Boeravinone B alleviates gut dysbiosis during myocardial infarction-induced cardiotoxicity in rats

Myocardial infarction (MI) is the most common heart disease, and also, it is one of the leading causes of death from cardiovascular disease. It is well known that MI causes additional injury during blood flow restoration in ischaemic myocardium. Boeravinone B (BB) is a well-known antioxidant and anti-inflammatory drug. We investigated the cardioprotective effect of BB drug against isoproterenol (ISO)-induced MI in rats in this experimental study, along with we analysed its underlying mechanism. Adult Sprague Dawley (SD) rats were treated subcutaneously with ISO (45 mg/kg), then divided into groups and then given BB drug was administered orally. The cardioprotective effect of BB on ISO-induced MI rats was analysed by estimating the heart injury markers, antioxidant pro-inflammatory cytokines and inflammatory parameters. We also detected quantified expression of inflammation and apoptosis-related marker protein family. We estimated the effect of BB drug on GUT microbiota in ISO-induced MI rats and scrutinized the histopathological variations in heart tissues. BB treatment significantly (P < .001) diminished the level of heart markers such as lactate dehydrogenase (LDH), troponin (TnT), creatine kinase (CK) and creatine kinase isoenzymes MB (CK-MB). BB treatment also altered the antioxidant parameters and reduced the pro-inflammatory cytokines in the serum and tissues. Additionally, the histopathological aspects demonstrated that the pathological changes observed in the heart tissue of the ISO group rats were suppressed by the BB treatment to varying degrees. Furthermore, the expressions of caspase-3, p53, caspase-9, Bax, interleukin-6 (IL-6), cytochrome C, neutrophil gelatinase-associated lipocalin (NGAL), tumour necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB) and interleukin-1β (IL-1β) in the heart tissue were down-regulated whereas the Bcl-2 expression seemed to be enhanced. BB treatment not only alleviated ISO-induced gut dysbiosis by its enhanced specified Firmicutesto-Bacteroidetes (F/B) ratio but also maintained the relative abundance of major bacteria such as Clostridium IV, Butyricicoccus, Clostridium XIVs, Akkermansia and Roseburia. Collectively, our findings showed that the BB drug acted against myocardial infraction and prevented the damage by reducing the oxidative stress and controlling the inflammatory pathways, and gut microbiota.     

Protective effect of morin on cardiac mitochondrial function during isoproterenol-induced myocardial infarction in male Wistar rats

Abstract

Altered mitochondrial function and free radical-mediated tissue damage have been suggested as an important pathological event in isoproterenol (ISO)-induced cardiotoxicity. This study was undertaken to know the preventive effect of morin on mitochondrial damage in ISO-induced cardiotoxicity in male Wistar rats. Myocardial infarction (MI) in rats was induced by ISO (85 mg/kg) at an interval of 24 hours for 2 days. Morin was given to rats as pre-treatment for 30 days orally using an intragastric tube. ISO-treated rats showed a significant elevation of mitochondrial thiobarbituric acid reactive substances (TBARS) and hydrogen peroxide (HP) level and pre-treatment with morin significantly prevented the increase of TBARS and HP level to near normality. The level of enzymic and non-enzymic antioxidants was decreased significantly in ISO-treated rats and pre-treatment with morin significantly increased the levels of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase, and reduced glutathione to normality. The activities of mitochondrial enzymes such as isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase were decreased significantly in ISO-treated myocardial ischemic rats and upon pre-treatment with morin restored these enzymes activity to normality. In addition, the decreased activities of cytochrome-C oxidase and NADH-dehydrogenases were observed in ISO-treated rats and pre-treatment with morin prevented the activities of cytochrome-C oxidase and NADH-dehydrogenase to normality. Pre-treatment with morin favorably restored the biochemical and functional parameters to near normal indicating morin to be a significant protective effect on cardiac mitochondrial function against ISO-induced MI in rats.     

