Cardiac Dysfunction In Rats Research Articles

Evaluation of Cardioprotective Effects of Genistein against Diabetes-induced Cardiac Dysfunction in Rats

Purpose: To investigate the possible cardioprotective effects and potential pharmacological mechanism of genistein.Methods: Six-week old ZDF and lean rats were randomized into 4 groups (8 rats/group), including group 1 (control lean rats); group 2 (lean rats treated with genistein, 2.5 mg/kg); group 3 (control ZDF rats); and group 4 (ZDF treated with genistein). Two groups (2 and 4) were treated with genistein for 12 weeks, and cardiac functions and metabolic alterations were determined. Macrophage/monocyte chemo-attractant protein-1 (MCP-1), vascular cellular adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) secretion and their messenger RNA transcription level also were observed.Results: Genistein attenuated diabetes-induced cardiac dysfunction and pathological alterations, by improving glucose tolerance and insulin resistance; facilitating Akt activation and glucose utilization, and attenuating oxidative stress and interrelated MAP kinase and NF-κB signalling pathways. In addition, genistein treatment markedly reduced diabetic-induced MCP-1 (83.33 %), VCAM-1 (74.66 %) and ICAM-1 (71.42 %) secretion and mRNA transcription in ZDF rats.Conclusion: The results demonstrate the putative effects of genistein against cardiovascular dysfunction by improving glucose homeostasis, attenuating oxidative stress and reduced diabeticinduced endothelial dysfunction in ZDF rats. Thus, genistein is a potential candidate for the prevention of cardiovascular diseases.Keywords: Cardiac dysfunction, Genistein, Oxidative stress, Inflammatory response, Insulin resistance, Glucose tolerance

Mitochondrial Ultrastructural Alterations and Declined M2 Receptor Density Were Involved in Cardiac Dysfunction in Rats after Long Term Treatment with Autoantibodies against M2 Muscarinic Receptor.

BackgroundPrevious studies showed that autoantibodies (M2-AA) against the second extracellular loop of M2 muscarinic receptor (M2AChR-el2) from dilated cardiomyopathy (DCM) serum could induce DCM-like morphological changes in mice hearts. However, the effects of M2-AA on the cardiac function during the process of DCM and the potential mechanisms are not fully known. The present study was designed to dynamically observe the cardiac function, mitochondrial changes, and M2 receptor binding characteristics in rats long-term stimulated with M2-AA in vivo.MethodsM2-AA-positive model was established by actively immunizing healthy male Wistar rats with synthetic M2AChR-el2 peptide for 18 months. Meanwhile, vehicle group rats were administrated with physiological saline. The change of mitochondrial membrane potential (ΔΨm) was detected by radionuclide imaging. The ultrastructure of mitochondria was observed under electron microscopy. The M2 receptor binding characteristics were determined by radioactive ligand binding assay.ResultsAfter immunization for 12 months, compared with vehicle group, M2AChR-el2-immunized rats showed decreased myocardial contractility and cardiac diastolic function evidenced by declined maximal rate of rise of ventricular pressure and increased left ventricular end-diastolic pressure, respectively. Additionally, mitochondrial swelling and vacuolation were observed. At 18 months, M2AChR-el2-immunized rats manifested significant decreased cardiac systolic and diastolic function and pathological changes such as enlargement of right ventricular cavity and wall thinning; and the mitochondrial damage was aggravated. Furthermore, the M2 receptor maximum binding capacity (Bmax) of the M2AChR-el2-immunized rats significantly decreased, while the M2 receptor dissociation constant (Kd) was increased.ConclusionsOur study suggested that long-term stimulation with M2-AA leaded to the ventricular dilatation and gradual deterioration of cardiac dysfunction. Mitochondrial damage and the down-regulation of M2 receptor density and affinity may be involved in the process.

Cardioprotection by curcumin post-treatment in rats with established chronic kidney disease.

