Diabetic Rat Hearts Research Articles

Empagliflozin reduces the levels of CD36 and cardiotoxic lipids while improving autophagy in the hearts of Zucker diabetic fatty rats

The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial made evident the potentiality of pharmacological sodium-glucose cotransporter 2 (SGLT2) inhibition for treating patients with diabetes and cardiovascular disease. Since the effect of empagliflozin or other SGLT2 inhibitors on the whole cardiac metabolic profile was never analysed before, and with the purpose to contribute to elucidate the benefits at cardiac level of the use of empagliflozin, we explored the effect of the treatment with empagliflozin for six weeks on the cardiac metabolomic profile of Zucker diabetic fatty rats, a model of early stage T2DM, using untargeted metabolomics approach. Empagliflozin reduced significantly the cardiac content of sphingolipids (ceramides and sphingomyelins) and glycerophospholipids (major bioactive contributing factors linking insulin resistance to cardiac damage) and decreased the cardiac content of the fatty acid transporter cluster of differentiation 36 (CD36); induced significant decreases of the cardiac levels of essential glycolysis intermediaries 2,3-bisphosphoglycerate and phosphoenolpyruvate, and regulated the abundance of several amino acids of relevance as tricarboxylic acid suppliers and/or in the metabolic control of the cardiac function as glutamic acid, gamma-aminobutyric acid and sarcosine. Empagliflozin treatment activated the cardioprotective master regulator of cellular energyhomeostasis AMP-activatedproteinkinase (AMPK) and enhanced autophagy at cardiac level, while it decreased significantly the cardiac mRNA levels of the pro-inflammatory cytokines interleukin-6 (IL-6), chemerin, TNF-α and MCP-1, reinforcing the hypothesis of a direct role for empagliflozin in attenuating cardiac inflammation. Our results provide an advancement on the knowledge of the mechanisms linking the therapy with empagliflozin with protective effects on the development of cardiometabolic diseases whose course is associated with remarkable cardiac bioenergetics dysregulation and disarrangement in cardiac metabolome and lipidome.

Mitochondrial dysfunction plays a key role in the abrogation of cardioprotection by sodium hydrosulfide post-conditioning in diabetic cardiomyopathy rat heart.

Our previous study demonstrated that hydrogen sulfide post-conditioning (HPOC) renders cardioprotection against ischemia-reperfusion (I/R) injury in normal rat by preserving mitochondria. But its efficacy in ameliorating I/R in the diabetic heart with (DCM) or without cardiomyopathy (DM) is unclear and is the focus of the present study. Normal (N), diabetes mellitus (streptozotocin, 35mg/kg; normal diet), and DCM (streptozotocin, 35mg/kg; high-fat diet) rats were subjected to I/R (30min global ischemia followed by 60min reperfusion) in presence and absence of HPOC using ex vivo Langendorff perfusion system. At the end of heart perfusion, subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) fractions from the tissue were isolated and measured for the ATP production, electron transport chain (ETC) enzyme activity, and membrane potential. The prominent I/R-associated injury in DCM rat was not subsequently attenuated by HPOC protocol unlike in the normal or diabetic rat heart (latter rat heart showed moderate protection) (HPOC recovery on infarct size: N 75% vs. DM 63% vs. DCM 48%). The baseline ATP content and subsequent ATP-producing capacity in DCM rat heart were low as compared with those in normal or DM rat heart, especially in SSM. HPOC protocol reversed the I/R-induced low mitochondrial ATP content and low ATP-producing capacity (both in non-energized and energized with glutamate/malate) significantly in normal and DM hearts, but not in DCM heart. Moreover in DCM, decreased activity of mitochondrial electron chain enzymes (complexes I, II, III, and IV) in SSM (26%, 88%, 57%, and 17%) and IFM (76%, 89%, 60%, and 13%) from sham control was maintained even after the conditioning of heart with hydrogen sulfide donor. Results altogether suggest that significantly higher levels of perturbing mitochondria in DCM rat heart underline the deteriorated cardiac recovery by HPOC.