Berbamine ameliorates isoproterenol-induced myocardial infarction by inhibiting mitochondrial dysfunction and apoptosis in rats

Berbamine (BBM), a bisbenzylisoquinoline alkaloid from roots, bark, and stem of Berberis plant such as Berberis aristata has a wide range of pharmacological activities. However, the evidence for the cardioprotective effect of BBM is inadequate and the molecular mechanism of BBM remains unclear. This study investigated the underlying molecular mechanism of BBM-mediated cardioprotection on isoproterenol (ISO)-induced mitochondrial dysfunction and apoptosis in rats. The assays of mitochondria antioxidant status, mitochondrial marker enzymes, and electron microscopic analysis of mitochondria revealed BBM significantly prevented the mitochondrial dysfunction induced by ISO. The ISO-induced elevation of mitochondrial oxidative stress was also curbed by BBM. Furthermore, pretreatment with BBM protected the heart tissue from ISO-induced apoptosis as evident from decreased terminal dUTP nickend-labeling positive cells and decreased expression of Bax, cytochrome c, cleaved caspase-9, and caspase-3, and poly (ADP-ribose) polymerase and increased expression of Bcl-2 in ISO-induced rats. These current findings suggest that BBM exerts a significant cardioprotective effect on ISO-induced myocardial infarction in rats.     

Protective efficacy of ellagic acid on glycoproteins, hematological parameters, biochemical changes, and electrolytes in myocardial infarcted rats

The cardioprotective property of ellagic acid in rats has been reported previously. The present study reveals the protective role of ellagic acid in biochemical parameters including serum iron, plasma iron binding capacity, uric acid, glycoprotein, and electrolytes along with hematological parameters. Rats were subcutaneously injected with isoproterenol (ISO) (100 mg/kg) for 2 days to induce myocardial infarction. ISO-induced rats showed a significant increase in their levels of serum iron, serum uric acid, and blood glucose, and a significant decrease in their levels of plasma iron binding capacity, serum total protein, albumin/globulin ratio, and heart glycogen, when compared with normal control rats. The altered hematological parameters were also observed in ISO-induced rats when compared with normal control rats. Pretreatment with ellagic acid at doses of 7.5 and 15 mg/kg produced significant beneficial effect by returning all the above-mentioned biochemical and hematological parameters to near normal levels.     

Effect of relaxin on myocardial ischemia injury induced by isoproterenol

The omnipresent 6-kDa polypeptide relaxin (RLX) is emerging as a multifunctional endocrine and paracrine factor in a broad range of target tissues including cardiovascular tissues. To explore the pathophysiological roles of RLX in ischemic cardiovascular diseases, we studied the changes in RLX mRNA level in the myocardium and the effect of RLX supplements in rats with isoproterenol (ISO)-induced myocardial injury. In ISO-treated rats, RLX levels in myocardia and plasma increased 3.7- and 6.9-fold, respectively (P<0.01), the mRNA level increased significantly in myocardia compared with controls. Co-administration of RLX (0.2 and 2.0 microg/kg/d) and ISO increased left-ventricular pressure development and decreased left ventricular end-diastolic pressure (LVDEP) (all P<0.01). Malondialdehyde content in myocardia and lactate dehydrogenase and creatine phosphokinase activities in plasma in RLX-treated rats decreased markedly compared with that in ISO-treated alone rats (P<0.01 or P<0.05). In the high-dose RLX group, fibroblastic hyperplasia was relieved in myocardia, hydroxyproline level was lower, by 33% (P<0.05), and endothelin content in plasma was lower, by 31% (P<0.01) than in the ISO-alone group. Compared with control group, any indexes in sham rats treated with high-dose RLX were unaltered (all P>0.05). These results showed an up-regulation of myocardial RLX during ISO-induced myocardial ischemia injury and the protective effect of RLX on ISO-induced cardiac inhibition and fibrosis, which suggests that RLX could be an endogenous cardioprotective factor in ischemic heart diseases.     