The pathogenic mechanisms leading to cardiovascular disorders in patients with chronic kidney disease have not been clearly established, although increased oxidative stress has been pointed out as a potential cause. Therefore, as cardiovascular events are still the first cause of death in patients with chronic kidney disease and traditional drugs or therapies rarely have effects on cardiac complications, we sought to determine the effect of curcumin in treating cardiac dysfunction in rats with established chronic renal disease. Treatment consisted in daily administration of curcumin (120 mg/kg/day) dissolved in 0.05% carboxymethylcellulose via oral gavages during 30 days, beginning from day 30 after 5/6 nephrectomy (5/6Nx). Cardiac function, markers of oxidative stress, activation of PI3K/Akt/GSK3β and MEK1/2-ERK1/2 pathway, metalloproteinase-II (MMP-2) content, overall gelatinolytic activity, ROS production and mitochondrial integrity were evaluated after 1-month treatment. Curcumin restored systolic blood pressure, diminished interventricular and rear wall thickening, decreased left ventricle dimension at end-systole (LVSd) and restored ejection fraction in nephrectomized rats. Also, it diminished metalloproteinase-II levels and overall gelatinase activity, decreased oxidative stress and inhibited the mitochondrial permeability transition pore opening. Our findings suggest that curcumin might have therapeutic potential in treatment of heart disease in patients with established CKD by attenuating oxidative stress-related events as cardiac remodeling, mitochondrial dysfunction and cell death.

Mitochondrial aldehyde dehydrogenase activity protects against lipopolysaccharide‑induced cardiac dysfunction in rats.

Myocardial dysfunction in sepsis is associated with an increased risk of mortality. The mitochondrial aldehyde dehydrogenase (ALDH2) enzyme is crucial for protecting the heart from ischemic injury. The aim of the present study was to determine the role of ALDH2 in cardiac dysfunction induced by lipopolysaccharide (LPS). Male rats were treated intraperitoneally with LPS, and their stroke volume and cardiac output were evaluated using an M‑mode echocardiograph. The expression levels and activity of ALDH2, nitric oxide content and inducible nitric oxide synthase (iNOS) activity, and the opening of the mitochondrial permeability transition pore (MPTP) were also evaluated. Treatment with LPS (5, 10, or 20 mg/kg) resulted in a steady decrease in cardiac output and stroke volume. The ALDH2 activity was decreased in a dose‑dependent manner; however, the ALDH2 protein expression levels remained unchanged. Alda‑1, a specific activator of ALDH2, increased the activity of ALDH2 and lessened LPS‑induced cardiac dysfunction. A marked opening of the MPTP was observed 12 h following treatment with LPS, which was prevented by Alda‑1. The improvement in cardiac function in response to treatment with Alda‑1, was partially prevented by treatment with the MPTP inhibitor atractyloside. LPS treatment induced an increase in iNOS activation and inhibition of ALDH2 activity. The iNOS selective inhibitor, aminoguanidine, partially reversed the LPS‑induced ALDH2 activity decrease and MPTP opening. These results indicate that ALDH2 activity may have a role in protecting against LPS‑induced cardiac dysfunction. The potential mechanism may involve inhibition of MPTP opening and iNOS expression.

Cardioprotective effects of isoflurane in a rat model of stress-induced cardiomyopathy (takotsubo)

BackgroundStress-induced cardiomyopathy (SIC) is a common syndrome with substantial morbidity and mortality. SIC is common in intensive care units' patients. No therapeutic intervention for SIC has been evaluated in randomized clinical trial so far. Our aim was to investigate whether isoflurane is cardioprotective in an experimental SIC model. MethodsWe induced SIC-like cardiac dysfunction in rats with intraperitoneal injection of isoprenaline (50mg/kg) and performed this study in two parts. First, we pre-treated rats with isoflurane (1.5%, n=12), pentobarbital (50mg/kg, n=12) and ketamine (80mg/kg, n=12) and compared to controls (n=12). We used glyburide, an ATP-dependent potassium channel blocker (n=6), to test whether isoflurane-protection is mediated through KATPm. In a second set of experiments, we treated rats with two different doses of isoflurane i.e. 0.75% (n=12) and 1.5% (n=12) before induction of SIC and compared to controls. We assessed left ventricular function and morphology in all rats by transthoracic echocardiography. We also measured peak body temperature, blood gases, acid–base homeostasis, blood pressure and heart rate. ResultsThe extent of apical akinesia was lowest and cardiac function was best in the isoflurane treated rats. The protective effects were not attenuated by glibenclamide. Higher dose of isoflurane was more cardioprotective than the lower dose. This was persistent after the adjustment for changes in hemodynamics and blood biochemistry induced by anesthesia. ConclusionsIsoflurane prevented SIC-like cardiac dysfunction in rats. This protection was not mediated via KATPm. Our study provides an experimental foundation for future clinical trials in SIC.

