Myocardial Dysfunction In Rats Research Articles

Mechanistic Role of Methanolic Extract of Taraxacum officinale Roots as Cardioprotective Against Ischemia-Reperfusion Injury-Induced Myocardial Infarction in Rats.

Taraxacum officinale play an important role in the prophylaxis and treatment of cardiovascular disease (CVD). Taraxacum officinale is proven as promising antioxidant in earlier studies and one of its constituent "cichoric acid" is shown to have vasorelaxant property. Therefore, present study mainly designed to investigate the cardioprotective effects of Taraxacum officinale against ischemia-reperfusion injury (I/R injury)-induced myocardial dysfunction in rats. This study not only explored the overall cardioprotective potential but also tried to explore its molecular mechanism using pharmacological inhibition via L-NAME and glibenclamide. Pretreatment of methanolic extract of Taraxacum officinale significantly attenuated (p < 0.001) increased levels of lactate dehydrogenase (LDH), creatine kinase (CK), infarct size, and thiobarbituric acid reactive substance (TBARS), while it increased the reduced levels of protein content, glutathione (GSH), and catalase (CAT) activity. Results showed that pretreatment with methanolic extract of Taraxacum officinale provides cardioprotection against I/R induced myocardial dysfunction, at least, may be mediated through the endogenous release of nitric oxide.

Abstract 9706: A Novel High Energy Phosphate Source Resuscitates Poorly Functioning Donor Hearts

Introduction: Over 60% of the time donor hearts cannot be utilized for transplant, mostly because of poor left ventricular ejection fraction (EF) of ≤40% due to stress cardiomyopathy (i.e., demand ischemia) with depletion of myocardial adenosine triphosphate (ATP). The bioenergetic cyclocreatine phosphate (CCrP) is an FDA Orphan Designated Drug for heart transplantation . When CCrP is given prophylactically in an isoprenaline (ISO) rat model of demand ischemia, it restored ATP and maintained contractility. Hypothesis: We hypothesized that administering CCrP therapeutically after ISO-induced myocardial dysfunction in rats (simulating rejected donor hearts), will prevent ischemic injury and sustain long-term restoration of EF. Methods: Wistar male rats (180-220 g) were injected SC with ISO (85 and 170 mg/kg/day) for two consecutive days. CCrP (n=6, 0.8 gm/kg/day ip) and saline control (n=4) were administered 1 hour after completing the course of ISO injections and then daily for 2 weeks. A negative control group was injected with saline (n=4). Serum CK-MB and ECG/ST were measured 24 hours after last ISO injection. Evidence of stress cardiomyopathy was assessed after 14 days by ECHO analysis for EF and levels of hs-Troponin I (TnI) and BNP. One-way ANOVA analysis was used. Results: Table I shows two main benefits of therapeutically administered CCrP in this stress cardiomyopathy model: 1) poor heart function was quickly restored in the acute phase (24 hours), as indicated by normal ECG/ST and CK-MB levels; and 2) the restoration of function was sustained over the long term (14 days), as indicated by normal EF% and levels of hs-TnI and BNP. Conclusions: The bioenergetic CCrP is a novel cardioprotective drug that appears to salvage cardiac dysfunction and restore normal EF% in a rat model of stress cardiomyopathy. If this benefit translates into clinical organ donors with poor heart function, CCrP could be used to increase heart utilization for transplantation.

Isosteviol sodium attenuates high fat/high cholesterol-induced myocardial dysfunction by regulating the Sirt1/AMPK pathway

A fat-rich diet triggers obesity, and promotes cardiomyocyte injury. Till now, no prior investigations suggested a beneficial role of Isosteviol Sodium (STVNa) in cardiac activity in high fat diet (HFD)-exposed obese rats. However, there is evidence that STVNa accelerates healing of multiple tissue injuries. Herein, we explored the underlying mechanism behind the STVNa-based protection against HFD-induced myocardial dysfunction (MCD) in a rat model of myocardial injury. We employed dosages of 1, 10, and 20 mg/kg STVNa to treat MCD in rats fed with a HFD. Based on our results, STVNa repressed MCD (as indicated by ecocardiographic analysis), myocardium function, pathological structure, and myocardial enzymes. Mechanistically, the STVNa-mediated protection against HFD-induced MCD involved inhibition of inflammation and oxidative stress. Furthermore, using Western blot analysis, we revealed that the critical members of the Sirt1/AMPK network were markedly activated in the STVNa-treated group, relative to HFD-fed controls. Collectively, these evidences suggested that the STVNa offered strong protection against HFD-induced MCD. Moreover, this effect was mediated by the activation of the Sirt1/AMPK network, which, in turn, promoted lipid metabolism.

The Emerging Roles of Chromogranins and Derived Polypeptides in Atherosclerosis, Diabetes, and Coronary Heart Disease.