Grape seed proanthocyanidins ameliorates isoproterenol-induced myocardial injury in rats by stabilizing mitochondrial and lysosomal enzymes: an in vivo study

This study was designed to examine the effects of grape seed proanthocyanidins (GSP) against myocardial injury (MI) induced by isoproterenol (ISO), in a rat model. Induction of rats with ISO (85 mg/kg body weight, subcutaneously) for 2 days resulted in a significant decrease in the activities of heart mitochondrial enzymes (isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase and alpha-ketoglutarate dehydrogenase) and respiratory chain enzymes (NADH dehydrogenase and cytochrome c oxidase). The activities of lysosomal enzymes (alpha-d-glucuronidase, alpha-d-N-acetylglucosaminidase, cathepsin-D, acid phosphatases and alpha-d-galactosidase) were increased significantly in the heart and serum of ISO-induced rats. The prior administration of GSP for 6 days a week for 5 weeks significantly increased the activities of mitochondrial and respiratory chain enzymes and significantly decreased the activities of lysosomal enzymes in the heart tissues of ISO-induced rats, which proves the stress stabilizing action of GSP. Oral administration of grape seed proanthocyanidins alone (50, 100 and 150 mg/kg) to normal rats did not show any significant effect in all the parameters studied. These biochemical functional alterations were supported by the macroscopic enzyme mapping assay of ischemic myocardium. Thus, this study shows that 100 and 150 mg/kg of GSP gives protection against ISO-induced MI and demonstrates that GSP has a significant effect in the protection of heart.     

Preventive effect of naringin on lipids, lipoproteins and lipid metabolic enzymes in isoproterenol-induced myocardial infarction in Wistar rats

This study was designed to evaluate the preventive effect of naringin in isoproterenol (ISO)-induced myocardial infarction (MI) in rats. Rats were pretreated with naringin (10, 20, and 40 mg/kg body weight) orally for a period of 56 days. After the treatment period, ISO (85 mg/kg body weight) was administered subcutaneously to rats at an interval of 24 h for 2 days. There was a significant increase in the levels of total, ester, and free cholesterol, triglycerides (TG), and free fatty acids (FFA) in serum and heart and decrease in heart phospholipids (PL) in ISO-induced rats. Altered levels of lipoproteins and activities of 3-hydroxy-3-methylglutaryl-Coenzyme reductase A in liver and heart, lecithin cholesterol acyl transferase and lipoprotein lipase in plasma were also observed in ISO-induced rats. Pretreatment with naringin (10, 20, and 40 mg/kg) for a period of 56 days significantly decreased the levels of total, ester, and free cholesterol, TG, FFA in serum and heart and increased PL in heart. It also minimized the alterations in serum lipoproteins and lipid metabolic enzymes in ISO-induced rats. Thus, naringin has a lipid-lowering effect in ISO-induced MI rats.     

Chronic effects of platinum(IV) complex and its diamine ligand on rat heart function: comparison with cisplatin

Mitochondrial dysfunction plays crucial role in the pathologenesis of myocardial infarction (MI). The present study evaluated the protective effect of α-bisabolol against isoproterenol (ISO)-induced mitochondrial dysfunction and apoptosis in rats. Male albino Wistar rats were pre- and co-treated with intraperitoneal injection of α-bisabolol (25 mg/kg body weight) daily for 10 days. To induce experimental MI, ISO (85 mg/kg body weight) was injected subcutaneously to the rats at an interval of 24 h for 2 days (9th and 10th day). ISO-induced MI was indicated by the decreased activities of heart creatine kinase and lactate dehydrogenase in rats. ISO administration also enhanced the concentrations of heart mitochondrial lipid peroxidation products and decreased the activities/concentrations of mitochondrial antioxidants, Kreb’s cycle dehydrogenases and mitochondrial electron transport chain complexes I, II?+?III and IV in rats. Furthermore, ISO triggers calcium overload and ATP depletion in the rat’s heart mitochondria followed by the mitochondrial cytochrome-C release and the activation of intrinsic pathway of apoptosis by upregulating the myocardial pro-apoptotic Bax, P⁵³, APAF-1, active caspase-3, active caspase-9 and down regulating the expressions of anti-apoptotic Bcl-2. α-Bisabolol pre and co-treatment showed considerable protective effects on all the biochemical and molecular parameters studied. Transmission electron microscopic study and mitochondrial swelling assay confirmed our biochemical and molecular findings. The in vitro study on hydroxyl radical also revealed the potent free radical scavenging activity of α-bisabolol. Thus, α-bisabolol attenuates mitochondrial dysfunction and intrinsic pathway of apoptosis in ISO-induced myocardial infarcted rats.

