Myocardial Ischemia Injury In Rats Research Articles

In Vivo Study on Doxycycline Protective Mechanisms during Myocardial Ischemia Injury in Rats.

The fact that during myocardial ischemia/reperfusion (I/R) injury, myosin light chain 1 (MLC1) and troponin I (TnI) are degraded by matrix metalloproteases activity has already been well established in both in vitro and ex vivo studies. However, I/R injury is a complex issue based on several overlapping mechanisms. Increased activity of myosin light chain kinase and nitric oxide synthase due to oxidative stress leads to post-translational modifications of MLC1, thus leading to the increased degradation of these proteins. Wistar rats were subjected to left anterior descending coronary artery occlusion. To measure the pharmacological effect of doxycycline, transthoracic echocardiography as well as biochemical tests, concentrations of TnI, LDH, MLC1, MMP-2 and MMP-9 were performed. Gelatinize activity and cytotoxicity level were also assessed; Results: I.p., administration of doxycycline before LAD occlusion surgery increased TnI and LDH content in the heart and decreased cytotoxicity. A reduction of MMP-2 and MMP-9 concentration and MMP-2 activity after administration of Doxy was also observed, as well as improvement in echocardiographic parameters just 7 days after surgery. Inhibition of MMPs by doxycycline, in vivo, may serve as a protective agent in future therapy.

Lagopsis supina ameliorates myocardial ischemia injury by regulating angiogenesis, thrombosis, inflammation, and energy metabolism through VEGF, ROS and HMGB1 signaling pathways in rats

BackgroundLagopsis supina (Steph. ex. Willd.) Ikonn.-Gal. is an important traditional Chinese medicine used to treat various ailments. However, its impact on myocardial ischemia (MI) injury remains unknown. PurposeThis research aimed to reveal the therapeutic effect, potential mechanism, and metabolomics of L. supina against MI injury in rats. MethodsThe therapeutic effects of the ethanolic extract of L. supina (LS) and its four fractions (LSA∼D) on a left anterior descending (LAD) artery occlusion-induced MI model rat were explored. The pharmacodynamics including myocardial infraction area, myocardial tissue pathology and apoptosis, and serum biochemical parameters (CK, CK-MB, CTn-T, SOD, ET-1, NO, eNOS, VEGF, TXB2, 6-keto-PGF1α, TNF-α, IL-6, and CRP) were evaluated. The 24 related protein expressions were detected using western blotting assay. Simultaneously, the qualitative and quantitative analyses of microporous adsorption resin with 30% (LSC) and 60% (LSD) aqueous ethanol fractions were performed using UHPLC-MS and HPLC. Moreover, the serum metabolomics analysis of rats was profiled using UHPLC-MS. ResultsLS exerted remarkable alleviating effect on MI in rats. Importantly, LSC and LSD, two effective fractions of LS, significantly reduced myocardial infraction area, alleviated myocardial tissue pathology and apoptosis, regulated serum biochemical parameters. Furthermore, LSC and LSD markedly up-regulated the levels of VEGF-A, VEGFR-2, PKC, Bcl-2, Nrf2, HO-1, and thrombin, as well as prominently down-regulated the protein expression of Notch 1, p-PI3K, p-PI3K/PI3K, p-Akt, p-Akt/Akt, Bax, cleaved-caspase-3, cleaved-caspase-3/caspase-3, vWF, p-Erk, p-Erk/Erk, HMGB1, p-p38, p-p38/p38, p-p65, and p-p65/p65. A total of 26 candidate biomarkers were significantly regulated by LSC and LSD and they are mainly involved in amino acid metabolism, glycerophospholipid metabolism, and sphingolipid metabolism. Finally, phenylethanols and flavonoids may be major bio-constituents of LSC and LSD against MI. ConclusionsThis work, for the first time, demonstrated that L. supina had a significant therapeutic effect on MI in rats. Additionally, LSC and LSD, two bio-fractions from L. supina, exerted their potential to ameliorate MI injury by promoting angiogenesis, inhibiting thrombosis, blocking inflammation, and facilitating energy metabolism through promotion of VEGF pathway, as well as suppression of ROS and HMGB1 pathways in rats. These findings suggest that LSC and LSD hold promise as potential therapeutic agents for MI injury in clinical application.