Chromogranin A (CgA), B (CgB), and C (CgC), the family members of the granin glycoproteins, are associated with diabetes. These proteins are abundantly expressed in neurons, endocrine, and neuroendocrine cells. They are also present in other areas of the body. Patients with diabetic retinopathy have higher levels of CgA, CgB, and CgC in the vitreous humor. In addition, type 1 diabetic patients have high CgA and low CgB levels in the circulating blood. Plasma CgA levels are increased in patients with hypertension, coronary heart disease, and heart failure. CgA is the precursor to several functional peptides, including catestatin, vasostatin-1, vasostatin-2, pancreastatin, chromofungin, and many others. Catestatin, vasostain-1, and vasostatin-2 suppress the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human vascular endothelial cells. Catestatin and vasostatin-1 suppress oxidized low-density lipoprotein-induced foam cell formation in human macrophages. Catestatin and vasostatin-2, but not vasostatin-1, suppress the proliferation and these three peptides suppress the migration in human vascular smooth muscles. Chronic infusion of catestatin, vasostatin-1, or vasostatin-2 suppresses the development of atherosclerosis of the aorta in apolipoprotein E-deficient mice. Catestatin, vasostatin-1, vasostatin-2, and chromofungin protect ischemia/reperfusion-induced myocardial dysfunction in rats. Since pancreastatin inhibits insulin secretion from pancreatic β-cells, and regulates glucose metabolism in liver and adipose tissues, pancreastatin inhibitor peptide-8 (PSTi8) improves insulin resistance and glucose homeostasis. Catestatin stimulates therapeutic angiogenesis in the mouse hind limb ischemia model. Gene therapy with secretoneurin, a CgC-derived peptide, stimulates postischemic neovascularization in apolipoprotein E-deficient mice and streptozotocin-induced diabetic mice, and improves diabetic neuropathy in db/db mice. Therefore, CgA is a biomarker for atherosclerosis, diabetes, hypertension, and coronary heart disease. CgA- and CgC--derived polypeptides provide the therapeutic target for atherosclerosis and ischemia-induced tissue damages. PSTi8 is useful in the treatment of diabetes.

Gαi-biased apelin analog protects against isoproterenol-induced myocardial dysfunction in rats.

Apelin receptor (APJ) activation by apelin-13 (APLN-13) engages both Gαi proteins and β-arrestins, stimulating distinct intracellular pathways and triggering physiological responses like enhanced cardiac contractility. Substituting the C-terminal phenylalanine of APLN-13 with α-methyl-l-phenylalanine [(l-α-Me)Phe] or p-benzoyl-l-phenylalanine (Bpa) generates biased analogs inducing APJ functional selectivity toward Gαi proteins. Using these original analogs, we proposed to investigate how the canonical Gαi signaling of APJ regulates the cardiac function and to assess their therapeutic impact in a rat model of isoproterenol-induced myocardial dysfunction. In vivo and ex vivo infusions of either Bpa or (l-α-Me)Phe analogs failed to enhance rats' left ventricular (LV) contractility compared with APLN-13. Inhibition of Gαi with pertussis toxin injection optimized the cardiotropic effect of APLN-13 and revealed the inotropic impact of Bpa. Moreover, both APLN-13 and Bpa efficiently limited the forskolin-induced and PKA-dependent phosphorylation of phospholamban at the Ser16 in neonatal rat ventricular myocytes. However, only Bpa significantly reduced the inotropic effect of forskolin infusion in isolated-perfused heart, highlighting its efficient bias toward Gαi. Compared with APLN-13, Bpa also markedly improved isoproterenol-induced myocardial systolic and diastolic dysfunctions. Bpa prevented cardiac weight increase, normalized both ANP and BNP mRNA expressions, and decreased LV fibrosis in isoproterenol-treated rats. Our results show that APJ-driven Gαi/adenylyl cyclase signaling is functional in cardiomyocytes and acts as negative feedback of the APLN-APJ-dependent inotropic response. Biased APJ signaling toward Gαi over the β-arrestin pathway offers a promising strategy in the treatment of cardiovascular diseases related to myocardial hypertrophy and high catecholamine levels.NEW & NOTEWORTHY By using more potent Gαi-biased APJ agonists that strongly inhibit cAMP production, these data point to the negative inotropic effect of APJ-mediated Gαi signaling in the heart and highlight the potential protective impact of APJ-dependent Gαi signaling in cardiovascular diseases associated with left ventricular hypertrophy.

Protective effect of glycyrrhizin on coronary microembolization-induced myocardial dysfunction in rats.