Catechin ameliorates cardiac dysfunction in rats with chronic heart failure by regulating the balance between Th17 and Treg cells.

Disequilibrium of the cytokine network was reported to play an important role in the progression of chronic heart failure (CHF). Catechin exerts cardioprotection through treating many kinds of angiocardiopathy. However, the effects of catechin on CHF are currently unclear. Therefore, the main aim of this study was to investigate the efficacy of catechin on CHF rats as well as its relationship to immunoregulation. CHF was induced in rats by ligation of the abdominal aorta. Myocardial function was evaluated by left ventricular systolic pressure and left ventricular end-diastolic pressure. The cytokine level was measured by enzyme-linked immunosorbent assay. Th17 and Treg levels in peripheral blood and spleen were analyzed by flow cytometry. The results showed that catechin treatment (50, 100mg/kg/day) markedly improved myocardial function in rats treated with abdominal aortic coarctation. Severity of myocardial dysfunction in CHF rats significantly correlated with serum values of interleukin-17 (IL-17)/IL-10. Further results indicated catechin obviously inhibited immune activation, regulated unbalanced levels of IL-17/IL-10, and reversed abnormal polarization of TH17 as well as Treg in peripheral blood and spleen. Taken together, oral administration of catechin effectively suppressed abdominal aorta ligation-induced CHF in rats, which was closely associated with its modulation on Th17 and Treg.

Targeted NGF siRNA delivery attenuates sympathetic nerve sprouting and deteriorates cardiac dysfunction in rats with myocardial infarction.

Nerve growth factor (NGF) is involved in nerve sprouting, hyper-innervation, angiogenesis, anti-apoptosis, and preservation of cardiac function after myocardial infarction (MI). Positively modulating NGF expression may represent a novel pharmacological strategy to improve post-infarction prognosis. In this study, lentivirus encoding NGF short interfering RNA (siRNA) was prepared, and MI was modeled in the rat using left anterior descending coronary artery ligation. Rats were randomly grouped to receive intramyocardial injection of lentiviral solution containing NGF-siRNA (n = 19, MI-SiNGF group), lentiviral solution containing empty vector (n = 18, MI-GFP group) or 0.9% NaCl solution (n = 18, MI-control group), or to receive thoracotomy and pericardiotomy (n = 17, sham-operated group). At 1, 2, 4, and 8 wk after transduction, rats in the MI-control group had higher levels of NGF mRNA and protein than those in the sham-operated group, rats in the MI-GFP group showed similar levels as the MI-control group, and rats in the MI-SiNGF group had lower levels compared to the MI-GFP group, indicating that MI model was successfully established and NGF siRNA effectively inhibited the expression of NGF. At 8 wk, echocardiographic and hemodynamic studies revealed a more severe cardiac dysfunction in the MI-siRNA group compared to the MI-GFP group. Moreover, rats in the MI-siRNA group had lower mRNA and protein expression levels of tyrosine hydroxylase (TH) and growth-associated protein 43-positive nerve fibers (GAP-43) at both the infarcted border and within the non-infarcted left ventricles (LV). NGF silencing also reduced the vascular endothelial growth factor (VEGF) expression and decreased the arteriolar and capillary densities at the infarcted border compared to the MI-GFP group. Histological analysis indicated a large infarcted size in the MI-SiNGF group. These findings suggested that endogenous NGF silencing attenuated sympathetic nerve sprouting and angiogenesis, enlarged the infarct size, aggravated cardiac dysfunction, and potentially contributed to an unfavorable prognosis after MI.

Significant reversal of cardiac upregulated endothelin-1 system in a rat model of sepsis by landiolol hydrochloride