Protective Effect of Ginsenosides Rg1 on Ischemic Injury of Cardiomyocytes After Acute Myocardial Infarction.

Acute myocardial infarction (AMI) leads to anoxia and ischemia of cardiomyocytes, followed by apoptosis. This study investigated the protective effect of ginsenoside Rg1 (Rg1) on myocardial ischemia injury in rats with AMI. Rats were randomly divided into five groups: group A (blank control group), group B (hypoxia/reoxygenation group), group C (hypoxia/reoxygenation + 10mg/L Rg1), group D (hypoxia/reoxygenation + 20mg/L Rg1) and group E (hypoxia/reoxygenation + 40mg/L Rg1). The survival rate, apoptosis rate, expression of cyclin-dependent kinase 4 (CDK4), fibroblast growth factor 9 (FGF9), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), microvessel density and myocardial infarction area of rats in each group were compared. The expressions of CDK4 and FGF9, the contents of SOD and GSH-Px in groups C, D and E injected with Rg1 were significantly promoted compared to group B without Rg1 injection (P < 0.05). The survival rate of myocardial cells was significantly increased while the apoptosis rate was significantly decreased in group C, D, E compared to group B (P < 0.05). On the 3rd, 7th and 10th day following Rg1 treatment, the infarct area of E group was significantly decreased in three groups C, D, E, and the microvessel density of infarct area was significantly increased compared with group B (P < 0.05). So, Rg1 can improve the survival rate of myocardial cells, reduce the apoptosis rate and the area of myocardial infarction, and increase the microvessel density of infarct area, thus playing a protective role in ischemic myocardial cells of AMI rats.

Modulation effects of danshen-honghua herb pair on gut microbiota of acute myocardial ischemia model rat.

In the recent years, a growing number of studies have shown that the occurrence of myocardial ischemia (MI) is closely related to the gut microbiota (GM). The Danshen-Honghua herb pair (DHHP), a classic combination in traditional Chinese herbal formulas, has been widely applied throughout history to cure cardiovascular disease, exhibiting remarkable clinical efficacy to treat ischemic heart disease (IHD). However, the intrinsic regulation mechanism of DHHP in treating MI remains unclear. This study aims to investigate the possible protective mechanism of DHHP in rats with acute myocardial ischemia (AMI) induced by isoproterenol (ISO) through 16S rRNA gene sequencing technique. Pharmacodynamic results showed that DHHP significantly ameliorated the pathological changes and improved the abnormal cardiac enzymes levels in the AMI rats. In addition, GM analysis demonstrated that DHHP effectively ameliorated the ISO-induced dysbiosis of the GM community, mainly by enhancing the GM diversity and increasing the relative abundance of Bacteroides, Roseburia, unclassified_f__Lachnospiraceae, and Lachnospiraceae_NK4A136_group, the abundance ratio of Bacteroidetes to Firmicutes, and decreasing the relative abundance of Escherichia-Shigella and Enterococcus. In summary, this study revealed that DHHP could improve ischemic myocardial injury in rats, and that its regulation mechanism is associated with significantly ameliorating the composition of GM, thus contributing to further our understanding of the anti-MI mechanisms of DHHP.

Mechanism of paeonol combined with paeoniflorin against myocardial ischemia injury:based on proteomics

The study aims to investigate the effect of the compatibility of paeonol and paeoniflorin(hereinafter referred to as the compatibility) on the expression of myocardial proteins in rats with myocardial ischemia injury and explore the underlying mechanism of the compatibility against myocardial ischemia injury. First, the acute myocardial infarction rat model was established by ligation of the anterior descending branch of the left coronary artery. The model rats were given(ig) paeonol and paeoniflorin. Then protein samples were collected from rat cardiac tissue and quantified by tandem mass tags(TMT) to explore the differential proteins after drug intervention. The experimental results showed that differential proteins mainly involved phagocytosis engulfment, extracellular space, and antigen binding, as well as Kyoto encyclopedia of genes and genomes(KEGG) pathways of complement and coagulation cascades, syste-mic lupus erythematosus, and ribosome. In this study, the target proteins and related signaling pathways identified by differential proteomics may be the biological basis of the compatibility against myocardial ischemia injury in rats.