Coronary microembolization (CME)‐induced inflammation and cardiomyocyte apoptosis are two key factors contributing to CME‐induced myocardial dysfunction. High‐mobility group box‐1 (HMGB1) plays essential role in progression of CME‐induced injury and inhibition of HMGB1 has been shown to be protective. In present study, the potential effects of glycyrrhizin, a HMGB1 inhibitor, on CME‐induced myocardial dysfunction are evaluated. Using a rat model of CME, we administrated glycyrrhizin in rats prior to CME induction. The level of HMGB1, TNF‐α, iNOS, IL‐6, IL‐1β, cleaved caspase‐3, Bax, and Bcl‐2 were measured. The serum level of cardiac troponin I, creatine kinase, was detected. The cardiac function and cardiomyocyte apoptosis were evaluated. The activation of TLR4/NF‐κB signaling pathway was analyzed. Glycyrrhizin prevented CME‐induced production of HMGB1, TNF‐α, iNOS, IL‐6, and IL‐1β. Glycyrrhizin inhibited CME‐induced cardiomyocyte apoptosis and the expression of cleaved caspase‐3 and Bax, while enhanced the expression of Bcl‐2. Glycyrrhizin decreased cardiac troponin I and creatine kinase levels and improved cardiac function. Glycyrrhizin prevented the activation of HMGB1/TLR4/NF‐κB signaling pathway. Glycyrrhizin ameliorated myocardial dysfunction in CME rats by preventing inflammation and apoptosis of cardiomyocytes.

Carbon monoxide attenuates LPS-induced myocardial dysfunction in rats by regulating the mitochondrial dynamic equilibrium

Lipopolysaccharide (LPS) induces myocardial dysfunction by damaging the mitochondrial structure in cardiomyocytes. Since low levels of carbon monoxide can confer cytoprotective effects against end-organ damage from endotoxic shock, we tested whether treatment with carbon monoxide-releasing molecule-2 (CORM-2) could ameliorate LPS-induced myocardial dysfunction in rats by maintaining the dynamic equilibrium between the mitochondrial fusion and fission processes. Cardiac function, myocardial histopathology, myocardial enzymes, and changes in myocardial mitochondrial function and mitochondrial fusion-fission protein expression were assessed in rats. The mitochondrial structure and morphology were studied by electron microscopy, and the expression levels of key proteins involved in the mitochondrial dynamics were assessed by Western blot assay. Cardiac dysfunction and increased myocardial enzyme activity together with myocardial pathological damage, mitochondrial dysfunction, and impaired mitochondrial dynamics homeostasis were observed in the LPS-challenged septic rats. However, these observations were reversed by CORM-2, which effectively inhibited cardiac and mitochondrial damage in the LPS-challenged rats and improved the survival rate of the animals. In conclusion, CORM-2 regulates the LPS-induced imbalance of the dynamic mitochondrial fusion and fission processes, thereby effectively ameliorating the LPS-induced myocardial dysfunction and improving the survival of the rats.

Repression of autophagy in diabetic cardiomyopathy via RhoA/ROCK2 signaling pathways

Activated RhoA and ROCK is associated with many cardiovascular diseases (CVD) such as congestive heart failure (CHF), atherosclerosis and hypertension. However, the role of RhoA/ROCK2 signaling pathway in initiating diabetic cardiomyopathy (DCM) has not been fully elucidated. Here, we studied the role of RhoA/ROCK2 signaling pathway in induction of DCM through autophagy suppression in diabetic rat animal models. Broadly, we investigated the potential role and mechanism of diabetes induced myocardial dysfunction in rats. DCM was induced by injections of streptozocin (STZ) in experimental Wistar rats. The experimental rats were randomized to be treated with fasudil and lentivirus carrying the RhoA cDNA. Haemodynamic changes, assessment of cardiac weight index, histopathological examinations, cardiomyocyte autophagy and expression of RhoA and ROCK2 mRNAs were compared between groups. The expression of RhoA and ROCK mRNAs was found significantly increased in cardiac tissues compared with control group. The RhoA overexpression significantly decreased the values of left ventricular ejection fraction (LVEF), ±dp/dt max and repressed autophagy. RhoA/ROCK2 signaling pathway repressed autophagy in diabetic cardiomyopathy indicating that it may serve as a potential therapeutic target for DCM treatment

Effects of carbon monoxide release molecule-2 on sepsis-induced myocardial dysfunction in rats