AimsLandiolol hydrochloride, an ultra-short-acting highly cardio-selective β-1 blocker, has become useful for various medical problems. Recent studies have demonstrated that co-treatment with landiolol protects against acute lung injury and cardiac dysfunction in rats of lipopolysaccharide (LPS)-induced systemic inflammation, and was also associated with a significant reduction in serum levels of the inflammation mediator HMGB-1 and histological lung damage. Endothelin (ET)-1, a potent vasoconstrictor, has been implicated in pathogenesis of sepsis and sepsis-induced multiple organ dysfunction syndrome. Here, we investigated whether landiolol hydrochloride can play important roles in ameliorating LPS-induced alterations in cardiac ET system of septic rats. Main methodsEight-week-old male Wistar rats were administered LPS only for 3h and the rest were treated with LPS as well as with landiolol non-stop for 3h. Key findingsAt 3h after LPS (only) administration, circulatory tumor necrosis factor (TNF)-α level, blood lactate concentration and percentage of fractional shortening of heart were significantly increased. In addition, LPS induced a significant expression of various components of cardiac ET-1 system compared to control. Finally, treatment of LPS-administered rats with landiolol for 3h normalized LPS-induced blood lactate levels and cardiac functional compensatory events, without altering levels of plasma TNF-α and ET-1. Most strikingly, landiolol treatment significantly normalized various components of cardiac ET-1 signaling system in septic rat. SignificanceTaken together, these data led us to conclude that landiolol may be cardio-protective in septic rats by normalizing the expression of cardiac vasoactive peptide such as ET, without altering the circulatory levels of inflammatory cytokines.

Acute Inhibition of Excessive Mitochondrial Fission After Myocardial Infarction Prevents Long‐term Cardiac Dysfunction

BackgroundIschemia and reperfusion (IR) injury remains a major cause of morbidity and mortality and multiple molecular and cellular pathways have been implicated in this injury. We determined whether acute inhibition of excessive mitochondrial fission at the onset of reperfusion improves mitochondrial dysfunction and cardiac contractility postmyocardial infarction in rats.Methods and ResultsWe used a selective inhibitor of the fission machinery, P110, which we have recently designed. P110 treatment inhibited the interaction of fission proteins Fis1/Drp1, decreased mitochondrial fission, and improved bioenergetics in three different rat models of IR, including primary cardiomyocytes, ex vivo heart model, and an in vivo myocardial infarction model. Drp1 transiently bound to the mitochondria following IR injury and P110 treatment blocked this Drp1 mitochondrial association. Compared with control treatment, P110 (1 μmol/L) decreased infarct size by 28±2% and increased adenosine triphosphate levels by 70+1% after IR relative to control IR in the ex vivo model. Intraperitoneal injection of P110 (0.5 mg/kg) at the onset of reperfusion in an in vivo model resulted in improved mitochondrial oxygen consumption by 68% when measured 3 weeks after ischemic injury, improved cardiac fractional shortening by 35%, reduced mitochondrial H2O2 uncoupling state by 70%, and improved overall mitochondrial functions.ConclusionsTogether, we show that excessive mitochondrial fission at reperfusion contributes to long‐term cardiac dysfunction in rats and that acute inhibition of excessive mitochondrial fission at the onset of reperfusion is sufficient to result in long‐term benefits as evidenced by inhibiting cardiac dysfunction 3 weeks after acute myocardial infarction.

Mg supplementation attenuates ritonavir-induced hyperlipidemia, oxidative stress, and cardiac dysfunction in rats

Use of protease inhibitors (PI) in HIV patients is associated with hyperlipidemia and increased risk of coronary heart disease. Chronic systemic and cardiac effects of ritonavir (RTV), a universal PI booster, and Mg supplementation were examined. RTV was administered (75 mg·kg(-1)·day(-1) po) to Lewis × Brown-Norway hybrid (LBNF1) rats for up to 8 wk; significant increases in plasma triglyceride and cholesterol occurred from 8 days to 8 wk. At 5 wk, the expression of selected hepatic genes (CYP7A1, CITED2, G6PC, and ME-1), which are key to lipid catabolism/synthesis, were altered toward lipogenesis. Dietary Mg supplementation (six-fold higher) completely reversed the altered expression of these genes and attenuated both hypertriglyceridemia and hypercholesterolemia. Neutrophils isolated from the RTV-treated rats displayed a three-fold higher basal and a twofold higher stimulated superoxide production; plasma isoprostane and red blood cell (RBC) GSSG levels were elevated two- to three-fold. All oxidative indices were normalized by Mg supplementation. After 5 wk, RTV caused significant decreases in cardiac left ventricular (LV) shortening fraction and LV ejection fraction; mitral valve early/late atrial ventricular filling (E/A) ratio was reduced accompanied by LV posterior wall thinning. Immunohistochemical staining revealed significant white blood cell (WBC) infiltration (5 wk) and prominent fibrosis (8 wk) in the RTV hearts. Mg supplementation attenuated RTV-induced declines in systolic and diastolic (improved mitral valve E/A ratio) function (>70%), lessened LV posterior wall thinning (by 75%), and substantially decreased the pathological markers. The known clinical hyperlipidemia effects of RTV can be mimicked in the LBNF1 rats; in association, systemic oxidative stress and progressive cardiac dysfunction occurred. Remarkably, Mg supplementation alone suppressed RTV-mediated hyperlipidemia, oxidative stress, and cardiac dysfunction.