Cardioprotective effect of the polysaccharide from Ophiopogon japonicus on isoproterenol-induced myocardial ischemia in rats

The polysaccharide (OJP1), extracted from the root of Ophiopogon japonicus, is a well-known traditional Chinese medicine used to treat cardiovascular diseases. The present study was set up to investigate the cardioprotective effect of OJP1 on isoproterenol (ISO)-induced myocardial ischemia injury in rats. Results showed that pretreatment with OJP1 (100, 200 and 300 mg/kg) significantly reduced ISO-induced ST-segment elevation and the heart index, attenuated the levels of marker enzymes (AST, LDH, CK and CK-MB), along with a significantly enhanced the activities of ATPases. Moreover, pretreatment with OJP1 not only enhanced the activities of SOD, GPx and CAT in serum and myocardium, but also decreased the level of MDA. The biochemical and histopathological analysis also showed that OJP1 can alleviate the myocardial injury induced by ISO. Taken together, our results indicated that oral administration of OJP1 offered significant cardioprotective effect against the damage induced by ISO through enhancement of endogenous antioxidants.

Cardioprotective effects of glycyrrhizic acid involve inhibition of calcium influx via L-type calcium channels and myocardial contraction in rats.

Glycyrrhizic acid (GA) is one of the main active components in licorice and has often been reported to have cardioprotective effects. However, the underlying cellular mechanisms remain unclear. The aim of this study is to verify the protective effects of GA against isoproterenol (ISO)-induced myocardial ischemia injury in rats. Another aim is to explore the cellular mechanisms based on the L-type Ca2+ channel, myocardial cell contraction, and intracellular Ca2+ ([Ca2+]i) transient. The results show that GA reduced the ST segment elevation, decreased the heart rate, prevented ISO-induced QT-interval shortening, improved heart morphology, and decreased the activity of CK and LDH. GA blocked ICa-L in a dose-dependent manner. The concentration for 50% of the maximal effect (EC50) of GA was 145.54μg/mL, and the maximal inhibition was 47.43 ± 0.75% at 1000μg/mL. However, GA did not affect the dynamical properties of the Ca2+ channel. GA reversibly reduced the amplitude of cell contraction in a dose-dependent manner and slowed down its deflection and recovery, as well as the [Ca2+]i transient. The data demonstrate that GA inhibits L-type Ca2+ channels, decreases the [Ca2+]i transient, and shows a negative cardiac inotropic effect in the ventricular myocardial cells of adult rats. It also protects the myocardia from ischemia injury induced by ISO.

Functional Metabolomics Characterizes a Key Role for N-Acetylneuraminic Acid in Coronary Artery Diseases.

As new biomarkers of coronary artery diseases (CAD) emerge via metabolomics, the underlying functional mechanisms remain to be elucidated. Functional metabolomics aims to translate metabolomics-derived biomarkers to disease mechanisms. A cohort of 2324 patients who underwent coronary angiography from 4 independent centers was studied. A combination of ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry in the negative ion mode was used for untargeted analysis of metabolites in plasma. Significant differential metabolites were identified by cross-comparisons with and within CAD types, including normal coronary artery, nonobstructvie coronary atherosclerosis, stable angina, unstable angina, and acute myocardial infarction. A tandem liquid chromatography-mass spectrometry-based approach using isotope-labeled standard addition was subsequently performed for targeted analysis of the metabolic marker N-acetylneuraminic acid (Neu5Ac). A functional metabolomics strategy was proposed to investigate the role of Neu5Ac in the progression of CAD by using in vitro and in vivo models. We identified a total of 36 differential metabolites, 35 of which were confirmed with reference compounds. Elevation of Neu5Ac was observed in plasma during CAD progression in center 1 (P=4.0e-64, n=2019) and replicated in 3 independent centers (n=305). The increased level of Neu5Ac in plasma was confirmed by accurate targeted quantification. Mechanistically, Neu5Ac was able to trigger myocardial injury in vitro and in vivo by activation of the Rho/Rho-associated coiled-coil containing protein kinase signaling pathway through binding to RhoA and Cdc42, but not Rac1. Silencing neuraminidase-1, the enzyme that regulates Neu5Ac generation, ameliorated oxygen-glucose deprivation-induced injury in cardiomyocytes and ligation/isoprenaline-induced myocardial ischemia injury in rats. Pharmacological inhibition of neuraminidase by anti-influenza drugs, oseltamivir and zanamivir, also protected cardiomyocytes and the heart from myocardial injury. Functional metabolomics identified a key role for Neu5Ac in acute myocardial infarction, and targeting neuraminidase-1 may represent an unrecognized therapeutic intervention for CAD.