To investigate the protective effect of carbon monoxide release molecule-2 (CORM-2) on sepsis-induced myocardial dysfunction in rats. 140 healthy male Sprague-Dawley (SD) rats were divided into sham operation (Sham) group, model group, CORM-2 pretreatment group, inactivated carbon monoxide release molecule-2 (iCORM) pretreatment group, and dimethyl sulfoxide (DMSO) control group by random number table, with 28 rats in each group. The rat sepsis model was reproduced by intraperitoneal injection of 10 mg/kg lipopolysaccharide (LPS). The rats in the Sham group were injected intraperitoneally with the same dose of normal saline (NS). The rats in the CORM-2 and iCORM-2 pretreatment groups were injected intraperitoneally with 8 mg/kg CORM-2 or iCORM-2 at 1 hour before LPS injection, respectively, and those in the DMSO group were injected intraperitoneally with the same dose of DMSO, but the rats in the Sham group and the model group were not treated after injection of NS or LPS. Twenty rats were randomly selected from each group to observe 10-day survival rate. Transthoracic echocardiography was performed on the remaining 8 rats at 12 hours after modeling, and the left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS) were calculated to evaluate heart function. The blood of the inferior vena cava was harvested, then serum myocardial troponin I (cTnI) and brain natriuretic peptide (BNP) levels were measured by enzyme-linked immunosorbent assay (ELISA). Then the rats were sacrificed, and the myocardial tissues were harvested, the pathological morphology and ultrastructure of myocardium were observed. (1) Survival rates: all rats in the Sham group survived; compared with the Sham group, the survival rates of the model group, CORM-2 pretreatment group, iCORM-2 pretreatment group and DMSO control group were significantly decreased at 10 days [10% (2/20), 70% (14/20), 25% (5/20), 15% (3/20) vs. 100% (20/20), all P < 0.01]. However, the 10-day survival rate in the CORM-2 pretreatment group was significantly higher than those in the model group, iCORM-2 pretreatment group and DMSO control group (all P < 0.01). (2) Cardiac function: compared with the Sham group, LVEF and LVFS in the model group, CORM-2 pretreatment group, iCORM-2 pretreatment group and DMSO control group were significantly decreased, and left ventricular dilatation was obvious, indicating myocardial dysfunction in rats. However, LVEF and LVFS in the CORM-2 pretreatment group were significantly higher than those in the model group, iCORM-2 pretreatment group, and DMSO control group [LVEF: 0.760±0.029 vs. 0.634±0.021, 0.629±0.066, 0.673±0.023; LVFS: (39.32±2.38)% vs. (29.75±1.52)%, (29.61±4.15)%, (32.43±1.66)%, all P < 0.05], and the left ventricular dilatation in the septic rats was attenuated. (3) Myocardial injury markers: compared with the Sham group, serum cTnI and BNP levels were significantly higher in the model group, CORM-2 pretreatment group, iCORM-2 pretreatment group and DMSO control group. However, the levels of cTnI and BNP in the CORM-2 pretreatment group were significantly lower than those in the model group, iCORM-2 pretreatment group and DMSO control group [cTnI (ng/L): 3 283.54±803.50 vs. 6 449.18±1 105.10, 5 919.21±1 068.27, 6 349.80±1 153.08; BNP (ng/L): 3 456.62±905.85 vs. 6 070.18±1 287.62, 5 581.13±1 161.17, 5 974.89±988.89, all P < 0.05]. (4) Myocardial histopathological observation: optical microscope showed that the pathological changes in myocardial tissue of the model group, iCORM-2 pretreatment group and DMSO control group were severe. Transmission electron microscopy showed mitochondrial swelling, and some vacuoles changed. But the myocardial pathological morphology and mitochondrial ultrastructural integrity of the CORM-2 pretreatment group were significantly better than other groups of sepsis. CORM-2 can attenuate myocardial dysfunction and improve survival rate of septic rats, especially to protect myocardial mitochondrial integrity in sepsis.

Valproic acid attenuates sepsis-induced myocardial dysfunction in rats by accelerating autophagy through the PTEN/AKT/mTOR pathway

AimsSepsis is a leading cause of death and disability worldwide. Autophagy may play a protective role in sepsis-induced myocardial dysfunction (SIMD). The present study investigated whether valproic acid (VPA), a class I histone deacetylase (HDAC) inhibitor, can attenuate SIMD by accelerating autophagy. Main methodsA sepsis model was established via the cecum ligation and puncture of male Sprague–Dawley rats. Cardiac injuries were measured using serum markers, echocardiographic cardiac parameters, and hematoxylin and eosin staining. Cardiac mitochondria injuries were detected with transmission electron microscopy, adenosine triphosphate (ATP) and cardiac mitochondrial DNA (mtDNA) contents. Cardiac oxidative levels were measured using redox markers in the cardiac homogenate. Real-time polymerase chain reaction (RT-PCR) and Western blot were performed to detect the expression levels of relative genes and proteins. HDAC binding to the phosphatase and tensin homolog deleted on chromosome ten (PTEN) promoters and histone acetylation levels of the PTEN promoters were analyzed via chromatin immunoprecipitation and quantitative RT-PCR. Key findingsVPA can ameliorate SIMD by enhancing the autophagy level of the myocardium to reduce mitochondrial damage, oxidative stress, and myocardial inflammation in septic rats. Moreover, this study demonstrated that VPA induces autophagy by inhibiting HDAC1- and HDAC3-mediated PTEN expression in the myocardial tissues of septic rats. SignificanceThis study found that VPA attenuates SIMD through myocardial autophagy acceleration by increasing PTEN expression and inhibiting the AKT/mTOR pathway. These findings preliminarily suggest that VPA may be a potential approach for the intervention and treatment of SIMD.