P3487Pre-ischemic succinate dehydrogenase inhibition is protective against ischemia-reperfusion injury in rat and human myocardium with and without diabetes mellitus

Abstract Background Ischemia-reperfusion (IR) injury can be attenuated through modulation of mitochondrial metabolism with succinate dehydrogenase (SDH) inhibition by dimethyl malonate (DiMAL). However, it is unknown whether SDH inhibition yields protection in aged, diabetic individuals and whether protection translate into human cardiac tissue. Purpose We wished to evaluate if SDH inhibition can be protective in aged, diabetic rat hearts and could be translated to the human myocardium. Methods We studied infarct size in aged non-diabetic and diabetic rat hearts subjected to isolated, retrograde perfusion and global ischemia and reperfusion. The hearts were randomized to: Sham hearts, IR injured hearts and IR injured hearts co-perfused with 0.1 mM or 0.6 mM DiMAL. Infarct size and mitochondrial respiratory capacity were evaluated post-ischemic. To translate our findings into human cardiac tissue, we tested the efficacy of DiMAL treatment in human atrial trabeculae from patients with and without diabetes mellitus undergoing cardiac surgery. We randomized atrial trabeculae to: IR injury, IR injury treated with ischemic preconditioning (IPC) and IR injury treated with 5 mM DiMAL. Contractile force recovery and mitochondrial respiratory capacity were evaluated post-ischemic. Results In non-diabetic rat hearts, DiMAL 0.1 mM reduced infarct size/area-at-risk (IS/AAR) compared to IR hearts (53±7% vs. 69±6% of IS/AAR; p<0.05). In diabetic hearts, an increased concentration of 0.6 mM DiMAL was required to confer protection (62±13% vs. 80±8% of IS/AAR; p<0.05). Mitochondrial complex I linked respiratory capacity was higher in both Sham and DiMAL 0.1 mM groups than with DiMAL 0.6 mM in non-diabetic hearts (157.4±26.5 and 140.0±35.3 vs. 81.8±42.4 pmol O2/(s*mg); p<0.01 and p<0.05). In trabeculae from humans without diabetes mellitus, IPC and DiMAL improved contractile force recovery compared to IR (43±12% and 43±13% vs. 23±13%, p<0.05). In trabeculae from patients with diabetes, IPC but not DiMAL administration improved contractile force recovery compared to IR (48±16% and 19±7% vs. 25±13%, p<0.01 and p>0.99). Mitochondrial complex I linked respiration capacity did not improve by IPC or DiMAL compared to IR in non-diabetic trabeculae (p>0.99). Conclusion Inhibition of the SDH by DiMAL protects the aged non-diabetic and diabetic heart from IR injury but the threshold for cardioprotection is increased in diabetic rat hearts. DiMAL provides cardioprotection similar to IPC in non-diabetic trabeculae but does not protect the human diabetic myocardium when given in identical concentrations. SDH inhibition can provide protection in both animal and human tissue and may provide a new target for pharmacologic conditioning in patients.

Effect of sevoflurane on phosphorylation of connexin 43 at ser368 in ventricular myocardium in isolated hearts of diabetic rats

