Protective effects of BiP inducer X (BIX) against diabetic cardiomyopathy in rats

2020 ◽  
Author(s):  
Gholamreza Idari ◽  
Pouran Karimi ◽  
Samad Ghaffari ◽  
Seyed Isaac Hashemy ◽  
Baratali Mashkani
Keyword(s):  
Er Stress ◽  
Diabetic Cardiomyopathy ◽  
Cell Apoptosis ◽  
Cardiac Fibrosis ◽  
Tissue Expression ◽  
Myocardial Cell ◽  
Diabetic Rats ◽  
Mrna Levels ◽  
Protective Effects ◽  
Cardiac Cell

Diabetic cardiomyopathy (DC) is associated with impaired endoplasmic reticulum (ER) function, development of ER stress, and induction of cardiac cell apoptosis. Preventive effects of BiP inducer X (BIX) were investigated against DC characteristic changes in a type 2 diabetes rat model. To establish diabetes, a high-fat diet and a single dose of streptozotocin were administered. Then, animals were assigned into following groups: control, BIX, diabetic animals monitored for one, two, and three weeks. Diabetic rats treated with BIX for one, two, and three weeks. Expressions of various ER stress and apoptotic markers were assessed by immunoblotting method. CHOP gene expression was assessed by Real-time PCR. Tissue expression of BiP was evaluated by immunohistochemistry method. Hematoxylin and eosin and Masson's trichrome staining were performed to assess histological changes in the left ventricle. Cardiac cell apoptosis was examined using TUNEL assay. BIX administration suppressed the activation of the ER stress markers and cleavage of pro-caspase 3 in the diabetic rats. Likewise, tissue expression of BiP protein was increased, while CHOP mRNA levels were decreased. These results were accompanied by reducing cardiac fibrosis and myocardial cell apoptosis suggesting protective effects of BIX against the development of DC by decreasing cardiomyocyte apoptosis and fibrosis.

Abstract P410: A Novel Curcumin Formulation, ASD-cur Suppressed Heart Failure After Myocardial Infarction In Rats

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Hidemichi Takai ◽  
Tatsuya Morimoto
Keyword(s):  
Heart Failure ◽  
Plasma Concentration ◽  
Cardiac Fibrosis ◽  
Myocardial Cell ◽  
Left Ventricular ◽  
Cell Diameter ◽  
Maximum Plasma ◽  
Mrna Levels ◽  
Time Curve ◽  
Sd Rats

Introduction: Curcumin prevents the development of heart failure and is a potential treatment for heart failure. Although curcumin is known to be safe, its therapeutic efficiency is limited due to its low bioavailability. To overcome this problem, we developed ASD-Cur, an amorphous formulation of curcumin. In this study, we investigated the effect of ASD-Cur and compared it with Theracurmin ® , a colloidal submicron dispersion of curcumin. Methods: Male SD rats were orally administrated with ASD-Cur or Theracurmin ® (10 mg/kg curcumin). The plasma levels of curcumin were measured at 0.25, 0.5, 1, 2, 4 and 6 hours after administration. Twelve healthy volunteers, who had provided written informed consent, were administrated with ASD-Cur and Theracurmin ® containing 30 mg curcumin, and plasma curcumin concentrations were determined at 0.5, 1, 2, 4, and 8 hours. Next, male SD rats were subjected to MI or sham surgery. One week after surgery, the MI rats were randomly assigned to 4 groups: vehicle, ASD-Cur (0.2 mg/kg curcumin) or Theracurmin ® (0.2 or 0.5 mg/kg curcumin). Oral administration of these compounds was repeated for 6 weeks. After echocardiographic examinations, myocardial cell diameter, perivascular fibrosis, mRNA levels, and the acetylation of histone H3K9 were measured. Results: After administration in rats, the area under the plasma concentration-time curve ( AUC 0-6h ) and the maximum plasma concentration ( C max ) of ASD-Cur were 3.7-fold and 9.6-fold higher than those of Theracurmin ® , respectively. The AUC 0-8h and C max of ASD-Cur in humans were 3.4-fold and 5.4-fold higher than those of Theracurmin ® , respectively. Echocardiographic analysis showed that 0.2 mg/kg ASD-Cur and 0.5 mg/kg Theracurmin ® significantly improved the MI-induced deterioration of FS and left ventricular hypertrophy to the same extent. Both treatments significantly suppressed MI-induced increases in myocardial cell diameter, perivascular fibrosis, mRNA levels of hypertrophic markers and cardiac fibrosis, and acetylation of histone H3K9 to the same extent. Conclusion: These findings indicated that ASD-Cur has greater bioavailability than Theracurmin ® , and could exhibit greater therapeutic potency towards for MI-induced heart failure at a lower dose.