Protective effect of carbon monoxide releasing molecules 2 on post-resuscitation myocardial dysfunction in rats

Objective: To investigate the protective effect of carbon monoxide releasing molecule 2 (CORM-2) on post-resuscitation myocardial dysfunction in rats. Methods: Forty male SD rats which were healthy were randomly divided into 5 groups: sham operated group(sham group), cardiopulmonary resuscitation(PCR) group, DMSO group, inactivated CORM-2(iCORM-2) group and CORM-2 group (n=8 each). Established the model of post-cardiac arrest myocardial dysfunction by intravenous potassium chloride (4 ℃) injection combined with asphyxiation for 4 minutes and then followed by artificial chest compression for 3 minutes. Sham group: rats were instrumented with catheter without inducing cardiac arrest and resuscitation, and intraperitoneal injection of 0.9% normal saline (4 ml/kg) was performed 12 hours before catheterization. CPR group: rats were instrumented with catheters and underwent CPR, and intraperitoneal injection of 0.9% normal saline (4 ml/kg) was performed 12 hours before surgery.CORM-2 group: rats were instrumented with catheters and underwent CPR, intraperitoneally injected the prepared CORM-2 solution (4 mg/kg) at 12 hours before surgery. DMSO group: rats were instrumented with catheters and underwent CPR, intraperitoneally injected the prepared DMSO solution (4 ml/kg) at 12 hours before surgery. iCORM-2 group: rats were instrumented with catheters and underwent CPR, iCORM-2 solution (4 mg/kg) was intraperitoneally injected at 12 hours before surgery. Hemodynamic data (MAP, +dp/dtmax, -dp/dt) were continuously monitored and recorded for 4 hours after resuscitation (or catheterization) in each group. Myocardial tissue specimen and blood samples were taken after resuscitation (or catheterization). The myocardial ultrastructure was observed by transmission electron microscope. Lactate dehydrogenase (LDH) activity was measured by lactate-pyruvate method. Serum creatine kinase isoenzyme (CK-MB) concentration was measured by ELISA. Western blot was used to detect the levels of Caspase-3, Caspase-9 and Cyt-C protein in myocardial tissue. Results: MAP, +dp/dtmax and -dp/dt at 0.5, 1, 2, 3 and 4 hours post resuscitation were significantly lower than those immediately after catheterization in CRP, DMSO, iCORM-2 groups (all P<0.05). MAP at 0.5, 1, 2, 3, and 4 hours post resuscitation were significantly lower in CRP, DMSO and iCORM-2 groups than those at respective time points in sham group (all P<0.05), while MAP was similar between CORM-2 group and Sham group at these time points (all P>0.05). +dp/dtmax and -dp/dt values at 0.5, 1, 2, 3, and 4 hours post resuscitation were lower than those at respective time points in sham group and significance was found at 0.5, 1 and 2 hours post resuscitation (both P<0.05), while +dp/dtmax and -dp/dt values were similar between CORM-2 group and sham group at various time points (all P>0.05). Myocardial ultrastructure, especially mitochondrial structural integrity was better preserved in the CORM-2 group than those in the other resuscitation groups at 4 hours after resuscitation. Serum LDH activity and CK-MB concentration were significantly elevated at 4 hours after resuscitation in the CPR group, DMSO group and iCORM-2 group than those in sham group (all P<0.01); CK-MB concentration was also higher in CORM-2 group than that in sham group,and LDH level was similar between CORM-2 group and sham group (P>0.05). Serum LDH activity and CK-MB concentrations were significantly lower in the CORM-2 group than those in the other resuscitation groups (all P<0.01). The myocardial expressions of Caspase-3, Caspase-9 and Cyt-C at 4 hours after resuscitation were significantly higher in the CPR group, DMSO group and iCORM-2 group than those in sham group; the myocardial expressions of Caspase-3 and Caspase-9 were significantly higher in CORM-2 group than those in sham group (both P<0.05), while Cyt-C expression was similar between CORM-2 group and sham group. The expressions of the above 3 proteins were significantly lower in the CORM-2 group than those in the other resuscitation groups (all P<0.05). Conclusions: CORM-2 can effectively alleviate post-resuscitation myocardial injury in rats with cardiopulmonary resuscitation and improve cardiac function. Protecting myocardial mitochondria and inhibiting mitochondrial apoptosis pathway may serve as the protective mechanisms in this model.

Erythropoietin alleviates post-resuscitation myocardial dysfunction in rats potentially through increasing the expression of angiotensin II receptor type 2 in myocardial tissues.