Objective To evaluate the effect of sevoflurane on phosphorylation of connexin 43 (Cx43) at Ser368 (Cx43 Ser368) in ventricular myocardium in isolated hearts of diabetic rats. Methods Twenty-four clean-grade healthy adult male Sprague-Dawley rats, aged 3 months, weighing 180-220 g, were used in this study.The diabetic model was established by intraperitoneally injecting streptozotocin 60 mg/kg.The hearts were rapidly excised and retrogradely perfused with K-H solution saturated with 95% O2-5% CO2 at 37 ℃ in a Langendorff apparatus.Sixteen Langendorff-perfused diabetic hearts were divided into 3 groups (n=8 each) using a random number table method: diabetes mellitus group (group D) and sevoflurane group (group DS). Another 8 Langendorff-perfused normal hearts of rats were selected and served as control group (group C). After 15 min equilibration with K-H solution, the hearts were continuously perfused for 30 min with K-H solution in group C and group D and with K-H solution saturated with 2.5% sevoflurane in group DS.S1S2 program-controlled stimulation was performed at the end of perfusion, the occurrence of induced ventricular arrhythmia (VA) and the maximal pacing cycle length (PCL) of induced VA were recorded, and conduction velocity (CV) was calculated.The expression of phosphorylated Cx43 at Ser368 (p-Cx43 Ser368) in ventricular myocytes was determined by Western blot. Results Compared with group C, the incidence of induced VA was significantly increased, the maximal PCL of induced VA was prolonged, the CV was decreased, and the expression of p-Cx43 Ser368 was up-regulated in group D (P<0.05). Compared with the incidence of induced VA was significantly decreased, the maximal PCL of induced VA was shortened, the CV was increased, and the expression of p-Cx43 Ser368 was down-regulated in group DS (P<0.05). Conclusion The mechanism by which sevoflurane stabilizes the ventricular electrical conduction is associated with decreasing the phosphorylation of Cx43 at Ser368 in diabetic rats. Key words: Anesthetics, inhalation; Diabetes mellitus; Connexins

Protective effects of acarbose against vascular endothelial dysfunction through inhibiting Nox4/NLRP3 inflammasome pathway in diabetic rats

The cardiovascular efficacy of glucose-lowering drugs is needed due to the cardiovascular complication in type 2 diabetes mellitus (T2DM). Acarbose is an α-glucosidase inhibitor that suppresses postprandial hyperglycemia, however, the cardiovascular protection of acarbose has still remained controversial. NLRP3 inflammasome activation mediated tight junction disruption, a hallmark event of endothelial barrier dysfunction leading to endothelial hyperpermeability in diabetes. Given the anti-inflammatory property of acarbose, it was investigated that acarbose protected against vascular endothelial barrier dysfunction through inhibiting NLRP3 inflammasome in vascular endothelial cells in T2DM rats. The rat aortic endothelial cells (RAECs) were incubated with high glucose (HG, 30 mM) for 24 h in vitro. It was found that HG significantly induced the formation and activation of NLRP3 inflammasome, which was markedly blocked by acarbose treatment. Furthermore, acarbose blocked the Nox4-dependent superoxide (O2.-) generation, which regulated NLRP3 inflammasome in RAECs. Importantly, we found that acarbose remarkably enhanced the junction protein expression of ZO-1 and VE-Cadherin and consequently abolished vascular hyperpermeability, which was associated with inhibiting NLRP3 inflammasome in RAECs. In vivo, acarbose intervention relieved vascular leakage in the heart of diabetic rats injected with Evans blue dye and the vasodilatory response to acetylcholine, which was accompanied with the restoration of ZO-1, VE-Cadherin, Nox4 and NLRP3 inflammasome in the aortal endothelium of diabetic rats. Taken together, our data indicated that acarbose ameliorated endothelial barrier dysfunction by directly inhibiting NLRP3 inflammasome which was dependent on inhibiting Nox4 oxidase-dependent O2.- production. These properties might carry a potential significance for acarbose in cardiovascular protection in diabetic patients.