Prevention effect of Ligusticum chuanxiong extraction against oxidative stress injury induced by myocardial ischemia through activation of Nrf2 signaling pathway

Ligusticum chuanxiong is one of the common traditional Chinese medicinal herbs for treating various cardiovascular and cerebrovascular diseases, and a number of previous studies have demonstrated that the extract of L. chuanxiong has strong antioxidative activity. This paper was mainly aimed to investigate the effects and possible mechanisms of L. chuanxiong extraction on oxidative stress induced by myocardial ischemia injury in rats. The rats were subcutaneously injected with isoprenaline hydrochloride to induce myocardial ischemia injury and treated for 2 weeks. Then the cardiac indexes of the rats were recorded. The concentration of malondialdehyde (MDA) and activities of serum creatine kinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) were measured by colorimetry. Light microscope was used to observe the morphological changes of myocardium, and the protein expressions of nuclear factor E2 related factor 2 (Nrf2), quinone oxidoreductase (NQO1) and hemeoxygenase-1 (HO-1) in cardiac tissue were evaluated by Western blot. The results showed that L. chuanxiong extraction could decrease cardiac indexes and the values of CK, LDH and AST in blood serum, increase activities of serum SOD and T-AOC, reduce serum MDA concentration, improve myocardium structure after ischemia injury, and up-regulate the protein expressions of Nrf2, NQO1 and HO-1 in cardiac tissue. These findings revealed that the cardioprotective effects of L. chuanxiong extraction may be related to inhibiting oxidative stress through the activation of Nrf2 signaling pathway.

GW27-e0155 Effects of hydrogen sulfide on inflammatory factors in acute myocardial ischemia injury in rats

GW27-e0155 Effects of hydrogen sulfide on inflammatory factors in acute myocardial ischemia injury in rats

Mechanisms underlying the cardioprotective effect of Salvianic acid A against isoproterenol-induced myocardial ischemia injury in rats: Possible involvement of L-type calcium channels and myocardial contractility

Ethnopharmacological relevanceSalvianic acid A (SAA), which is the main water-soluble fraction in Radix Salviae Milthiorrhizae, has been widely applied for treating cardiovascular diseases in China. Aim of the studyTo explore the effects of SAA against myocardial ischemia injury induced by isoproterenol (ISO) in rats and to clarify its underlying myocardial protective mechanisms based on l-type calcium channels and myocardial contractility. Materials and methodsThe myocardial ischemia injured rat model was induced by administering ISO (85mg/kg) subcutaneously at evenly spaced intervals throughout the day and night for 2 consecutive days. Serum cardiac biomarkers were analyzed, and heart tissues were isolated and prepared for histopathology assay. The regulatory effects of SAA on the L-type calcium current (ICa-L) in rat ventricular myocytes were observed by the patch clamp technique. The IonOptix Myocam detection system was used to observe the contractility of isolated rat ventricular myocytes. ResultsSAA significantly ameliorated changes in heart morphology and electrocardiographic patterns and reduced serum levels of creatine kinase and lactate dehydrogenase in the ISO-induced myocardial ischemia injured rat model. Meanwhile, SAA reduced ICa-L in a concentration-time dependent way with an IC50 of 1.47×10−5M, upshifted the current-voltage, activation, and inactivation curves of ICa-L, and significantly inhibited the amplitude of the cell shortening. ConclusionsThese results indicate that SAA exhibits significant cardioprotective effects against the ISO-induced myocardial ischemia injury, potentially through inhibiting ICa-L and decreasing myocardial contractility.