Activation of renin-angiotensin system (RAS) is one of the pathological mechanisms associated with myocardial ischemia-reperfusion injury following resuscitation. The present study aimed to determine whether erythropoietin (EPO) improves post-resuscitation myocardial dysfunction and how it affects the renin-angiotensin system. Sprague-Dawley rats were randomly divided into sham, vehicle, epinephrine (EP), EPO and EP + EPO groups. Excluding the sham group, all groups underwent cardiopulmonary resuscitation (CPR) 4 min after asphyxia-induced cardiac arrest (CA). EP and/or EPO was administrated by intravenous injection when CPR began. The results demonstrated that the vehicle group exhibited lower mean arterial pressure, left ventricular systolic pressure, maximal ascending rate of left ventricular pressure during left ventricular isovolumic contraction and maximal descending rate of left ventricular pressure during left ventricular isovolumic relaxation (+LVdP/dt max and -LVdP/dt max, respectively), and higher left ventricular end-diastolic pressure, compared with the sham group following return of spontaneous circulation (ROSC). Few significant differences were observed concerning the myocardial function between the vehicle and EP groups; however, compared with the vehicle group, EPO reversed myocardial function indices following ROSC, excluding-LVdP/dt max. Serum renin and angiotensin (Ang) II levels were measured by ELISA. The serum levels of renin and Ang II were significantly increased in the vehicle group compared with the sham group, which was also observed for the myocardial expression of renin and Ang II receptor type 1 (AT1R), as determined by reverse transcription-quantitative polymerase chain reaction and western blotting. EPO alone did not significantly reduce the high serum levels of renin and Ang II post-resuscitation, but changed the protein levels of renin and AT1R expression in myocardial tissues. However, EPO enhanced the myocardial expression of Ang II receptor type 2 (AT2R) following ROSC. In conclusion, the present study confirmed that CA resuscitation activated the renin-Ang II-AT1R signaling pathway, which may contribute to myocardial dysfunction in rats. The present study confirmed that EPO treatment is beneficial for protecting cardiac function post-resuscitation, and the roles of EPO in alleviating post-resuscitation myocardial dysfunction may potentially be associated with enhanced myocardial expression of AT2R.

Impact of Garlic on Cardioprotective Potential of Ramipril on Ischemia-Reperfusion Induced Myocardial Dysfunction in Rats

Garlic Allium sativum is one of the most popular herbs used worldwide to reduce various risk factors associated with cardiovascular diseases Angiotensin converting enzyme inhibitor ACE such as Ramipril RAM has been proved to work under conditions of myocardial damage however there is no report on elucidating the impact of garlic on its cardioprotective potential In the current study role of garlic homogenate GH mg kg along with RAM mg kg was investigated in ischemia reperfusion induced myocardial damage in rats Sprague dawley rats g were divided into group n Rats were given treatment for days with ramipril and days with Garlic in their respective groups At the end of treatment heart was isolated under anesthesia and mounted at modified Langendorff rsquo s apparatus and myocardial damage was induced by no flow global ischemia and reperfusion Percentage recovery in terms of developed tension and heart rate during post ischemia LDH and CK MB activities in perfusate and heart tissue homogenate HTH superoxide dismutase SOD and Catalase HTH and histopathological scores were evaluated Administration of GH and RAM resulted in elevation of LDH and CK MB activities in HTH with a simultaneous fall in perfusate Prophylactic administration of RAM and GH demonstrated good recovery in developed tension and heart rate compared to ischemic control Moreover SOD and Catalase activities were also increased in treated groups Corroborating with the biochemical results histological scores were diminished in all treated groups To conclude concurrent administration of RAM with GH showed better cardioprotective potential than their individual treatment

Dynamic evaluation of myocardial dysfunction in rats after cardiopulmonary resuscitation

Objective To observe the dynamic changes of myocardial structure and dysfunction during post-resuscitation period in order to establish a rat mode of post-resuscitation myocardial dysfunction after cardiac arrest resulted from electric stimulation-induced ventricular fibrillation (VF) and cardiopulmonary resuscitation (CPR). Methods A total of 40 male Sprague-Dawley (SD) rats were randomly(random number) assigned into post-resuscitation (PR) 4 h, PR 12 h, PR 24 h, PR 72 h and sham groups. VF was induced by an alternating electric current delivered to the right ventricular endocardium and untreated for 8 min. Biphasic waveform defibrillation was attempted and mechanical ventilation was synchronized after 6 min of CPR. Myocardial function was assessed with serum myocardial enzyme activity, echocardiography, mitochondrial respiratory function and histopathologic findings at different intervals. Results Thirty-two animals were successfully resuscitated with restoration of spontaneous circulation (ROSC) in 86% (32/37)rats. Compared with sham group, severe systolic and diastolic heart failure were found at 4 h after ROSC and then gradually improved without significant difference(P>0.05) in ejection fraction at PR 72 h after ROSC was found, whereas thickened ventricular wall and increased myocardial performance index as well as interstitial proliferation were observed at 72 h after ROSC. Conclusions A rat model of post-resuscitation myocardial dysfunction after cardiac arrest resulted from electric stimulation-induced VF and CPR was successfully established. Key words: Cardiac arrest; Cardiopulmonary resuscitation; Myocardial dysfunction; Mitochondrion; Animal model

Inhibition of prolyl hydroxylase 3 ameliorates cardiac dysfunction in diabetic cardiomyopathy