scholarly journals Thyroxine Affects Lipopolysaccharide-Induced Macrophage Differentiation and Myocardial Cell Apoptosis via the NF-κB p65 Pathway Both In Vitro and In Vivo

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Shan Zhu ◽  
Yuan Wang ◽  
Hongtao Liu ◽  
Wen Wei ◽  
Yi Tu ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cardiac Dysfunction ◽  
Cell Apoptosis ◽  
Cardiac Injury ◽  
Myocardial Cell ◽  
M2 Macrophage ◽  
Mrna Levels ◽  
Cytokine Mrna ◽  
M1 Macrophage

Background. Numerous studies have demonstrated that the inflammatory response is involved in the progression of lipopolysaccharide- (LPS-) induced myocardial cell apoptosis. Accumulating evidence has shown that thyroxine participates in diseases by downregulating the inflammatory response. This study aimed at investigating whether thyroxine alleviates LPS-induced myocardial cell apoptosis. Methods. Bone marrow-derived macrophages (Mø) were treated with LPS and thyroxine, and Mø differentiation and Mø-related cytokine expression were measured. The effect of Mø differentiation on mouse cardiomyocyte (MCM) apoptosis was also detected in vitro. In addition, C57BL/6 mice underwent thyroidectomy and were treated with LPS 35 days later; subsequently, Mø differentiation and myocardial cell apoptosis in hearts were analyzed. To determine whether the nuclear factor-kappa B (NF-κB) p65 pathway mediates the effect of thyroxine on Mø differentiation and myocardial cell apoptosis, the specific NF-κB p65 pathway inhibitor JSH-23 was administered to mice that underwent a thyroidectomy. Results. Levothyroxine treatment significantly reduced the activation of the NF-κB p65 pathway, decreased M1 macrophage (Mø1) differentiation and Mø1-related cytokine mRNA levels in LPS-treated Mø, and increased M2 macrophage (Mø2) differentiation and Mø2-related cytokine mRNA expression. The protective effects of levothyroxine on MCM apoptosis mediated by LPS-treated Mø were alleviated by JSH-23. In mice, thyroidectomy aggravated LPS-induced cardiac injury and cardiac dysfunction, further promoted NF-κB p65 activation, and increased cardiac Mø1 expression and myocardial cell apoptosis but decreased cardiac Mø2 expression. JSH-23 treatment significantly ameliorated the thyroidectomy-induced increases in myocardial cell apoptosis and Mø differentiation. Conclusions. Thyroxine alleviated the Mø1/Mø2 imbalance, reduced the inflammatory response, decreased myocardial cell apoptosis, and protected against cardiac injury and cardiac dysfunction in LPS-treated mice. Thyroxine may be a novel therapeutic strategy to prevent and treat LPS-induced cardiac injury.

scholarly journals Novel Insights Into the Pathogenesis of Diabetic Cardiomyopathy and Pharmacological Strategies

2021 ◽  
Vol 8 ◽  
Author(s):  
Felipe Muñoz-Córdova ◽  
Carolina Hernández-Fuentes ◽  
Camila Lopez-Crisosto ◽  
Mayarling F. Troncoso ◽  
Ximena Calle ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Clinical Manifestations ◽  
Myocardial Cell ◽  
Cardiomyocyte Hypertrophy ◽  
Autophagic Flux ◽  
Low Grade ◽  
Cellular Processes ◽  
Pharmacological Targets

Diabetic cardiomyopathy (DCM) is a severe complication of diabetes developed mainly in poorly controlled patients. In DCM, several clinical manifestations as well as cellular and molecular mechanisms contribute to its phenotype. The production of reactive oxygen species (ROS), chronic low-grade inflammation, mitochondrial dysfunction, autophagic flux inhibition, altered metabolism, dysfunctional insulin signaling, cardiomyocyte hypertrophy, cardiac fibrosis, and increased myocardial cell death are described as the cardinal features involved in the genesis and development of DCM. However, many of these features can be associated with broader cellular processes such as inflammatory signaling, mitochondrial alterations, and autophagic flux inhibition. In this review, these mechanisms are critically discussed, highlighting the latest evidence and their contribution to the pathogenesis of DCM and their potential as pharmacological targets.