Abstract 185: Transient Neonatal High Oxygen Exposure Leads to Cardiac Dysfunction and Renin Angiotensin System Activation in Rats

Preterm infants are exposed to high oxygen (O2) pressure (relative to intrauterine levels) leading to systemic oxidative stress and impaired vascular development; as children and adults, preterm born subjects have higher blood pressure. In rats, high O2 exposure induces vascular dysfunction, in part mediated by the renin angiotensin system (RAS). However, impact of neonatal high O2 exposure on heart development and whether RAS activation prevails in the heart is unknown. We aimed to assess early heart alterations and activation of RAS after neonatal high O2 exposure. METHODS AND RESULTS: Sprague-Dawley pups were kept with their mother in 80% O2 (O2, n=8) or room air (Ctrl, n=8) from days 3-10 of life. Hearts were extracted at day 3 (pre O2-exposure, P3), day 5 (during, P5), 10 (after, P10) and 4 wks to assess myocardium hypertrophy (HE), fibrosis (Masson’s trichrome) and RAS components gene expressions by RT-PCR. Echocardiography was performed at 4 weeks to assess heart function. RAS components mRNA expression in O2 vs Ctrls shows up-regulation of AT1a and ACE2 genes at P5 (AT1a: 152±28 vs 58±16/ACE2: 140±20 vs 77±6% of P3) and P10 (AT1a: 374±35 vs 250±30 /ACE2: 326±70 vs 208±18% of P3) relative to values at P3. With age, AT1b and AT2 expressions decrease in Ctrls, whereas are maintained in O2-exposed rats to values similar to P3 (Ctrl vs O2, P5: AT1b: 18±5 vs 71±12/AT2: 48±20 vs 120±16; P10: AT1b: 33±9 vs 105±26/AT2: 27±8 vs 77±7% of P3). At P10, cardiomyocyte surface area is increased in O2 vs Ctrls (4.9±0.2 vs 2.9±0.1 μm2). At 4 wks, O2 group show increased fibrosis (49±4 vs 29±2 % pixels), left ventricular (LV) cavity diameter (3.6±0.2 vs 3.0±0.1 mm) and systolic dysfunction by decreased fraction of shortening (39±2 vs 47±2 %). AT1b gene expression (2.6±1.7 vs 0.3±0.2) is increased and AT2 receptor (7.5±0.9 vs 6.0±0.6) is decreased in O2 group vs Ctrl. CONCLUSION: Neonatal O2 exposure activates RAS in hearts. AT1 receptor is up-regulated at all ages studied in O2-exposed rat hearts while AT2 is up-regulated at P5 and P10. At 4 wks, AT1/AT2 imbalance prevails in O2 group hearts along with LV dysfunction and enhanced fibrosis and hypertrophy. RAS activation by neonatal O2-exposure might significantly impact in heart development and programming of cardiac dysfunction in rats.

High-phosphorus/zinc-free diet aggravates hypertension and cardiac dysfunction in a rat model of the metabolic syndrome