Prolyl hydroxylase 3 (PHD3) is a member of the prolyl hydroxylases (PHDs) family and is induced by hypoxia. It plays a critical role in regulating the abundance of hypoxia-inducible factor (HIF). Its expression is increased in diabetic rat hearts; however, its role remains unclear. We investigated the potential role and mechanism of action of PHD3 in the setting of diabetes-induced myocardial dysfunction in rats. In vivo, type 2 diabetic rat model was induced via a high-fat diet and intraperitoneal injection of streptozotocin. PHD3 expression was knocked down using lentivirus-mediated short-hairpin RNA (shRNA). In vitro, primary neonatal cardiomyocytes and H9c2 cardiomyoblasts were cultured in 33.3 mM glucose (high glucose, HG) and 5.5 mM glucose (normal glucose, NG), the latter of which was used as a control. PHD3-siRNA was used to inhibit the expression of PHD3 and to investigate the role of PHD3 in HG-induced apoptosis in H9c2 cardiomyoblasts. Rats with diabetic cardiomyopathy (DCM) exhibited severe left ventricular dysfunction as well as myocardial apoptosis and fibrosis. PHD3 expression was increased in the myocardial tissues of diabetic rats, and inhibition of PHD3 ameliorated the disease. Additionally, the inhibition of PHD3 significantly decreased HG-induced apoptosis and MAPK activation in H9c2 cardiomyoblasts. Our results suggest that PHD3 inhibition ameliorates myocardial dysfunction in the setting of diabetic cardiomyopathy.

(−)-Epigallocatechin-gallate (EGCG) stabilize the mitochondrial enzymes and inhibits the apoptosis in cigarette smoke-induced myocardial dysfunction in rats

The present study brings out the preventive role of (-)-epigallocatechin-gallate (EGCG) on cardiac mitochondrial metabolism and apoptosis in cigarette smoke (CS)-exposed rats. The CS-exposed rats showed significantly decreased activities of TCA cycle enzymes and mitochondrial enzymatic antioxidants, on the other hand, mitochondrial lipid peroxidation was increased and GSH level was decreased. Further, CS exposure was found to induce cardiac apoptosis through release of cytochrome c into the cytosol, cleavage of pro-caspase-3 to active caspase-3, up-regulation of pro-apoptotic (Bax) and down-regulation of antiapoptotic (Bcl-2) molecules. The CS-induced apoptosis was further confirmed by mitochondrial and nuclear ultra structural apoptotic features as evaluated by electron microscopic studies. EGCG supplementation shelters the activities of TCA cycle enzymes and antioxidant enzymes, with concomitant decrease in lipid peroxidation and increase in GSH level. EGCG administration inhibited apoptosis through the inhibition of cytochrome c release into cytosol, activation of pro-caspase-3, down regulation of Bax and significant up regulation of Bcl-2. EGCG reversed the ultra structural apoptotic alterations of mitochondria and nucleus. The present study has provided experimental evidences that the EGCG treatment enduring to cardio protection at mitochondrial level.

β-Adrenergic receptors desensitization is not involved in exercise-induced cardiac fatigue: NADPH oxidase-induced oxidative stress as a new trigger

Prolonged strenuous exercise (PSE) induces transient left ventricular (LV) dysfunction. Previous studies suggest that β-adrenergic pathway desensitization could be involved in this phenomenon, but it remains to be confirmed. Moreover, other underlying mechanisms involving oxidative stress have been recently proposed. The present study aimed to evaluate the involvement of both the β-adrenergic pathway and NADPH oxidase (Nox) enzyme-induced oxidative stress in myocardial dysfunction in rats following PSE. Rats were divided into 4 groups: controls (Ctrl), 4-h exercised on treadmill (PSE), and 2 groups in which Nox enzyme was inhibited with apocynin treatment (Ctrl APO and PSE APO, respectively). We evaluated cardiac function in vivo and ex vivo during basal conditions and isoproterenol stress. GSH/GSSG ratio, cardiac troponin I (cTnI) release, and lipid peroxidation (MDA) were evaluated. PSE induced a decrease in LV developed pressure, intrinsic myocardial contractility, and relaxation associated with an increase in plasma cTnI release. Our in vivo and ex vivo results demonstrated no differences in myocardial response to isoproterenol and of effective dose 50 between control and PSE rats. Interestingly, the LV dysfunction was reversed by apocynin treatment. Moreover, apocynin prevented cellular oxidation [GSH/GSSG ratio: PSE APO rats vs. PSE rats in arbitrary units (au): 1.98 ± 0.07 vs. 1.35 ± 0.10; P < 0.001]. However, no differences in MDA were observed between groups. These data suggest that myocardial dysfunction observed after PSE was not due to β-adrenergic receptor desensitization but could be due to a signaling oxidative stress from the Nox enzyme.

New lipoic acid derivative drug sodium zinc dihydrolipoylhistidinate prevents cardiac dysfunction in an isolated perfused rat heart model*