Methane attenuates myocardial ischemia injury in rats through anti-oxidative, anti-apoptotic and anti-inflammatory actions

Myocardial infarction (MI) remains the most frequent cardiovascular disease with high mortality. Recently, methane has been shown protective effects on small intestinal ischemia–reperfusion injury. We hypothesized that methane-rich saline (MS) could protect the myocardium again MI via its anti-oxidative, anti-apoptotic and anti-inflammatory effects. In experiment 1, tetrazolium chloride staining and detection of myocardial enzymes and oxidative and inflammatory parameters were performed at 12h after MI to determine the optimal dose at which intraperitoneal MS exerted the best protective effects on MI. In experiment 2, rats were treated with 10ml/kg MS. Myocyte apoptosis was detected 72h after MI, and cardiac function and myocardial remodeling were evaluated 4 weeks after MI. Results showed different dose of MS reduced infarct area, decreased myocardial enzymes, inhibited inflammation and oxidative stress following MI. The optimal dose of MS was 10mg/kg. Moreover, treatment with 10mg/kg MS for 3 days significantly reduced myocyte apoptosis, improved cardiac function and inhibited myocardial remodeling (reduced anterior wall thickness, attenuated myocyte hypertrophy, and decreased myocardial collagen). MS protects the myocardium of MI rats via its anti-oxidative, anti-inflammatory, anti-apoptotic and anti-remodeling activities. Thus, MS provides a novel and promising strategy for the treatment of ischemic heart diseases.

Effect of hydrogen sulfide on inflammatory cytokines in acute myocardial ischemia injury in rats

Hydrogen sulfide (H2S) is believed to be involved in numerous physiological and pathophysiological processes, and now it is recognized as the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide; however, the effects of H2S on inflammatory factors in acute myocardial ischemia injury in rats have not been clarified. In the present study, sodium hydrosulfide (NaHS) was used as the H2S donor. Thirty-six male Sprague Dawley rats were randomly divided into five groups: Sham, ischemia, ischemia + low-dose (0.78 mg/kg) NaHS, ischemia + medium-dose (1.56 mg/kg) NaHS, ischemia + high-dose (3.12 mg/kg) NaHS and ischemia + propargylglycine (PPG) (30 mg/kg). The rats in each group were sacrificed 6 h after the surgery for sample collection. Compared with the ischemia group, the cardiac damage in the rats in the ischemia + NaHS groups was significantly reduced, particularly in the high-dose group; in the ischemia + PPG group, the myocardial injury was aggravated compared with that in the ischemia group. Compared with the ischemia group, the levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in the serum of rats in the ischemia + medium- and high-dose NaHS groups were significantly reduced, and the expression of intercellular adhesion molecule-1 (ICAM-1) mRNA and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) protein in the myocardial tissues of rats was significantly reduced. In the ischemia + PPG group, the TNF-α, IL-1β and IL-6 levels in the serum were significantly increased, the expression of ICAM-1 mRNA was increased, although without a significant difference, and the expression of NF-κB was increased. The findings of the present study provide novel evidence for the dual effects of H2S on acute myocardial ischemia injury via the modulation of inflammatory factors.

Hydrogen sulfide reduces regional myocardial ischemia injury through protection of mitochondrial function.

Hydrogen sulfide (H2S) is a signaling gasotransmitter, involved in various physiological and pathological processes. H2S-donating drugs have been tested to conjugate the beneficial effects of H2S with other pharmaceutical properties. It has been shown that the endogenous cystathionine-γ-lyase (CSE)/H2S pathway participates in myocardial ischemia injury in isolated hearts in rats. The present study aimed to investigate the cytoprotective action of H2S against acute myocardial ischemia injury in rats. Isolated rat hearts were perfused and subjected to ischemic conditions for 4 h. The hearts were assigned to five groups: Sham, model, infarct plus low-dose (5 µmol/l) NaHS, infarct plus middle-dose (10 µmol/l) NaHS and infarct plus high-dose (20 µmol/l) NaHS. The administration of NaHS enhanced the activity of CSE, increased the content of H2S and reduced infarct volumes following myocardial ischemia injury. Furthermore, the administration of NaHS attenuated the injury to organelles (including the mitochondria, nucleus and myofilaments) by reducing lactate dehydrogenase activity, decreasing the level of mitochondrial malondialdehyde and increasing the activities of superoxide dismutase and glutathione peroxidase in the ischemic myocardial mitochondria. These protective effects of H2S against myocardial ischemia injury appeared to be mediated by its antioxidant activities and the preservation of mitochondrial function.