Melatonin and the heart circadian clock of euglycemic and type 2 diabetic male rats: a transcriptional evaluation

Diabetes increases risk of various comorbidities, including retinopathy, neuropathy, and cardiovascular disease, comprising both ischemic and non-ischemic cardiomyopathy. Cardiac dysfunction during diabetes is associated with perturbations at histologic, metabolic, biochemical and molecular levels. The circadian clock is misaligned in multiple organs during diabetes, including the heart. Such alterations in clock function have been postulated to play a causal role in cardiac dysfunction even though the mechanisms leading to circadian misalignment are currently unknown. Melatonin has been reported to alter heart circadian clock components and its circulating levels are decreased during diabetes. These observations led to the hypothesis that decreased melatonin levels during diabetes could be related to mismanagement of the heart clock. To evaluate this hypothesis, in the current study male Wistar and non-obese type 2 diabetic Goto-Kakizaki (GK) rats were given melatonin supplementation in their drinking water during the dark phase (for 12-wks), followed by assessment of clock component and the mRNA expression of the clock-controlled genes in the hearts of these animals. Melatonin supplementation significantly altered mRNA expression of targeted genes in both euglycemic and diabetic rat hearts. Collectively, under the condition of diabetes, the jeopardized pineal melatonin synthesis with misalignment of cardiac circadian clock components may likely mediate heart metabolic dysfunction, and/or even cause cardiovascular diseases.

Altered mRNA Expression of ATP-Sensitive and Inward Rectifier Potassium Channel Subunits in Streptozotocin-Induced Diabetic Rat Heart and Aorta

Altered mRNA Expression of ATP-Sensitive and Inward Rectifier Potassium Channel Subunits in Streptozotocin-Induced Diabetic Rat Heart and Aorta

The cardioprotective effects of diallyl trisulfide on diabetic rats with ex vivo induced ischemia/reperfusion injury.

Diallyl trisulfide (DATS) is distinguished as the most potent polysulfide isolated from garlic. The aim of our study was to investigate effects of oral administration of DATS on healthy and diabetic rats, with special attention on heart function. Rats were randomly divided into four groups: CTRL (healthy rats), DATS (healthy rats treated with DATS), DM (diabetic rats), DM + DATS (diabetic rats treated with DATS). DATS (40mg/kg of body weight) was administered every other day for 3weeks, at the end of which rats underwent echocardiography, glycemic measurement and redox status assessment. Isolated rat hearts were subjected to 30min global ischemia and 60min reperfusion, after which heart tissue was counterstain with hematoxylin and eosin and cardiac Troponin T staining (cTnT), while expression of Bax, B cell lymphoma 2 (Bcl-2), caspase-3, caspase-9 and superoxide dismutase-2 were examined in the left ventricle. DATS treatment significantly reduced blood glucose levels of diabetic rats, and improved cardiac function recovery, diminished oxidation status, attenuated cardiac remodeling and inhibited myocardial apoptosis in healthy and diabetic rats. DATS treatment causes promising cardioprotective effects on ex vivo-induced ischemia/reperfusion (I/R) injury in diabetic and healthy rat heart probably mediated by inhibited myocardial apoptosis. Moreover, appropriate DATS consumption may provide potential co-therapy or prevention of hyperglycemia and various cardiac complications in rats with DM.

Influence of melatonin on the activity of main enzymes of cori cycle in skeletal muscles, heart, liver and kidneys of alloxan-induced diabetic rats

Influence of melatonin on the activity of main enzymes of cori cycle in skeletal muscles, heart, liver and kidneys of alloxan-induced diabetic rats

Nicorandil alleviates apoptosis in diabetic cardiomyopathy through PI3K/Akt pathway.