     

The Novel Mas agonist,CGEN-856S,Attenuates Isoproterenol-Induced Cardiac Remodeling and Myocardial Infarction Injury in Rats

CGEN-856S is a novel Mas agonist. Herein, we examined the effects of this peptide on isoproterenol (ISO)-induced cardiac remodeling and myocardial infarction (MI) injury. We also sought to determine whether CGEN-856S activates the underlying mechanisms related to Mas receptor activation. Heart hypertrophy and fibrosis were induced by ISO (2 mg·kg⁻¹·day⁻¹) in Wistar rats. After a 7-day treatment period with CGEN-856S (90 µg·kg⁻¹·day⁻¹) or vehicle, the cardiomyocyte diameter was evaluated in left ventricular sections stained with hematoxylin and eosin, and immunofluorescence labeling and quantitative confocal microscopy were used to quantify the deposition of type I and III collagen and fibronectin in the left ventricles. MI was induced by coronary artery ligation, and CGEN-856S (90 µg·kg⁻¹·day⁻¹) or saline was administered for 14 days. The Langendorff technique was used to evaluate cardiac function, and left ventricular sections were stained with Masson’s trichrome dye to quantify the infarct area. Using Chinese hamster ovary cells stably transfected with Mas cDNA, we evaluated whether CGEN-856S alters AKT and endothelial nitric oxide synthase (eNOS) phosphorylation. CGEN-856S reduced the degree of ISO-induced hypertrophy (13.91±0.17 µm vs. 12.41±0.16 µm in the ISO+CGEN-856S group). In addition, the Mas agonist attenuated the ISO-induced increase in collagen I, collagen III, and fibronectin deposition. CGEN-856S markedly attenuated the MI-induced decrease in systolic tension, as well as in +dT/dt and -dT/dt. Furthermore, CGEN-856S administration significantly decreased the infarct area (23.68±2.78% vs. 13.95±4.37% in the MI+CGEN-856S group). These effects likely involved the participation of AKT and NO, as CGEN-856S administration increased the levels of p-AKT and p-eNOS. Thus, our results indicate that CGEN-856S exerts cardioprotective effects on ISO-induced cardiac remodeling and MI-mediated heart failure in rats through a mechanism likely involving the eNOS/AKT pathway.     

Cardioprotective effect of total paeony glycosides against isoprenaline-induced myocardial ischemia in rats