Cardiac dysfunction is reported in patients with the metabolic syndrome. We assessed the effects of high-phosphorus and zinc-free diet on cardiovascular system in spontaneously hypertensive rats (SHR)/NDmcr-cp (SHR/cp), a rat model of the metabolic syndrome. We also investigated the effects of N-acetyl-L-cysteine (NAC), an antioxidant, on the development of cardiac dysfunction under such conditions. Male SHR/cp and control [Wistar Kyoto (WKY)] rats were divided into three groups and fed control diet (P 0.3% w/w, Zn 0.2% w/w) or high-phosphorus and zinc-free (P 1.2% w/w, Zn 0.0% w/w) diet. The latter group was treated with either NAC (1.5 mg/g per day) or vehicle from 6 to 18 weeks of age (n=6 or 8 for each group). High-phosphate and zinc-free diet increased systolic blood pressure in both WKY and SHR/cp. Echocardiography showed that high-phosphate and zinc-free diet markedly reduced left ventricular systolic and diastolic function in SHR/cp. Histopathologically, the same diet induced severe myocardial fibrosis in SHR/cp, and this effect was prevented by NAC. Whereas treatment with NAC prevented diastolic dysfunction induced by the same diet in WKY, it only improved systolic function but not diastolic function in SHR/cp. High-phosphate and zinc-free diet induced hypertension and cardiac dysfunction. These changes hamper the protective effects of NAC in the metabolic syndrome. The present study showed that consumption of high-phosphorus and zinc-free diet increased the myocardial expression of connective tissue growth factor and reduced the expression of metallothionein, which enhanced the development of severe cardiac dysfunction in rats with the metabolic syndrome. The results suggest that the metabolic syndrome seems to aggravate cardiac dysfunction and hamper the protective effects of antioxidant, NAC.

Male rats are more prone to develop Takotsubo-like cardiac dysfunction in response to high-dose catecholamine than are female rats

Purpose: Stress-induced cardiomyopathy (SIC), also known as Takotsubo cardiomyopathy, is characterized by severe but potentially reversible left ventricular dysfunction in the absence of an explanatory coronary artery obstruction. In contrast to ischemic heart disease and acute myocardial infarction, which predominantly affect males, approximately 90% of SIC patients are women. Although little is known about the pathomechanism behind the syndrome, excess levels of catecholamine are believed to play an important role. We and others have shown that SIC-like cardiac dysfunction can be induced in the rat by administration of high dose catecholamine. Recently, chronic stress has been proposed to predispose an individual to develop SIC. The aim of this manuscript was to study the effect of gender on the development of SIC-like cardiac dysfunction in rats. Methods: A total of 243 ten weeks old male (n=114) and female (n=111) Sprague-Dawley rats were used in this study. The rats were housed five in each cage according to current guidelines. At the start of the experiment the rats were injected with 50 mg/kg isoproterenol intraperitoneally, a protocol that induces SIC-like left ventricular (LV) apical ballooning. Echocardiography was used to assess extent of LV akinesia as well as indices of cardiac function. Generalized linear models, multiple regression and Cox proportional hazards models were used to determine the influence of gender, developed body temperature, orchidectomy and ovarectomy on degree of LV akinesia, cardiac function and survival. Results: In all fitted models, male gender was associated with significantly greater extent of LV akinesia and increased survival. Orchidectomy was associated with less widespread akinesia and ovarectomy with increased LV akinesia. Development of high body temperature in response to isoprenaline was associated with greater extent of LV akinesia. Conclusion: Our data indicate that male gender is associated with development of SIC-like cardiac dysfunction in rats and that development of SIC may be protective. We propose that the discrepancy between our findings and the female overrepresantation observed in the clinical setting may be explained by differences in the degree of chronic stress, i.e. that it is more stressful for male rats to be housed together than it is for female rats whereas modern society may be more stressful for women than it is for men.

Hind-limb Exercise Reduces Cardiac Dysfunction in Rats with Complete Spinal Cord Injury

Hind-limb Exercise Reduces Cardiac Dysfunction in Rats with Complete Spinal Cord Injury

Cardiac Dysfunction in Rats with Dietary-Induced Insulin Resistance Associated with Pharmacologically-induced Dyslipidemia

Metabolic disorders such as insulin resistance (IR) and dyslipidemia (DL) might contribute to the induction of diabetic cardiomyopathy (DCM). However, few relevant animal models are currently available for studying the time-course of DCM and evaluating experimental therapeutics. The present study proposes a rodent model of dietary-induced IR combined or not with DL in order to investigate the impact of chronic IR and DL on in vivo myocardial function. Male rats were fed a western-type diet (65% fat; 15% fructose; WD). DL was induced by combining the western diet with i.p. injections of a nonionic surface-active agent (P-407; 0.2 mg/kg, 3 times/wk; P-407). A chow diet was used as control. At 11 and 14 weeks, cardiac function was assessed by echocardiography. Fasting blood glucose increased in WD group while plasma lipids markedly accumulated in P-407 treated rats. Echocardiographic data showed no significant difference in cardiac geometry under basal conditions. Diastolic dysfunction was evidenced at 14 weeks by a significant decrease in E/A ratio in the P-407 group. Moreover, fractional shortening was significantly depressed under dobutamine stress in WD group at 14 weeks whereas systolic dysfunction appeared as early as 11 weeks and worsened at 14 weeks in P-407 animals. Finally, myocardial TNF-alpha tissue content increased in P-407 group. In conclusion, DL exacerbated cardiac lipotoxicity and functional complications associated with IR. This experimental model of combined IR and DL closely mimics the main clinical manifestations of DCM and might therefore constitute a useful tool for the evaluation of pharmacological treatments.