Nicorandil exerts myocardial protection through its antihypoxia and antioxidant effects. Here, we investigated whether it plays an anti‐apoptotic role in diabetic cardiomyopathy. Sprague‐Dawley rats were fed with high‐fat diet; then single intraperitoneal injection of streptozotocin was performed. Rats with fasting blood glucose (FBG) higher than 11.1 mmol/L were selected as models. Eight weeks after the models were built, rats were treated with nicorandil (7.5 mg/kg day and 15 mg/kg day respectively) for 4 weeks. H9c2 cardiomyocytes were treated with nicorandil and then stimulated with high glucose (33.3 mmol/L). TUNEL assay and level of bcl‐2, bax and caspase‐3 were measured. 5‐HD was used to inhibit nicorandil. Also, PI3K inhibitor (Miltefosine) and mTOR inhibitor (rapamycin) were used to inhibit PI3K/Akt pathway. The results revealed that nicorandil (both 7.5 mg/kg day and 15mg/kg day) treatment can increase the level of NO in the serum and eNOS in the heart of diabetic rats compared with the untreated diabetic group. Nicorandil can also improve relieve cardiac dysfunction and reduce the level of apoptosis. In vitro experiments, nicorandil (100 µmol) can attenuate the level of apoptosis stimulated by high glucose significantly in H9C2 cardiomyocyte compared with the untreated group. The effect of nicorandil on apoptosis was blocked by 5‐HD, and it was accompanied with inhibition of the phosphorylation of PI3K, Akt, eNOS, and mTOR. After inhibition of PI3K/Akt pathway, the protective effect of nicorandil is restrained. These results verified that as a NO donor, nicorandil can also inhibit apoptosis in diabetic cardiomyopathy which is mediated by PI3K/Akt pathway.

Vaspin prevents myocardial injury in rats model of diabetic cardiomyopathy by enhancing autophagy and inhibiting inflammation

NLRP3 inflammasome activation plays an important role in diabetic cardiomyopathy (DCM). It is known that autophagy is related to the activation of inflammasomes during oxidative stress. Visceral adipose tissue-derived serine protease inhibitor (Vaspin), is an adipocytokine that has been shown to exert a protective effect on autophagic activity, but whether and how Vaspin improves myocardial damage in DCM remain unclear. In this study, we explored the role of Vaspin in DCM using a streptozotocin (STZ)-induced diabetes model. Cardiac function, cardiomyocyte apoptosis, myocardial tissue morphology, and mitochondrial morphology in diabetic rats were improved after eight weeks of Vaspin treatment. Vaspin treatment augmented autophagy activation in diabetic rat hearts. Moreover, the activation of NLRP3 inflammasome was inhibited by Vaspin, followed by a decrease in the cleavage of caspase-1 and maturation of IL-1β and TNF-ɑ. In vitro studies found that the mitochondrial reactive oxygen species (ROS) generation as well as the depolarization of the mitochondrial membrane in H9C2cells induced by high glucose were attenuated by Vaspin. This inhibitory effect of Vaspin on NLRP3 inflammasome activation was due to the protection of autophagy activity and was abolished after the treatment of autophagy inhibitor (3-MA). These results demonstrate that Vaspin alleviates STZ-induced myocardial injury and renders a cardioprotective effect by suppressing NLRP3 inflammasome activation and promoting autophagy.

The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Restores Cardiomyocyte Contractility in a Rat Model of Early Diabetes.

In early diabetes, hyperglycemia and the associated metabolic dysregulation promote early changes in the functional properties of cardiomyocytes, progressively leading to the appearance of the diabetic cardiomyopathy phenotype. Recently, the interplay between histone acetyltransferases (HAT) and histone deacetylases (HDAC) has emerged as a crucial factor in the development of cardiac disorders. The present study evaluates whether HDAC inhibition can prevent the development of cardiomyocyte contractile dysfunction induced by a short period of hyperglycemia, with focus on the potential underlying mechanisms. Cell contractility and calcium dynamics were measured in unloaded ventricular myocytes isolated from the heart of control and diabetic rats. Cardiomyocytes were either untreated or exposed to the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) for 90 min. Then, a fraction of each group of cells was used to evaluate the expression levels of proteins involved in the excitation–contraction coupling, and the cardiomyocyte metabolic activity, ATP content, and reactive oxygen species levels. SAHA treatment was able to counteract the initial functional derangement in cardiomyocytes by reducing cell oxidative damage. These findings suggest that early HDAC inhibition could be a promising adjuvant approach for preventing diabetes-induced cardiomyocyte oxidative damage, which triggers the pro-inflammatory signal cascade, mitochondrial damage, and ventricular dysfunction.