Paeoniae radix is a traditional Chinese medicinal herb for treating some diseases; important components are total paeony glycosides (TPGs), an approved drug by the State Food and Drug Administration (SFDA) for the therapy of rheumatoid arthritis (RA). We firstly reported myocardial benefits of TPGs previously, and the present study is to further investigate the underlying mechanisms for preventing oxidative damage in cardiomyopathy. We measured the capacity of TPGs to scavenge free radicals in vitro. Then 60 SD rats were randomly divided into five groups: (1) a normal control group, (2) an isoprenaline (ISO)-induced myocardial ischemic model group, (3) a TPG treatment group (TPGs 269.4 mg/kg delivered by intragastric administration for 3 days before ISO administration and TPGs 449 mg/kg delivered for 3 days after ISO administration), (4) a TPG therapy group (TPGs 449 mg/kg delivered for 3 days after ISO administration), and (5) a positive control group (propranolol 15 mg/kg for 3 days after ISO administration). The ISO-induced myocardial ischemic model was established by subcutaneous injection of 1mg/kg/8h ISO (2 times). The activities of myocardial enzymes, including glutamic oxaloacetic transaminase (GOT), creatine kinase (CK), lactate dehydrogenase (LDH), antioxidant enzyme superoxide dismutase (SOD) as well as the content of lipid peroxidation product malondialdehyde (MDA) were detected. We found that TPGs potently eliminated hydroxyl radicals and superoxide in vitro using ESR assays. Compared with model rats, TPG treatment, TPG therapy and the positive control treatment exhibited significantly reduced activities of GOT, LDH, and CK (p < 0.01), increased activity of SOD (p < 0.01) and lower levels of MDA (p < 0.05). More interestingly, the protective effect of TPG treatment was even better than that of propranolol. These results suggest that TPGs significantly ameliorate ISO-induced myocardial ischemia and their action might be through reducing oxidative stress in ischemic myocardium.     

Cardioprotective activity of ethyl acetate extract of Cinnamomi Ramulus against myocardial ischemia/reperfusion injury in rats via inhibiting NLRP3 inflammasome activation and pyroptosis

BackgroundNLRP3 inflammasome activation and pyroptosis play an important role in myocardial ischemia/reperfusion injury (MI/RI). Cinnamomi ramulus (CR), is an important folk medicinal plant in China, which derived from the dried twig of Cinnamomum cassia (L.) Presl, has function of “warming and tonifying heart yang”, and traditionally utilized to treat the cold, blood-cold amenorrhea, phlegm, edema, arthralgia, and palpitations as well as improve blood circulation. The aqueous extract of C. ramulus was reported to show significant therapeutic potential for treating MI/RI. Whereas, there are no previous investigations in China or abroad has reported the cardioprotective effects and underlying mechanism of the ethyl acetate extract of C. ramulus (CREAE) and its bioactive substance cinnamic acid (CA) in triggering NLRP3 inflammasome activation and subsequent pyroptosis.PurposeThe present study aimed to assess the cardioprotective function of CREAE and CA against the MI/RI in rats and involved the underlying mechanisms.MethodsThe MI/RI model was established in male SD rats by occlusion of the left anterior descending coronary artery for 30 min followed by reperfusion for 120 min, respectively. The rats were intragastrically administered with CREAE (74 and 37 mg/kg) and CA (45 mg/kg) for 7 successive days before vascular ligation. The cardioprotective effects of CREAE and CA against myocardial injury of rats were detected by HE staining, TTC staining, echocardiograms, and myocardial enzymes detections. Serum levels of inflammatory factors, such as IL-6, IL-1β, and TNF-α, were analyzed by ELISA kits to evaluate the effects of CREAE and CA. The protein and gene expression levels of NLRP3 and the pyroptosis-related factors in heart tissue were conducted by western blot and RT-qPCR.ResultsOur results showed that CREAE and CA decrease myocardial infarct size and improve cardiac function, mitigate myocardial damage, and repress inflammatory response in rats after I/R. Mechanistically, our results revealed that CREAE and CA can dramatically suppress the activation of NLRP3 inflammasome and subsequent cardiomyocyte pyroptosis in myocardial tissues that as evidenced by downregulating the protein and gene expressions of NLRP3, ASC, IL-1β, caspase-1, gasdermin D, and N-terminal GSDMD.ConclusionsOur data indicated that CREAE and CA may attenuate MI/RI through suppression of NLRP3 inflammasome and subsequent pyroptosis-related signaling pathways.     