scholarly journals Catestatin attenuates endoplasmic reticulum induced cell apoptosis by activation type 2 muscarinic acetylcholine receptor in cardiac ischemia/reperfusion

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Feng Liao ◽  
Yang Zheng ◽  
Junyan Cai ◽  
Jinghui Fan ◽  
Jing Wang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Receptor Antagonist ◽  
Acetylcholine Receptor ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion ◽  
Cardiac Ischemia ◽  
Protective Effects ◽  
Muscarinic Acetylcholine

Abstract Catestatin (CST) is a catecholamine secretion inhibiting peptide as non-competitive inhibitor of nicotinic acetylcholine receptor. CST play a protective role in cardiac ischemia/reperfusion (I/R) but the molecular mechanism remains unclear. Cardiomyocytes endogenously produced CST and its expression was reduced after I/R. CST pretreatment decreased apoptosis especially endoplasmic reticulum (ER) stress response during I/R. The protection of CST was confirmed in H9c2 cardiomyoblasts under Anoxia/reoxygenation (A/R). In contrast, siRNA-mediated knockdown of CST exaggerated ER stress induced apoptosis. The protective effects of CST were blocked by extracellular signal-regulated kinases 1/2 (ERK1/2) inhibitor PD90895 and phosphoinositide 3-kinase (PI3 K) inhibitor wortmannin. CST also increased ERK1/2 and protein kinase B (Akt) phosphorylation and which was blocked by atropine and selective type 2 muscarinic acetylcholine (M2) receptor, but not type 1 muscarinic acetylcholine (M1) receptor antagonist. Receptor binding assay revealed that CST competitively bound to the M2 receptor with a 50% inhibitory concentration of 25.7 nM. Accordingly, CST inhibited cellular cAMP stimulated by isoproterenol or forskolin and which was blocked by selective M2 receptor antagonist. Our findings revealed that CST binds to M2 receptor, then activates ERK1/2 and PI3 K/Akt pathway to inhibit ER stress-induced cell apoptosis resulting in attenuation cardiac I/R injury.

scholarly journals P0719SRC KINASES AGGRAVATE DIABETIC KIDNEY INJURY THROUGH ACTIVATION OF ENDOPLASMIC RETICULUM STRESS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Debra Dorotea ◽  
Hunjoo Ha
Keyword(s):  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Er Stress ◽  
Kidney Injury ◽  
Diabetic Rats ◽  
Src Kinases ◽  
Mrna Levels ◽  
Diabetic Kidney ◽  
Kidney Fibrosis ◽  
In The Diabetic Kidney

Abstract Background and Aims Diabetic kidney disease (DKD) is the major cause of end-stage kidney disease which is characterized by prominent kidney fibrosis. Src family kinases (SFKs), a family of proto-oncogenes, has been acknowledged to mediate the development of kidney fibrosis. While, several studies in liver and skeletal muscle suggested the role of Src kinases in activating endoplasmic reticulum (ER) stress. The present study aimed to investigate the mechanism of Src kinases-ER stress in mediating the progression of DKD. Method Type 1 diabetes was induced by a single 60 mg/kg i.p injection of streptozotocin (STZ) in 7-week-old male, Sprague-Dawley rats. Diabetic rats received 8-week-treatment of either KF-1607 (30 mg/kg/day), a pharmacological inhibitor of SFKs, or losartan (1 mg/kg/day), a standard treatment for patients with DKD. Results Among SFKs, Fyn and Lyn kinases were particularly increased in the diabetic kidney. Inhibition of Src kinases by KF-1607 improved kidney function and inhibited tubular injury, presented by decreased serum creatinine, albuminuria, and urinary KIM-1 excretion. Pathological changes in the kidney, such as enhanced glomerular volume, tuft area, and fractional mesangial area, were ameliorated in KF-treated rats. Highly-accumulated collagen network as well as increased TGF-β and α-SMA mRNA levels in the diabetic kidney were also significantly reduced in response to KF treatment. Furthermore, it consistently attenuated kidney inflammation and oxidative stress. The renoprotective effects of KF were interestingly similar to those of losartan. We showed increases in protein levels of phosphorylated IRE-1α, ATF6, GRP78 as well as CHOP indicating an exacerbated ER stress in the diabetic kidney. These ER stress markers were significantly decreased in KF treated mice. Conclusion Altogether, Src kinases through activation of ER stress aggravates kidney injury in STZ-induced diabetic rats.