Antihyperglycemic, antioxidant and hypolipidemic effect of Capparis aphylla stem extract in streptozotocin induced diabetic rats.

Capparis aphylla, a xerophytic plant, has been used in traditional Indian medicine for treating diabetes and cardiovascular disease. The methanol extracts and active fraction from stem of C. aphylla administered to diabetic rats and blood glucose, antioxidant level, lipid, urea and creatinine level were assayed. The single oral dosing(300mg/kg b.wt) of methanol extract and active fraction(30mg/kg b.wt) from stem part of C. aphylla significantly reduced blood glucose levels in normal and diabetic rats (p<0.01) during oral glucose tolerance test. While total plasma cholesterol, triglycerides, VLDL and LDL levels were significantly (p<0.01) reduced, serum HDL was elevated by 116% after 7 days of active fraction oral administration in diabetic rats. Active fraction treatment lead to significant (p<0.01) increase in GSH and decreased MDA level in liver, heart and kidney of diabetic rat. Finding supported the traditional use of C. aphylla in the treatment of diabetes and cardiovascular disease.

β2 -Adrenoceptors indirectly support impaired β1 -adrenoceptor responsiveness in the isolated type 2 diabetic rat heart.

What is the central question of this study? Are there specific contributions of β1 - and β2 -adrenoceptor subtypes to the impaired β-adrenoceptor responsiveness of the type 2 diabetic heart? What is the main finding and its importance? In hearts isolated from the Zucker diabetic fatty rat model of type 2 diabetes, we showed that the β1 -adrenoceptors are the main subtype to regulate heart rate, contraction and relaxation. Notably, the β2 -adrenoceptor subtype actions seem to support function in the diabetic heart indirectly. Impaired β-adrenoceptor (β-AR) responsiveness causes cardiac vulnerability in patients with type 2 diabetes, but the independent contributions of β1 - and β2 -AR subtypes to β-AR-associated cardiac dysfunction in diabetes are unknown. Our aim was to determine the specific β1 - and β2 -AR responsiveness of heart rate (HR), contraction and relaxation in the diabetic heart. Isolated Langendorff-perfused hearts of Zucker type 2 diabetic fatty (ZDF) rats were stimulated with the β-AR agonist isoprenaline (1×10-11 to 3×10-8 moll-1 ) with or without the selective β1 -AR antagonist CGP20712A (3×10-8 moll-1 ) or the β2 -AR antagonist ICI-118,551 (5×10-8 moll-1 ), and HR, contraction and relaxation were measured. Diabetic hearts showed lower basal HR (non-diabetic 216±17beatsmin-1 versus diabetic 151±23beatsmin-1 , P<0.05). However, the β-AR-induced increase in HR was similar and was completely blocked by the β1 -AR antagonist, but not by the β2 -AR antagonist. The β-AR-induced increase in contraction and acceleration of relaxation was impaired in diabetic hearts, completely blocked by the β1 -AR antagonist and partly impaired by the β2 -AR antagonist. Western blots revealed 41% higher phosphorylation levels of AMP kinase (AMPK), a key regulator of cardiac energy metabolism, in diabetic hearts (non-diabetic 1.62±0.19a.u. versus diabetic 2.30±0.25a.u., P<0.05). In conclusion, the β1 -AR is the main subtype regulating chronotropic, inotropic and lusitropic β-AR responses in the healthy heart and the type2 diabetic heart. The β2 -AR subtype indirectly supports the β1 -AR functional response in the diabetic heart. This suggests that β2 -ARs could be an indirect target to improve the function of the heart in type 2 diabetes.