QiShenYiQi Pills, a Compound Chinese Medicine, Ameliorates Doxorubicin-Induced Myocardial Structure Damage and Cardiac Dysfunction in Rats

QiShenYiQi Pills (QSYQ) is a compound Chinese medicine used for treatment of cardiovascular diseases. The present study investigated the effects of QSYQ on the Doxorubicin- (DOX-) induced disorders in rat cardiac structure and function and the possible mechanism underlying. A total of 24 male Sprague-Dawley rats were administrated by intraperitoneal injections with DOX at a dose of 2.5 mg/kg, once every day for a total of 6 times. After the 6th injection, the rats were evaluated by echocardiographic analysis, and the animals with injured heart (n = 14) were divided into 2 groups and further treated with (n = 7) or without (n = 7) QSYQ by gavage at a dose of 0.2 g/day, once a day, over the next 2 weeks. Two weeks after QSYQ treatment, the following variables were assessed: myocardial blood flow (MBF) by Laser-Doppler Perfusion Imager, the ratio of heart weight to body weight (HW/BW), myocardial histology, myocardial content of ATP, AMP, free fatty acids (FFAs) and AMP/ATP by ELISA, and expression of PPARα, PGC-1α, and ATP 5D by Western blot. Statistical analysis was performed using one-way ANOVA followed by Turkey test for multiple comparisons. DOX challenge significantly increased left ventricular internal diameter and HW/BW and decreased the thickness of the left ventricular posterior wall, the left ventricle ejection fraction, and the left ventricle fractional shortening. DOX also increased AMP, FFA, and AMP/ATP, decreased ATP, and downregulated the protein content of ATP 5D, PPAR α, and PGC-1 α. All these DOX-induced cardiac insults were attenuated significantly by QSYQ treatment. These results show the potential of QSYQ to ameliorate DOX-induced disorders in cardiac structure and function; this effect may be related to the increase in myocardial ATP content via the upregulation of ATP 5D, PPAR α, and PGC-1 α and the oxidation of FFA.

The Protective Role of Resveratrol against Arsenic Trioxide-Induced Cardiotoxicity

Arsenic trioxide (As2O3) shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Unfortunately, limiting the application of this effective agent to APL patients is severe cardiotoxicity. Resveratrol, the natural food-derived polyphenolic compound, is well known for its antioxidant properties and protects the cardiovascular system. But the potential role of resveratrol against As2O3 in heart via nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) is unclear. The present study evaluated the effects of pretreatment with resveratrol and As2O3 on oxidative stress and cardiac dysfunction in rat. In the present study, resveratrol decreased As2O3-induced reactive oxygen species generation, oxidative DNA damage, and pathological alterations. In addition, cardiac dysfunction parameters, intracellular calcium and arsenic accumulation, glutathione redox ratio, and cAMP deficiency levels were observed in As2O3-treated rats; these changes were attenuated by resveratrol. Furthermore, resveratrol significantly prohibited the downregulation of both Nrf2 and HO-1 gene expressions that were downregulated by As2O3, whereas resveratrol did not alter As2O3-induced nitric oxide formation. Thus, the protective role of resveratrol against As2O3-induced cardiotoxicity is implemented by the maintenance of redox homeostasis (Nrf2-HO-1 pathway) and facilitating arsenic efflux. Our findings suggest coadministration with resveratrol, and As2O3 might provide a novel therapeutic strategy for APL.