Mangiferin mitigates diabetic cardiomyopathy in streptozotocin-diabetic rats

2013 ◽  
Vol 91 (9) ◽  
pp. 759-763 ◽  
Author(s):  
Jun Hou ◽  
Dezhi Zheng ◽  
Guocheng Zhong ◽  
Yonghe Hu
Keyword(s):  
Cardiac Function ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Fibrosis ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Matrix Metalloproteinase 2 ◽  
Severe Left Ventricular Dysfunction ◽  
Streptozotocin Diabetic Rats ◽  
Histopathologic Analysis ◽  
Myocardial Collagen

The purpose of this study was to investigate the cardioprotective effect of mangiferin on diabetic cardiomyopathy (DCM). The DCM model was induced by a high-fat diet and a low dose of streptozotocin. We evaluated the characteristics of DCM by serial echocardiography, electron microscopy, histopathologic analysis of cardiomyocyte fibrosis area, and Western blot analysis of matrix metalloproteinase-2 (MMP-2) and MMP-9 expression. Rats with DCM showed severe left ventricular dysfunction and cardiac fibrosis. Mangiferin mitigated DCM and prevented the accumulation of myocardial collagen. These anatomic findings were accompanied by significant improvements in cardiac function. Based on these results, we conclude that mangiferin has a therapeutic effect on DCM and improves cardiac function.

scholarly journals Exogenous Hydrogen Sulfide Alleviated Left Ventricular Fibrosis Via Enhancing Cardiac Autophagy and Decreasing Cardiomyocyte Apoptosis in StreptozotocinInduced Diabetic Rats: From Network Pharmacology to Experimental Pharmacology

2020 ◽  
pp. 1-8
Author(s):  
Shumin Liu ◽  
Cheng Fang ◽  
Feixue Dong ◽  
Liangyou Zhao ◽  
Yongwu Liu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Fibrosis ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Expression Level ◽  
Network Pharmacology ◽  
Control Group ◽  
Associated Proteins

Streptozotocin (STZ)-induced diabetes mellitus (DM) model shows the signal of cardiac dysfunction, which is manifested as myocardial fibrosis and hypertrophy. This study was designed to predict targets of sodium hydrosulfide (NaHS) for diabetic cardiomyopathy and its corresponding triggered pathways by network pharmacology analysis and test the effects of NaHS as well as its mechanism as possible modulators of left ventricular remodeling in diabetic rats. The drug-target networks were constructed via approaches of network pharmacology, and the predicted targets and pathways were validated by in vivo experiments. Rats were randomly divided into 3 groups (n=6/group): STZ-induced DM group (STZDM); STZ-induced DM treated with H2S group (STZ-NaHS); control group. The control group was treated with daily saline (i.p.); the diabetic model was induced by intraperitoneal (i.p.) injections of 40 mg/kg/day STZ. After 12 weeks, the rat cardiac function was determined, and the pathological morphology of the heart was analysed by Masson trichrome staining in each group. The expression level of matrix metalloproteinase 9 (AGEs), CSE, CBS and several autophagy associated proteins were detected by the ELISA analysis. Results from the PPI network implied that 27 targets were key regulators. The AGE-RAGE signaling pathway in diabetic complications and the apoptotic signaling pathway was discovered to be the key to anti-diabetic cardiomyopathy of NaHS upon the GO enrichment analyses and KEGG pathway. In the in vivo experiment, compared with the control group, cardiac fibrosis and attenuated left ventricular function were observed. Furthermore, compared with the control group, the expression level of CSE, CBS and autophagy associated proteins Atg5 was significantly decreased, while that of AGEs, autophagy associated proteins p62 and p-ERK1/2 was significantly increased in the STZDM group (P<0.05). In the STZ-NaHS group, cardiac fibrosis and ventricular dysfunction were ameliorated, the expression level of CSE, CBS and autophagy associated proteins Atg5 was increased, and the expression level of AGEs, autophagy associated proteins p62 and p-ERK1/2 was significantly decreased (P<0.05). In conclusion, H2S may alleviate cardiac fibrosis of the STZ-induced DM rat model by enhancing cardiac autophagy, inhibiting cardiomyocyte apoptosis and downregulating p-ERK1/2.

