to myocardial IR injury were significantly higher. Upregulated HDAC3 and downregulated SIRT1 expression were observed in diabetic and IR hearts, along with a lower Bmal1 level. Autophagy was rapidly increased in the hearts of diabetic or non-diabetic rats in the IR group compared with the sham group, but significantly attenuated in the hearts of diabetic rats compared with the hearts of non-diabetic rats after IR insult. Consistent with decreased autophagy, we observed increased HDAC3 expression and decreased SIRT1 and Bmal1 levels in the myocardial tissue of diabetic rats after IR. Inhibition of HDAC3 by the inhibitor RGFP966 and activation of SIRT1 by the agonist SRT1720 could significantly attenuate myocardial IR injury in diabetic rats by restoring Bmal1-regulated autophagy. Based on these findings, the disordered HDAC3/SIRT1 circuit (upregulated HDAC3 and downregulated SIRT1 levels) plays an important role in aggravating myocardial IR injury in diabetic rats by downregulating Bmal1-mediated autophagy. Treatments targeting HDAC3/SIRT1 to activate the autophagy may represent a novel strategy to alleviate myocardial IR injury in diabetes.

Xanthine oxidoreductase-mediated injury is amplified by upregulated AMP deaminase in type 2 diabetic rat hearts under the condition of pressure overload

BackgroundWe previously reported that upregulated AMP deaminase (AMPD) contributes to diastolic ventricular dysfunction via depletion of the adenine nucleotide pool in a rat model of type 2 diabetes (T2DM), Otsuka Long-Evans-Tokushima Fatty rats (OLETF). Meanwhile, AMPD promotes the formation of substrates of xanthine oxidoreductase (XOR), which produces ROS as a byproduct. Here, we tested the hypothesis that a functional link between upregulated AMPD and XOR is involved in ventricular dysfunction in T2DM rats. Methods and resultsPressure-volume loop analysis revealed that pressure overloading by phenylephrine infusion induced severer left ventricular diastolic dysfunction (tau: 14.7 ± 0.8 vs 12.5 ± 0.7 msec, left ventricular end-diastolic pressure: 18.3 ± 1.5 vs 12.2 ± 1.3 mmHg, p < 0.05) and ventricular-arterial uncoupling in OLETF than in LETO, non-diabetic rats, though the baseline parameters were comparable in the two groups. While the pressure overload did not affect AMPD activity, it increased XOR activity both in OLETF and LETO, with OLETF showing significantly higher XOR activity than that in LETO (347.2 ± 17.9 vs 243.2 ± 6.1 μg/min/mg). Under the condition of pressure overload, myocardial ATP level was lower, and levels of xanthine and uric acid were higher in OLETF than in LETO. Addition of exogenous inosine, a product of AMP deamination, to the heart homogenates augmented XOR activity. OLETF showed 68% higher tissue ROS levels and 47% reduction in mitochondrial state 3 respiration compared with those in LETO. Overexpression of AMPD3 in H9c2 cells elevated levels of hypoxanthine and ROS and reduced the level of ATP. Inhibition of XOR suppressed the production of tissue ROS and mitochondrial dysfunction and improved ventricular function under the condition of pressure overload in OLETF. ConclusionsThe results suggest that increases in the activity of XOR and the formation of XOR substrates by upregulated AMPD contribute to ROS-mediated diastolic ventricular dysfunction at the time of increased cardiac workload in diabetic hearts.

Expression of transient receptor potential vanilloid genes and proteins in diabetic rat heart.

Cardiac complications are leading causes of death in diabetic patients. Imbalance of Ca2+ homeostasis is a hallmark of cardiac dysfunction in diabetes, while TRPV channels are non-selective for cations and are permeable to Ca2+. Our aim was to evaluate the expression levels of TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6 genes and proteins in cardiac tissue at 3 days and 4, 8, and 12 weeks after induction of diabetes. Sprague-Dawley rats were assigned to control and DM groups. DM was induced by intraperitoneal injection of streptozotocin (60mg/kg). The expression levels of TRPV genes were analyzed by the quantitative reverse transcription polymerase chain reaction, and TRPV proteins were determined by western blotting. Compared to controls, the expression levels of TRPV2, TRPV3, and TRPV6 in diabetic myocardium did not change, while TRPV1 decreased at 4, 8, and 12 weeks, TRPV4 was upregulated at 3 days and 4, 8, and 12 weeks, TRPV5 mRNA increased at 8 and 12 weeks, and TRPV5 protein increased at 4, 8, and 12 weeks. Our findings showed that TRPV1, TRPV4, and TRPV5 are associated with the diabetic heart.