Acute effects of beta-blocker with intrinsic sympathomimetic activity on stress-induced cardiac dysfunction in rats

BackgroundWe have reported that α and β adrenergic blockers could protect against emotional stress-induced cardiac dysfunction but those protective effects of β adrenergic blockers with intrinsic sympathomimetic activity (ISA), such as celiprolol, are unknown. The purpose of this study is to evaluate whether ISA could relate with this protective effect. Methods and resultsRats medicated with celiprolol (8mg/kg), metoprolol (4mg/kg), or vehicle, were restrained for 30min (immobilization stress: IMO) to reproduce emotional stress, and anesthetized to release stress. We measured the fractional area change (FAC) using an echocardiography (SONOS5500) with s12 probe (frequency: 5–12MHz, frame rate: 120Hz) at the end of IMO and every 10min for 1h. During IMO, FAC in rats with a premedication of metoprolol was lower than in those with a premedication of vehicle or celiprolol. At 20min after IMO, FAC in rats with a premedication of celiprolol was significantly higher than that with a premedication of metoprolol or vehicle (84±9% vs. 65±3% or 60±7%, p<0.05). At 60min after IMO, FAC in rats with a premedication of vehicle or celiprolol recovered, but FAC in rats with a premedication of metoprolol did not. ConclusionAcute premedication with celiprolol could prevent a sudden drop of cardiac function after acute stress such as IMO. ISA might have an important role in preventing stress-induced cardiac dysfunction.

Myocardial Autophagy after Severe Burn in Rats

BackgroundAutophagy plays a major role in myocardial ischemia and hypoxia injury. The present study investigated the effects of autophagy on cardiac dysfunction in rats after severe burn.MethodsProtein expression of the autophagy markers LC3 and Beclin 1 were determined at 0, 1, 3, 6, and 12 h post-burn in Sprague Dawley rats subjected to 30% total body surface area 3rd degree burns. Autophagic, apoptotic, and oncotic cell death were evaluated in the myocardium at each time point by immunofluorescence. Changes of cardiac function were measured in a Langendorff model of isolated heart at 6 h post-burn, and the autophagic response was measured following activation by Rapamycin and inhibition by 3-methyladenine (3-MA). The angiotensin converting enzyme inhibitor enalaprilat, the angiotensin receptor I blocker losartan, and the reactive oxygen species inhibitor diphenylene iodonium (DPI) were also applied to the ex vivo heart model to examine the roles of these factors in post-burn cardiac function.ResultsAutophagic cell death was first observed in the myocardium at 3 h post-burn, occurring in 0.008 ± 0.001% of total cardiomyocytes, and continued to increase to a level of 0.022 ± 0.005% by 12 h post-burn. No autophagic cell death was observed in control hearts. Compared with apoptosis, autophagic cell death occurred earlier and in larger quantities. Rapamycin enhanced autophagy and decreased cardiac function in isolated hearts 6 h post-burn, while 3-MA exerted the opposite response. Enalaprilat, losartan, and DPI all inhibited autophagy and enhanced heart function.ConclusionMyocardial autophagy is enhanced in severe burns and autophagic cell death occurred early at 3 h post-burn, which may contribute to post-burn cardiac dysfunction. Angiotensin II and reactive oxygen species may play important roles in this process by regulating cell signaling transduction.

The EGFR tyrosine kinase inhibitor tyrphostin AG-1478 causes hypomagnesemia and cardiac dysfunction

We determined whether the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) N-​(3-​chlorophenyl)-​6,​7-​dimethoxy-​4-​quinazolinamine (tyrphostin AG-1478) causes hypomagnesemia and cardiac dysfunction in rats. Tyrphostin was administered (3 times per week, intraperitoneal injection, to achieve 21.4 mg·(kg body mass)(-1)·day(-1)) to normomagnesemic rats for 5 weeks. Levels of magnesium in the plasma of the tyrphostin-treated rats decreased significantly by the following amount: 17% at week 1, 27% at week 2, and 26%-35% between weeks 3 to 5. Levels of the plasma lipid peroxidation marker 8-isoprostane rose significantly: by 58% at week 1, 168% at week 3, and 113% at week 5. At week 5, blood neutrophils from the tyrphostin-treated group displayed a 2.26-fold higher basal level of O(2)(·-) generation; the ratio of oxidized glutathione (glutathione disulfide; GSSG) to reduced glutathione (GSH) in the red blood cells increased 2.5-fold. At week 5, echocardiography revealed that TKI treatment resulted in significant cardiac systolic dysfunction, with impaired diastolic function and dilated cardiomyopathy. Since hypomagnesemia alone can trigger oxidative stress and cardiac injury, we suggest that inhibition of EGFR-TK caused magnesium wasting, which partly contributed to decreased cardiac contractility.