A new hyperpolarized 13C ketone body probe reveals an increase in acetoacetate utilization in the diabetic rat heart

Emerging studies have recently shown the potential importance of ketone bodies in cardio-metabolic health. However, techniques to determine myocardial ketone body utilization in vivo are lacking. In this work, we developed a novel method to assess myocardial ketone body utilization in vivo using hyperpolarized [3-13C]acetoacetate and investigated the alterations in myocardial ketone body metabolism in diabetic rats. Within a minute upon injection of [3-13C]acetoacetate, the production of [5-13C]glutamate and [1-13C] acetylcarnitine can be observed real time in vivo. In diabetic rats, the production of [5-13C]glutamate was elevated compared to controls, while [1-13C]acetylcarnitine was not different. This suggests an increase in ketone body utilization in the diabetic heart, with the produced acetyl-CoA channelled into the tricarboxylic acid cycle. This observation was corroborated by an increase activity of succinyl-CoA:3-ketoacid-CoA transferase (SCOT) activity, the rate-limiting enzyme of ketone body utilization, in the diabetic heart. The increased ketone body oxidation in the diabetic hearts correlated with cardiac hypertrophy and dysfunction, suggesting a potential coupling between ketone body metabolism and cardiac function. Hyperpolarized [3-13C]acetoacetate is a new probe with potential for non-invasive and real time monitoring of myocardial ketone body oxidation in vivo, which offers a powerful tool to follow disease progression or therapeutic interventions.

Resveratrol improves mitochondrial energetic pathway and endothelial function in type 2 diabetic female rat heart submitted to ischemia-reperfusion injury

Type 2 diabetic women present high risk of mortality by cardiovascular (CV) disease in comparison to non-diabetic women. Most of anti-diabetic treatments do not decrease patient's CV mortality, therefore new approaches need to be found. Resveratrol (RSV) is a polyphenol found in grapes reported to be beneficial on oxidative stress, endothelial dysfunction and inflammation involved in CV complications of T2D. We have investigated the effect of RSV on the tolerance to ischemia-reperfusion (IR) injury of type 2 diabetic female Goto-Kakizaki (GK) rat hearts. Four groups were used: a control group, a GK group, a GK group with placebo and a GK group with RSV treatment at the dose of 1mg/kg/day in drinking water for 8 weeks. After 8 weeks of RSV treatment, tolerance to IR injury was assessed during ex vivo experiments, with simultaneous measurement of energy metabolism by 31P MRS, myocardial function and coronary flow. At the end of experiments, PCr, creatine, adenine nucleotides contents and citrate synthase activity were assessed in freeze-clamped hearts as well as nitric oxide and sirtuin pathways. Type 2 diabetic GK rats exhibited cardiac hypertrophy and lower myocardial tolerance to IR injury in comparison to controls. RSV attenuated cardiac hypertrophy and increased myocardial tolerance to IR injury by improving cardiac function, mitochondrial energetic and endothelial pathways. Interestingly, RSV increased ATP, PCr, creatine, total adenine nucleotide heart contents, citrate synthase activity, as well as eNOS, P-Akt and SIRT1 protein expressions in GK rat hearts. RSV induced cardioprotection against IR injury in type 2 diabetic female rats. Thus, RSV presents high potential for preventing and treating CV complications of type 2 diabetic women.

Polyphenol-enriched azuki bean (Vina angularis) extract reduces the oxidative stress and prevents DNA oxidation in the hearts of streptozotocin-induced early diabetic rats

We examined the changes in the heart of rats at the early stages of streptozotocin (STZ)-induced diabetes, and whether azuki bean extract (ABE) could influence these changes. The experimental diabetic rats received 0 or 40 mg/kg of ABE orally for 4 weeks, whereas the control group rats received distilled water. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and expression of proteins associated with peroxisomal FA β-oxidation as well as oxidative stress markers were examined. The levels of peroxisomal ACOX1 and catalase of the diabetic groups were significantly higher than those in the control group. The levels of p62, phosphorylated-p62 (p-p62) and HO-1 in the STZ group were significantly higher than those in the control group, and the levels of p-p62, HO-1, and 8-OHdG were significantly lower by ABE administration. The STZ-induced early diabetes increases the levels of proteins related to peroxisomal FA β-oxidation and oxidative stress markers in hearts. ABE protects diabetic hearts from oxidative damage.