Allisartan isoproxil attenuates oxidative stress and inflammation through the SIRT1/Nrf2/NF‑κB signalling pathway in diabetic cardiomyopathy rats.

Allisartan isoproxil is a new nonpeptide angiotensin II receptor blocker (ARB) precursor drug that is used to treat hypertension and reduce the risk of heart disease. The present study explored the effects of allisartan isoproxil on diabetic cardiomyopathy (DCM) and revealed the roles of hyperglycaemia-induced oxidative stress and inflammation. A rat DCM model was established by high-fat diet feeding in combination with intraperitoneal injection of streptozocin. Echocardiographs showed that diabetic rats exhibited significantly decreased cardiac function. Troponin T (cTnT) and B-type natriuretic peptide (BNP) were significantly increased in DCM rats as obtained by ELISA. Allisartan isoproxil significantly improved the EF% and E™/A™ ratio. Histopathologic staining showed that allisartan isoproxil prevented histological alterations, attenuated the accumulation of collagen, and ameliorated cTnT and BNP levels. Western blot and immunohistochemical results indicated that the expression levels of silent information regulator 2 homologue 1 (SIRT1) and nuclear factor erythroid 2-related factor 2 (Nrf2) were decreased in the hearts of diabetic rats, and antioxidant defences were also decreased. In addition, allisartan isoproxil decreased the expression of NF-κB p65 and the inflammatory cytokines TNF-α and IL-1β which were determined by reverse transcription-quantitative PCR in the diabetic heart. Western blotting and TUNEL staining results also showed that cardiac Bax and cleaved caspase-3 and the number of apoptotic myocardial cells were increased in the diabetic heart and decreased following treatment with allisartan isoproxil. In conclusion, the present results indicated that allisartan isoproxil alleviated DCM by attenuating diabetes-induced oxidative stress and inflammation through the SIRT1/Nrf2/NF-κB signalling pathway.

The Comparison of Antioxidant Effect of Aspirin, Metformin, Atorvastatin and Captopril Co-administration in the Heart and Kidney Tissues of Diabetic Rats.

The present study investigated the effects of co-administration of aspirin, metformin, atorvastatin and captopril on serum lipid profile and oxidative stress in the heart and kidney of streptozotocin-induced diabetic rats. In this study, rats were randomly divided into the following eleven groups: control (Cont.), and diabetic (D), as well as 9 groups that were treated with metformin (M, 300 mg/kg) or aspirin (ASA, 120 mg/kg) alone or in different combinations with captopril (C, 50 mg/kg), or atorvastatin (AT, 40 mg/kg), as follows: (D + M), (D + ASA), (D + M + ASA), (D + M + C), (D + M + AT), (D + M + C + ASA), (D + M + C + AT), (D + M + AT + ASA), and (D + M + C + AT + ASA). The rats in treatment groups daily received drugs by gavage for six weeks. Finally, serum lipid profile and levels of oxidative markers in the heart and kidney tissues were evaluated. In diabetic rats, blood levels of glucose, cholesterol, TG (triglyceride), LDL (low-density lipoprotein), MDA (malondialdehyde) and AIP (atherogenic index of plasma) significantly increased but those of HDL (high-density lipoprotein) and total thiol as well as SOD (superoxide dismutase) and CAT (catalase) activities significantly decreased. Treatment with different combinations of C, ASA, AT and M significantly ameliorated these parameters. This study showed that co-administration of ASA, M, C and AT, could improve glucose and lipid metabolism and oxidative stress markers in the kidneys and heart tissues of diabetic rats more markedly than the administration of these drugs alone.

Sestrin2 is involved in the Nrf2-regulated antioxidative signaling pathway in luteolin-induced prevention of the diabetic rat heart from ischemia/reperfusion injury.