Chinese medicinal formula Guanxin Shutong capsule protects the heart against oxidative stress and apoptosis induced by ischemic myocardial injury in rats

Guanxin Shutong capsule (GXSTC) is a Chinese medicinal formula that has been used clinically for the treatment of chest pain, depression, palpitation and cardiovascular diseases in China for almost 10 years. The aim of the present study was to investigate the protective mechanisms against oxidative stress and apoptosis that GXSTC exhibits in the hearts of rats with myocardial ischemia (MI). Infarct size and the levels of marker enzymes, including serum creatine kinase-isoenzyme (CK-MB), lactate dehydrogenase (LDH) and glutamate oxaloacetic transaminase (GOT), as well as the levels of nitric oxide (NO) and NO synthase (NOS) in the heart were measured by biochemical analysis assays. Levels of the antioxidants superoxide dismutase (SOD), catalase (CATA), and glutathione (GSH), and the oxidative stress marker malondialdehyde (MDA), were also determined. Following a 6-week period of ischemia, myocardial apoptosis, as well as the protein and mRNA expression of NADPH oxidase, was evaluated. Myocardial NADPH oxidase activity was measured by protein expression of p47phox and gp91phox using western blot analysis and mRNA expression of p22phox, p47phox, p67phox and gp91phox using reverse transcription polymerase chain reaction. The results showed that daily oral treatment of the rats with GXSTC reduced infarct size, myocardial apoptosis, the levels of serum MDA, LDH, CK-MB and GOT and heart GOT, and increased the activities of total SOD, CATA, NOS and the levels of NO and GSH compared with those in vehicle-treated MI model rats. Administration of GXSTC for 6 weeks also reduced the mRNA expression of the NADPH oxidase subunits p47phox and gp91phox protein, as well as the expression of Bax and caspase-3 proteins. By contrast, Bcl-2 protein expression increased. In conclusion, the results demonstrate that GXSTC attenuates myocardial injury via antioxidative and antiapoptotic effects.

Effects of hydrogen sulfide on inflammatory factors in acute myocardial ischemia injury in rats

Effects of hydrogen sulfide on inflammatory factors in acute myocardial ischemia injury in rats

Evaluation of the anti-myocardial ischemia effect of individual and combined extracts of Panax notoginseng and Carthamus tinctorius in rats

Ethnopharmacological relevanceThe decoction of combined Panax notoginseng (Burk) F.H. Chen and Carthamus tinctorius L. has a history of use in traditional medicine for the prevention and treatment of cardiovascular diseases such as angina pectoris and myocardial infarction. Aim of the studyIn this study, we investigated the effects of individual herbal extracts and combined extracts on anti-myocardial ischemia injuries in vivo, and determined the proper dosage of Panax notoginseng (EPN) combined with Carthamus tinctorius (ECT) that could strengthen their cardio-protective effects. Meanwhile, their potential anti-oxidative stress and anti-inflammation effect were assessed. Material and MethodsSD rats were orally given individual EPN 50, 100mg/kg, ECT 100, 200mg/kg, and different combinations between them. Myocardial infarction was produced by occlusion of the left anterior descending coronary artery for 24h. Infarct area was determined with 2,3,5-triphenyltetrazolium chloride (TTC) staining. The biomarkers related to myocardial ischemia injury were determined. Simultaneously, hemodynamic parameters were monitored as left ventricular systolic pressure (LVSP), LV end-diastolic pressure (LVEDP) and maximal rate of increase and decrease of left ventricular pressure (dP/dtmax). The oxidative stress indicators and inflammatory factors were also evaluated. ResultsThe results showed EPN or ECT significantly reduced infarct size, improved cardiac function, decreased levels of creatine kinase (CK) and lactate dehydrogenase (LDH) (all P<0.05 vs. control ). EPN or ECT alone also restrained the oxidative stress related to myocardial ischemia injury as evidenced by decreased malondialdehyde (MDA) and elevated superoxide dismutase (SOD) activity (all P<0.05 vs. control). However, this cardio-protective effect was further strengthened by their combinations. Among all the combinations, EPN 50mg/kg plus ECT 200mg/kg showed predominant potential to reduce infarct size (22.21±1.72%, P<0.05 vs. each single, respectively), preserve cardiac function (P<0.05 vs. ECT 200mg/kg for LVEDP and −dP/dtmax) after myocardial ischemia injury in rats. This heart protection was confirmed with the lowered cardiac troponin I (cTnI) (P<0.05 vs. ECT 200mg/kg and EPN 50mg/kg, respectively). Oxidative stress and inflammation are the two key factors in the pathogenesis of myocardial ischemia injury. In the present study, EPN 50mg/kg plus ECT 200mg/kg markedly increased SOD and GSH-Px activity (475.30±23.60U/ml, P<0.05 vs. each single, respectively), while elevated MDA level was significantly depressed. Meanwhile, the inflammatory cascade was inhibited as evidenced by decreased cytokines such as tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and interleukin-1β (IL-1β). ConclusionThese results demonstrated EPN, ECT and their combinations exhibited significant cardio-protective effects. The findings suggest EPN combined with ECT may be therapeutically more useful for ameliorating anti-myocardial ischemia injuries than individual herbal extract, and EPN 50mg/kg plus ECT 200mg/kg is the appropriate combination in the present research. The cardio-protective effect of this combination was achieved partially by decreasing oxidative stress and repressing inflammatory cascade.