Caveolins; An Assailant or An Ally of Various Cellular Disorders

Caveolae have impressive morphological highlights of the cytomembrane of mammalian cells which involve in wide diversity of cellular functions involving signaling pathways and cholesterol hastening. Caveolin proteins possess a 'scaffolding' domain which for caveolin-1 and caveolin-3 appear to act a dominant role in signal regulation through caveolae. Caveolin-1 is treated to be protein in the cytomembrane entrapped with caveolae in endothelial cells and vascular smooth muscle cells which diminish nitric oxide (NO) by fill up the calcium/calmodulin (Ca2+/CaM) confining point of endothelial nitric oxide synthase (eNOS), decrease NO generation produce endothelial dysfunction and atherosclerotic injury development. It is a cholesterol-binding layer protein associated with cell cholesterol transport and also shows cardioprotective action through ischemic preconditioning (IPC) in diabetic and postmenopausal rat heart. Additionally it is ensnared in the procedures of tumorigenesis, prostate disease, and inflammation. The present study in the paper is to explore the structural functionalities of caveolins and their contributory role in CVS disorders and various other diseases.

Fisetin ameliorates oxidative stress, inflammation and apoptosis in diabetic cardiomyopathy

AimsHyperglycemia-mediated oxidative damage has been described as a major mechanism leading to pathologic changes associated with diabetic cardiomyopathy (DCM). Fisetin is a bioactive flavonol molecule found in many plants and possesses various biological activities. The present study investigated the protective effect of fisetin on diabetes-induced cardiac injury. MethodsDiabetes was induced by streptozotocin (STZ) and both diabetic and control rats were treated with 2.5 mg/kg fisetin for six weeks. Key findingsDiabetic rats exhibited hyperglycemia, and increased glycosylated hemoglobin and serum lipids accompanied with significant hypoinsulinism. In addition, diabetic rats showed several histological alterations in the myocardium, and significantly increased serum troponin I, creatine kinase-MB and lactate dehydrogenase. Oxidative stress, inflammation and apoptosis markers were increased, whereas antioxidant defenses were significantly reduced in the diabetic heart. Treatment with fisetin alleviated hyperglycemia, hyperlipidemia and heart function markers, and minimized histological alterations in the myocardium. Fisetin suppressed oxidative stress, prevented inflammation and apoptosis, and boosted antioxidant defenses in the heart of diabetic rats. SignificanceFisetin attenuated the development of DCM via amelioration of hyperglycemia/hyperlipidemia-mediated oxidative stress, inflammation and apoptosis. Therefore, it might be worth considering the therapeutic potential of fisetin for human DCM.

FBXL10 regulates cardiac dysfunction in diabetic cardiomyopathy via the PKC β2 pathway

Diabetic cardiomyopathy (DCM) is a condition associated with significant structural changes including cardiac tissue necrosis, localized fibrosis, and cardiomyocyte hypertrophy. This study sought to assess whether and how FBXL10 can attenuate DCM using a rat streptozotocin (STZ)‐induced DCM model system. In the current study, we found that FBXL10 expression was significantly decreased in diabetic rat hearts. FBXL10 protected cells from high glucose (HG)‐induced inflammation, oxidative stress, and apoptosis in vitro. In addition, FBXL10 significantly activated PKC β2 signaling pathway in H9c2 cells and rat model. The cardiomyocyte‐specific overexpression of FBXL10 at 12 weeks after the initial STZ administration attenuated oxidative stress and inflammation, thereby reducing cardiomyocyte death and preserving cardiac function in these animals. Moreover, FBXL10 protected against DCM via activation of the PKC β2 pathway. In conclusion, FBXL has the therapeutic potential for the treatment of DCM.