Luteolin attenuates myocardial ischemia/reperfusion (I/R) injury in diabetes through activating the nuclear factor erythroid 2-related factor 2 (Nrf2)-related antioxidative response. Though sestrin2, a highly conserved stress-inducible protein, is regarded as a modulator of Nrf2 and reduces I/R injury, the effect of sestrin2 on luteolin-induced prevention of the diabetic heart from I/R injury remains unclear. We hypothesized that luteolin could relieve myocardial I/R injury in diabetes by activating the sestrin2-modulated Nrf2 antioxidative response. Diabetes was induced in rats using a single dose of streptozotocin (65 mg kg-1, i.p.) for 6 weeks, and then luteolin (100 mg kg-1 d-1, i.g.), Nrf2 inhibitor brusatol, or sestrin2 blocker leucine was administered for 2 consecutive weeks. After that, the hearts were isolated and exposed to global I/R (30 min/120 min). Luteolin markedly improved cardiac function, myocardial viability and expressions of Nrf2-regulated antioxidative genes, and reduced lactate dehydrogenase release, malondialdehyde, and 8-hydroxydeoxyguanosine in the diabetic I/R hearts. Ca2+-induced mitochondrial permeability transition and membrane potential disruption were markedly inhibited in luteolin-treated diabetic ventricular myocytes. All these effects of luteolin were significantly reversed by Nrf2 inhibitor brusatol or sestrin2 inhibitor leucine. Luteolin-induced diminished Keap1 and augmented nuclear translocation and ARE binding activity of Nrf2 were hampered by leucine in the diabetic I/R heart. In addition, luteolin-induced augmented transcription of sestrin2 was markedly blocked by brusatol in the diabetic I/R heart. These data suggest that sestrin2 and Nrf2 positively interact to promote antioxidative actions and attenuate mitochondrial damage, by which luteolin relieves diabetic myocardial I/R injury.

Effect of Continuous and Interval Exercise on the Necroptosis and Apoptosis of Endoplasmic Reticulum Proteins in the Heart of Diabetic Wistar Rats

Effect of Continuous and Interval Exercise on the Necroptosis and Apoptosis of Endoplasmic Reticulum Proteins in the Heart of Diabetic Wistar Rats

An injectable hydrogel to reverse the adverse microenvironment of diabetic infarcted heart

A library of injectable hydrogels shows the promising outcomes to restore an infarcted heart. However, none of them has been designed to meet diabetic patients. Here, a proof-of-concept research to build an injectable hydrogel to reverse the adverse microenvironment of injured diabetic hearts is reported. A hyper-branched poly (beta amino ester) polymer is abundant in acrylate and phenylboronic acid (PAE-PBA) to achieve a fast crosslinking with thiolated hyaluronic acid (HA-SH) and form a dynamic complexing with the targeted drug. Andrographolide nanoparticles (ADG NPs) to inhibit the over-expressing inflammatory factors and supramolecular nanofibers (IGF-1-F) with a superior bioactivity to insulin-like growth factor 1 (IGF-1) to regulate autophagy and apoptosis are conveniently encapsulated into the hydrogels. After being administered in diabetic infarcted rat hearts, the dynamic borate bond between PBA and ADG were broken and the hydrogel were degraded, accompanying with a controllable release of ADG and IGF-1-F. This functional hydrogel contributed to a remarkable decrease in the expression of inflammatory factors, a sharp inhibition of the infaust autophagy and apoptosis, and an obvious promotion in angiogenesis, demonstrating a strong capability to reverse the adverse microenvironments. Meanwhile, the infarcted area and the fibrosis area were reduced by 17.9% and 33.5%, respectively, accompanying with a high expression of cardiac related protein and well-ordered histological structures, suggesting a favorable restoration in the heart functions. This research presents the first try to explore an injectable hydrogel to reverse the villainous microenvironments of a diabetic infarcted heart, showing prominent implications in myocardial tissue engineering.

The tyrosine kinase inhibitor crizotinib influences blood glucose and mRNA expression of GLUT4 and PPARs in the heart of rats with experimental diabetes.

Tyrosine kinases inhibitors (TKIs) may alter glycaemia and may be cardiotoxic with importance in the diabetic heart. We investigated the effect of multi-TKI crizotinib after short-term administration on metabolic modulators of the heart of diabetic rats. Experimental diabetes mellitus (DM) was induced by streptozotocin (STZ; 80mg·kg-1, i.p.), and controls (C) received vehicle. Three days after STZ, crizotinib (STZ+CRI; 25mg·kg-1 per day p.o.) or vehicle was administered for 7days. Blood glucose, C-peptide, and glucagon were assessed in plasma samples. Receptor tyrosine kinases (RTKs), cardiac glucose transporters, and peroxisome proliferator-activated receptors (PPARs) were determined in rat left ventricle by RT-qPCR method. Crizotinib moderately reduced blood glucose (by 25%, P< 0.05) when compared to STZ rats. The drug did not affect levels of C-peptide, an indicator of insulin secretion, suggesting altered tissue glucose utilization. Crizotinib had no impact on cardiac RTKs. However, an mRNA downregulation of insulin-dependent glucose transporter Glut4 in the hearts of STZ rats was attenuated after crizotinib treatment. Moreover, crizotinib normalized Ppard and reduced Pparg mRNA expression in diabetic hearts. Crizotinib decreased blood glucose independently of insulin and glucagon. This could be related to changes in regulators of cardiac metabolism such as GLUT4 and PPARs.