Ethanolic Zingiber officinale R. extract pretreatment alleviates isoproterenol-induced oxidative myocardial necrosis in rats

Ethanolic Z. officinale (ZO) extract (200 mg/kg) pretreatment for 20 days in isoproterenol (ISO)-treated rats significantly increased the levels of endogenous myocardial antioxidants (catalase, superoxide dismutase and tissue glutathione), decreased the levels of serum marker enzymes (lactate dehydrogenase, creatine kinase, aspartate transaminase and alanine transaminase) and increased myocardial lipid peroxides. Histological examination of rat's heart section confirmed myocardial injury with ISO administration and near normal pattern with ethanolic ZO extract pretreatment. The results of the present study, for the first time, provide clear evidence that the ethanolic ZO extract pretreatment enhances the antioxidant defense against ISO-induced oxidative myocardial injury in rats and exhibit cardioprotective property.     

Protective effects of syringic acid,resveratrol and their combination against isoprenaline administered cardiotoxicity in wistar rats

ObjectiveTo evaluate the cardio-protection of syringic acid (SA) in combination with resveratrol (RV) in isoproterenol (ISO) induced myocardial infarcted (MI) rats.MethodsGroups of all rats were subjected oral pre-treatment at the beginning of the study with SA (50 mg/kg), RV (50 mg/kg) and combination (COMB) of SA (25 mg/kg) and RV (25 mg/kg) along with gallic acid (GA) (50 mg/kg) for 30 days. After sacrification, homogenate of heart tissue along with serum were utilized for further biochemical investigations. The effects on creatine kinase (CK), aspartate transaminase (AST), alanine transaminase (ALT) and gamma glutamyl transferase (GGT) were studied in serum and heart tissues. Glutathione-s-transferase (GST), glutathione peroxidase (GPX) and reduced glutathione (GSH), membrane bound enzymes and electrolytes were tested in heart tissues. Body weights and heart weights were also observed along with high sensitivity C-reactive protein (hs-CRP), uric acid and total protein content (TPC) in serum.ResultsCK, AST, ALT and GGT levels in serum were augmented significantly while these enzymes are decreased in cardiac tissue samples of ISO–treated rats. GST, GPX, GSH, Na⁺/K⁺, Mg²⁺, Ca²⁺ ATPases, K⁺ ions were significantly decreased while Na⁺ and Ca²⁺ ions were increased in the heart tissues of ISO-injected rats. Loss and gain of body and heart weights were noticed significantly in rats having ISO administration. ISO group showed significant increase in hs-CRP and Uric acid while significant decrease in TPC. All of actions of ISO were ameliorated by COMB.ConclusionsCOMB suppressed ISO induced MI in rats and exhibited cardio-protection.     

Insulin inhibits β-adrenergic action in ischemic/reperfused heart: a novel mechanism of insulin in cardioprotection

Objective Sympathetic overactivity is closely connected with cell injury and contractile dysfunction during myocardial ischemia/reperfusion (MI/R). Insulin exerts protection for the I/R heart and the underlying mechanisms remain unclear. This study aimed to investigate the ability of insulin to modulate β-adrenergic actions on myocardial contraction and post-ischemic injury in acute MI/R and the underlying mechanism. Methods Isolated hearts from adult SD rats were subjected to MI/R (30 min/2 h) and treated with isoproterenol (ISO) or/and insulin. Myocardial contraction, cardiomyocyte apoptosis, myocardial injury and infarction were assessed. In a separate study, isolated ventricular myocytes were subjected to simulated I/R (15/30 min) and myocyte shortening and intracellular Ca²⁺ transient in response to ISO during reperfusion were assessed with presence or absence of insulin. Results In isolated I/R hearts, insulin largely reversed the ISO-associated contractile functional impairment at 2 h after MI/R, inhibiting ISO-induced declines in heart rate and left ventricular systolic pressure by 34.0% and 23.0% and preventing ISO-induced elevation in left ventricular end-diastolic pressure by 28.7% respectively (all P < 0.05). In addition, ISO alone resulted in enlarged infarct size, elevated CK and LDH activity and increased apoptotic index in I/R hearts compared with vehicle, which were inhibited by treatment of insulin (all P < 0.05). Interestingly, in SI/R cardiomyocytes, insulin alone at 10⁻⁷ mol/l increased cell contraction whereas attenuated the positive inotropic response to ISO (10⁻⁹ mol/l) during R as evidenced by a 18.7% reduction in peak twitch amplitude and a 23.9% reduction in calcium transient amplitude (both P < 0.05). Moreover, insulin blunted ISO-mediated increase in PKA activity, enhanced the PKA-dependent phosphorylation of phospholamban (PLB), resulting in increased sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a) activity. Conclusion Insulin attenuated the contractile response to β-AR stimulation and suppressed ISO-elicited cardiac dysfunction and cell injury in MI/R. The inhibitory effect of insulin on the β-adrenergic action involved the inhibition of PKA-mediated Ca²⁺ transient and promotion of post-ischemic Ca²⁺ handling.     