scholarly journals Electrocardiographic and Histopathological Characterizations of Diabetic Cardiomyopathy in Rats

2021 ◽  
Author(s):  
Mahmoud E. Youssef ◽  
Mona F. El-Azab ◽  
Marwa A. Abdel-Dayem ◽  
Galal Yahya Metwally ◽  
Ibtesam S. Alanazi ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Plasma Levels ◽  
Cardiac Fibrosis ◽  
Troponin T ◽  
Diabetic Rats ◽  
P Wave ◽  
Ventricular Rate ◽  
Clinical Disorder ◽  
Collagen Formation ◽  
St Segment

Abstract Diabetes is a clinical condition that is associated with insulin deficiency and hyperglycemia. Cardiomyopathy, retinopathy, neuropathy, and nephropathy are well known complications of the elevated blood glucose. Diabetic cardiomyopathy is a clinical disorder that is associated with systolic and diastolic dysfunction along with cardiac fibrosis, inflammation, and elevated oxidative stress. In this study, diabetes was induced by intraperitoneal injection of streptozotocin (STZ) 50 mg/kg. We determined the plasma levels of cardiac troponin-T (cTnT), and creatinine kinase MB (CK-MB) by ELISA. Diabetic rats showed abnormal cardiac architecture and increased collagen production. significant elevation in ST-segment, prolonged QRS and QT-intervals, and increased ventricular rate were detected. Additionally, diabetic rats showed a prolongation in P wave duration and atrial tachyarrhythmia was observed. Plasma levels of cTnT and CK-MB were elevated. In conclusion, these electrocardiographic changes (elevated ST-segment, prolonged QT interval, and QRS complex, and increased heart rate) along with histopathological changes and increased collagen formation could be markers for the development of diabetic cardiomyopathy in rats.

scholarly journals SERCA2a stimulation by istaroxime improves intracellular Ca2+ handling and diastolic dysfunction in a model of diabetic cardiomyopathy

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
E Torre ◽  
M Arici ◽  
AM Lodrini ◽  
M Ferrandi ◽  
P Barassi ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Therapeutic Approach ◽  
Cardiac Fibrosis ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Intact Cells ◽  
Funding Sources ◽  
Promising Therapeutic Approach

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by CVie Therapeutics Limited (Taipei, Taiwan) and Windtree Therapeutics (Warrington, USA) Diabetic cardiomyopathy is a multifactorial disease characterized by an early onset of diastolic dysfunction (DD) that precedes the development of systolic impairment. Mechanisms that can restore cardiac relaxation improving intracellular Ca2+ dynamics represent a promising therapeutic approach for cardiovascular diseases associated to DD. Istaroxime has the double property to accelerate Ca2+ uptake into sarcoplasmic reticulum (SR) through the SR Ca2+ pump (SERCA2a) stimulation and to inhibit Na+/K+ ATPase (NKA). The project aims to characterize istaroxime effects at a concentration (100 nM) marginally affecting NKA, in order to highlight its effects dependent on the stimulation of SERCA2a in a model of mild diabetes. Streptozotocin (STZ) treated diabetic rats were studied at 9 weeks after STZ injection in comparison to controls (CTR). Istaroxime effects were evaluated in vivo and in left ventricular (LV) preparations. STZ animals showed 1) marked DD not associated to cardiac fibrosis, 2) LV mass reduction associated to reduced LV cell dimension and T-tubules loss, 3) reduced LV SERCA2 protein level and activity and 4) slower SR Ca2+ uptake rate, 5) LV action potential (AP) prolongation and increased short-term variability (STV) of AP duration, 6) increased diastolic Ca2+, 7) unaltered SR Ca2+ content and stability in intact cells. Acute istaroxime infusion (0.11 mg/kg/min for 15 min) reduced DD in STZ rats. Accordingly, in STZ myocytes istaroxime (100 nM) stimulated SERCA2a activity and blunted STZ-induced abnormalities in LV Ca2+ dynamics. In CTR myocytes, istaroxime increased diastolic Ca2+ level due to NKA blockade albeit minimal, while its effects on SERCA2a were almost absent. SERCA2a stimulation by istaroxime improved STZ-induced DD and intracellular Ca2+ handling anomalies. Thus, SERCA2a stimulation can be considered a promising therapeutic approach for DD treatment. Abstract Figure.

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