Protective effects of peel extracts of Irvingia wombolu on metabolic disorders in streptozotocin-induced diabetic rats

BackgroundDiabetes is widely recognized as associated with several structural and functional liver, kidney, and heart abnormalities. Therefore, the present study was conducted to evaluate the protective effect of peel extracts of Irvingia wombolu against diabetes complications.MethodsDiabetes was induced by intravenous administration of streptozotocin (STZ) (50 mg/kg) through the right jugular vein on rats and animals with blood glucose values of at least 250 mg/dl received orally aqueous extract of peel (AEP), hydroethanolic extract of peel (HEP), tolbutamide and DMSO 10%. Their effects on the concentration of blood glucose, total cholesterol, HDL-C, LDL-C, triglycerides, malondialdehyde (MDA) and activities of catalase (CAT), reduced glutathione (GSH), superoxide dismutase (SOD), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in diabetic and normal rats were investigated using standard methods.ResultsTwenty-one days of treatment with AEP and HEP at a dose of 400 mg/kg significantly (P < 0,05) reduced the fasting blood glucose to a point of reaching normal value. The antihyperlipidemic assessment of extracts revealed a significant (P < 0,05) decrease in total cholesterol, triglycerides, LDL levels, and a significant (P < 0,05) increase in HDL level in the plasma of treated diabetic rats. Furthermore, plasma biomarkers of liver and kidney dysfunction were significantly reduced in treated diabetic rats. We also observed increased activities of catalase, SOD, and reduced glutathione in diabetic treated rats.ConclusionThe present findings suggest that AEP and HEP have a protective effect on liver, kidney, and heart in experimental diabetic rats which can be beneficial in the management of diabetes and its complications.

Dapagliflozin Suppresses ER Stress and Improves Subclinical Myocardial Function in Diabetes: From Bedside to Bench.

Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor, is approved for treatments of patients with diabetes. The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial disclosed DAPA's benefits in symptomatic heart failure, but the underlying mechanism remains largely unknown. In this longitudinal and prospective study, we investigated changes of left ventricular functions including speckle tracking in patients with diabetes who were free from symptomatic heart failure post-DAPA treatment. Using a rat model with streptozotocin-induced diabetes, we measured the effects of DAPA on myocardial function. In patients with diabetes, following 6 months of DAPA treatment, despite no significant changes in left ventricular ejection fraction, the diastolic function and longitudinal strain improved. Likewise, compared with control, the diabetic rat heart developed pronounced fibrosis and a decline in strain and overall hemodynamics, all of which were mitigated by DAPA treatment. In contrast, despite insulin exerting a glucose-lowering effect, it failed to improve myocardial function and fibrosis. In our in vitro study, under high glucose cardiomyocytes showed significant activations of apoptosis, reactive oxygen species, and endoplasmic reticulum (ER) stress-associated proteins, which were attenuated by the coincubation of DAPA. Mechanistically, DAPA suppressed ER stress, reduced myocardial fibrosis, and improved overall function. The results can lead to further improvement in management of left ventricular function in patients with diabetes.

Combinative therapy of quercetin and vitamin Eameliorate intrinsic apoptotic via inhibition of mitochondrial pore shift in diabetic heart and liverameliorate intrinsic apoptotic via inhibition of mitochondrial pore shift in diabetic heart and liver