Dan-Shen-Yin protects the heart against inflammation and oxidative stress induced by acute ischemic myocardial injury in rats

Dan-Shen-Yin (DSY) is a well-known traditional Chinese formula which is widely used in clinical practice for the treatment of coronary heart disease (CHD) and has produced a favorable effect in China. The present study was designed to examine whether or not acute oral DSY can protect the heart against myocardial infarction in acute myocardial ischemic rats. If so, we would then investigate the anti-inflammatory and anti-oxidant mechanisms involved. The left anterior descending coronary artery was occluded to induce myocardial ischemia in the hearts of Sprague-Dawley rats. At the end of the 3-h ischemic period (or 24 h for infarction size), we measured the myocardial infarction size, inflammatory factors and the activities of anti-oxidative enzymes. DSY reduced the infarction size and the serum levels of C-reactive protein, interleukin-6, tumour necrosis factor-α and malondialdehyde and increased the activities of superoxide dismutase and the serum levels of glutathione. The results show that DSY exerts significant cardioprotective effects against acute ischemic myocardial injury in rats, possibly through its anti-inflammatory and anti-oxidant properties, and may thus be used as a potential therapeutic reagent for the treatment of CHD.

Hypoxia-inducible Vascular Endothelial Growth Factor-engineered Mesenchymal Stem Cells Prevent Myocardial Ischemic Injury

In the absence of repair mechanisms involving angiogenesis and cardiomyogenesis, loss of cardiomyocytes after myocardial injury is a primary causative factor in the progression toward heart failure. In an effort to reduce ischemic myocardial damage, we investigated the effects on infarcted myocardium of transplantation of genetically modified mesenchymal stem cells (MSCs) that specifically expressed vascular endothelial growth factor (VEGF) under hypoxic conditions. A hypoxia-inducible VEGF expression vector was introduced into MSCs (HI-VEGF-MSCs) using a nonviral delivery method, which were then used for the treatment of ischemic myocardial injury in rats. In HI-VEGF-MSCs, VEGF expression was significantly increased by hypoxia in vitro as compared to normoxia. Likewise, in vivo administration of HI-VEGF-MSCs induced ischemia-responsive VEGF production, leading to a significant increase in myocardial neovascularization after myocardial infarction. When compared with unmodified-MSCs, HI-VEGF-MSCs were retained in infarcted myocardium in greater numbers and remarkably reduced the number of apoptotic cells the infarcted area. Transplantation of HI-VEGF-MSCs resulted in a substantial attenuation of left ventricular remodeling in rat myocardial infarction. This study demonstrates that cell-based gene therapy using genetically engineered MSCs to express VEGF in response to hypoxic stress can be a promising therapeutic strategy for the treatment of ischemic heart disease.

Study on the structure–function relationship of 20(S)-panaxadiol and its epimeric derivatives in myocardial injury induced by isoproterenol

This study was aimed to investigate structure–function relationship of 20(S)-panaxadiol (PD) and its epimeric derivatives ((20S, 24S)-epoxy-dammarane-3β, 12β, 25-triol, PDD1 and (20S, 24R)-epoxy-dammarane-3β, 12β, 25-triol, PDD2) in myocardial ischemia injury in rats. It was shown that PD and PDD2 resulted in a reduction in creatine kinase activity. PD and PDD2 inhibited the elevation of malondialdehyde content, the reduction of superoxide dismutase and glutathione peroxidase activities. The pathohistological changes were ameliorated by PD and PDD2. The configuration of C-24 of funan ring was linked to the pharmacological action of 20(S)-panaxadiol and its epimeric derivatives.