Myocardial ischemia/reperfusion injury is a life-limiting condition. Reactive oxygen species are released upon reperfusion, resulting in damage to myocardial cells. Accordingly, antioxidant drugs have been shown to protect the myocardium against ischemia/reperfusion injury. The purpose of the present study was to determine the cardioprotective effects of the new lipoic acid-derivative drug sodium zinc dihydrolipoylhistidinate in a global ischemia isolated perfused rat heart model. Animals were randomly divided into five groups: 1) normal group, 2) control ischemia/reperfusion group, 3) high-dose sodium zinc dihydrolipoylhistidinate (1 ng/mL) plus ischemia/reperfusion group, 4) medium-dose sodium zinc dihydrolipoylhistidinate (0.1 ng/mL) plus ischemia/reperfusion group, or 5) low-dose sodium zinc dihydrolipoylhistidinate (0.01 ng/mL) plus ischemia/reperfusion group. University medical center research laboratory. Male Sprague-Dawley rats weighing 250-300 g. Hearts underwent ischemia/reperfusion after isolation with or without sodium zinc dihydrolipoylhistidinate treatment. We then conducted cardiac histopathology and transmission electron microscopy analyses and assessed cardiac function. In addition, we examined the effects of sodium zinc dihydrolipoylhistidinate on ischemia/reperfusion-induced mitochondrial dysfunction. We found that cardiac dysfunction and mitochondrial damage were significantly reduced after reperfusion by sodium zinc dihydrolipoylhistidinate treatment. However, only rats treated with high-dose sodium zinc dihydrolipoylhistidinate showed improved cardiac function. Furthermore, treatment with sodium zinc dihydrolipoylhistidinate significantly improved mitochondrial function in vitro. These findings suggest that sodium zinc dihydrolipoylhistidinate attenuates ischemia/reperfusion-induced myocardial dysfunction in rats. Furthermore, sodium zinc dihydrolipoylhistidinate exerted cardioprotective effects via preservation of mitochondrial function. Taken together, our results strongly support the potential therapeutic role of sodium zinc dihydrolipoylhistidinate in the treatment of ischemia/reperfusion injury.

Cardioprotective effects of gallic acid in diabetes-induced myocardial dysfunction in rats

Background:Normalization of hyperglycemia, hyperlipidemia, and oxidative stress is an important objective in preventing diabetes-induced cardiac dysfunction.Objective:This study was undertaken to examine the effects of gallic acid in myocardial dysfunctions associated with type-1 diabetes.Materials and Methods:Diabetes was induced by single intravenous injection of streptozotocin (STZ, 50 mg/kg i.v.). Gallic acid was administered daily at three different doses (100, 50, and 25 mg/kg p.o.) for 8 weeks at the end of which blood samples were collected and analyzed for various biochemical parameters.Results:Injection of STZ produced significant loss of body weight (BW), polyphagia, polydypsia, hyperglycemia, hypoinsulinemia, hyperlipidemia, hypertension, bradycardia, and myocardial functional alterations. Treatment with gallic acid significantly lowered fasting glucose, the AUCglucose level in a dose-dependent manner; however, the insulin level was not increased significantly at same the dose and prevented loss of BW, polyphagia, and polydypsia in diabetic rats. It also prevented STZ-induced hyperlipidemia, hypertension, bradycardia, structural alterations in cardiac tissue such as increase in force of contraction, left ventricular weight to body weight ratio, collagen content, protein content, serum lactate dehydrogenase, and creatinine kinase levels in a dose-dependent manner. Further, treatment also produced reduction in lipid peroxidation and increase in antioxidant parameters in heart of diabetic rats.Conclusion:The results of this study suggest that gallic acid to be beneficial for the treatment of myocardial damage associated with type-1 diabetes.

Exercise training inhibits inflammatory cytokines and more than prevents myocardial dysfunction in rats with sustained β‐adrenergic hyperactivity

Myocardial hypertrophy and dysfunction occur in response to excessive catecholaminergic drive. Adverse cardiac remodelling is associated with activation of proinflammatory cytokines in the myocardium. To test the hypothesis that exercise training can prevent myocardial dysfunction and production of proinflammatory cytokines induced by beta-adrenergic hyperactivity, male Wistar rats were assigned to one of the following four groups: sedentary non-treated (Con); sedentary isoprenaline treated (Iso); exercised non-treated (Ex); and exercised plus isoprenaline (Iso+Ex). Echocardiography, haemodynamic measurements and isolated papillary muscle were used for functional evaluations. Real-time RT-PCR and Western blot were used to quantify tumour necrosis factor alpha, interleukin-6, interleukin-10 and transforming growth factor beta(1) (TGF-beta(1)) in the tissue. NF-B expression in the nucleus was evaluated by immunohistochemical staining. The Iso rats showed a concentric hypertrophy of the left ventricle (LV). These animals exhibited marked increases in LV end-diastolic pressure and impaired myocardial performance in vitro, with a reduction in the developed tension and maximal rate of tension increase and decrease, as well as worsened recruitment of the Frank-Starling mechanism. Both gene and protein levels of tumour necrosis factor alpha and interleukin-6, as well as TGF-beta(1) mRNA, were increased. In addition, the NF-B expression in the Iso group was significantly raised. In the Iso+Ex group, the exercise training had the following effects: (1) it prevented LV hypertrophy; (ii) it improved myocardial contractility; (3) it avoided the increase of proinflammatory cytokines and improved interleukin-10 levels; and (4) it attenuated the increase of TGF-beta(1) mRNA. Thus, exercise training in a model of beta-adrenergic hyperactivity can avoid the adverse remodelling of the LV and inhibit inflammatory cytokines. Moreover, the cardioprotection is related to beneficial effects on myocardial performance.