Combinative therapy of quercetin and vitamin E ameliorate intrinsic apoptotic via inhibition of mitochondrial pore shift in diabetic heart and liverABSTRACTAims/hypothesis Complications due to excessive apoptosis is observed in all forms of diabetes. The Mitochondrial has been shown to perform critical role in apoptosis and in recent times employed in management of the complications arising from the disease. The present study is aimed to evaluate if treatment with a combination of quercetin/vitamin E would ameliorate excessive apoptosis in diabetic rat heart and liver. Methods: We treated streptozotocin (STZ)-induced diabetic male Wistar rat models with a combination of quercetin/vitamin E and investigated their ability to inhibit sensitivity of mitochondrial Permeability Transition (mPT) pore. We examined the effect on mitochondrial Adenosine Triphosphatase (mATPase) activity, mitochondrial lipid peroxidation (mLPO), excessive cytochrome c (cytc) release, activated caspase 3 and 9. Treatment was given daily and orally for 4 weeks.Results: Diabetic rat heart and liver showed mPT pore opening when compared with normal control and this was reversed by treatment with a combination of quercetin/vitamin E. Furthermore, treatment blunted the enhanced mATPase activity, mLPO, blood glucose and lesions observed in rats. A decreased cytc release was evident by treatment in diabetic rat heart and liver. Furthermore, treatment ameliorated diabetes-induced cardiomyocyte and hepatocyte excessive apoptosis via down-regulation of caspase 3 and 9 activation.Conclusion/interpretation: The findings show that treatment with a combination of quercetin/vitamin E diminished susceptibility to cardiomyocytic and hepatocytic excessive apoptosis in diabetes facilitated by shifts in mPT pore opening. It is also a blood glucose lowering molecule with potentials of treating diabetes-induced complications.Keywords: Diabetes. Mitochondrial. Apoptosis. Quercetin. Vitamin E. Heart. LiverWord Count 241

Curcumin alleviates oxidative stress and inhibits apoptosis in diabetic cardiomyopathy via Sirt1-Foxo1 and PI3K-Akt signalling pathways.

Diabetes is a disorder of glucose metabolism, and over 90% are type 2 diabetes. Diabetic cardiomyopathy (DCM) is one of the type 2 diabetes complications, usually accompanied by changes in myocardial structure and function, together with cardiomyocyte apoptosis. Our study investigated the effect of curcumin on regulating oxidative stress (OS) and apoptosis in DCM. In vivo, diabetes was induced in an experimental rat model by streptozoticin (STZ) together with high‐glucose and high‐fat (HG/HF) diet feeding. In vitro, H9c2 cardiomyocytes were cultured with high‐glucose and saturated free fatty acid palmitate. Curcumin was orally or directly administered to rats or cells, respectively. Streptozoticin ‐induced diabetic rats showed metabolism abnormalities and elevated markers of OS (superoxide dismutase [SOD], malondialdehyde [MDA], gp91phox, Cyt‐Cyto C), enhanced cell apoptosis (Bax/Bcl‐2, Cleaved caspase‐3, TUNEL‐positive cells), together with reduced Akt phosphorylation and increased Foxo1 acetylation. Curcumin attenuated the myocardial dysfunction, OS and apoptosis in the heart of diabetic rats. Curcumin treatment also enhanced phosphorylation of Akt and inhibited acetylation of Foxo1. These results strongly suggest that apoptosis was increased in the heart of diabetic rats, and curcumin played a role in diabetic cardiomyopathy treatment by modulating the Sirt1‐Foxo1 and PI3K‐Akt pathways.

The Effects of Valsartan on Cardiac Function and Pro-Oxidative Parameters in the Streptozotocin-Induced Diabetic Rat Heart

Abstract Diabetes mellitus is a major risk factor for cardiovascular diseases, while cardiovascular diseases are a leading cause of morbidity and mortality worldwide. The renin–angiotensin– aldosterone system controls renal, cardiovascular, adrenal function and regulates fluid and electrolyte balance as well as blood pressure. Because of his role, inhibition of reninangiotensin-aldosteron system is another therapy approach that reduces the risk of diabetes and cardiovascular disease. In this study, our goal was to evaluate effect of valsartan,as inhibitor of angiotensin II receptor type 1, on cardiac tissue and function, with focus on cardiodynamic and oxidative stress. The present study was carried out on 20 adult male Wistar albino rats (8 week old and with body masses of 180-200 g). Rats were divided randomly into 2 groups (10 animals per group). Healthy animals treated with 1 μM of valsartan and streptozotocin-induced diabetic animals perfused with 1 μM of valsartan 4 weeks after the induction of diabetes. Our results demonstrated that acute application of valsartan has different effect on cardiodynamics in rat heart of diabetic and healthy animals but did not improve cardiac function in hyperglycemia-induced changes. A challenge for further investigations are studies with chronic or acute administration, alone or in combination with other angiotensin-converting-enzyme inhibitor in various models of diabetes.