Cardioprotective effect of aqueous extract of Embelia ribes Burm fruits against isoproterenol-induced myocardial infarction in albino rats

In the present study, cardioprotective effect of aqueous extract of fruits of Embelia ribes Burm (ER) was evaluated in a rat model having acute myocardial infarction, induced by isoproterenol (5.25 and 8.5 mg/kg, sc, for two consecutive days). Aqueous ER extract (100 mg/kg) pretreatment orally for 40 days in isoproterenol (ISO)-treated rats significantly decreased the heart rate, systolic blood pressure, increased levels of serum lactate dehydrogenase, serum creatine kinase and myocardial lipid peroxides and significantly increased the myocardial endogenous antioxidants (glutathione, superoxide dismutase and catalase) levels. The results of biochemical observations in serum and heart tissues were supplemented by histopathological examination of rat's heart sections to confirm the myocardial injury. The results were comparable to that of gliclazide treated group. The present results provide evidence for the first time, that aqueous ER extract pretreatment ameliorated myocardial injury and enhanced the antioxidant defense against ISO-induced myocardial infarction in rats and exhibited cardioprotective property.     

Protocatechuic acid reverses myocardial infarction mediated by β-adrenergic agonist via regulation of Nrf2/HO-1 pathway,inflammatory, apoptotic,and fibrotic events

Myocardial infarction (MI) is an instant ischemic death of cardiomyocytes that remains a major global cause of mortalities. MI is accompanied by oxidative, inflammatory, apoptotic, and fibrotic insults. Protocatechuic acid (PCA) is a polyphenolic compound with various potent biological activities. In this study, we explored the possible cardioprotective role of PCA against isoproterenol (ISO)-mediated MI. Rats were either injected with ISO (85 mg/kg, subcutaneously) or pretreated with PCA (100 or 200 mg/kg, orally). PCA supplementation markedly normalized ISO-induced disturbed cardiac function markers (creatine kinase-MB, lactate dehydrogenase, and troponin T). Notably, PCA administration exerted remarkable increases in glutathione and its derived enzymes, superoxide dismutase, and catalase, as well as decreases in malondialdehyde and nitric oxide levels in the injured cardiac tissue. The molecular findings validated the augmented cellular antioxidative capacity by PCA via increasing the gene expressions of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1. The cardioprotective efficacy of PCA extended to suppress cardiac inflammation as demonstrated by the decreased levels of tumor necrosis factor-alpha, interleukin-1 beta, and nuclear factor kappa B. Additionally, PCA prevented cardiomyocyte loss and fibrosis by decreasing Bax, caspase-3, transforming growth factor-β1 and matrix metalloproteinase-9, and enhancing B-cell lymphoma 2 and tissue inhibitors of metalloproteinase-3. The cardiac histological screening further confirmed the PCA's protective action. The obtained data recommend PCA as an alternative therapeutic agent to attenuate the molecular, biochemical, and histological alterations associated with MI development.     

Preconditioning with diosgenin and treadmill exercise preserves the cardiac toxicity of isoproterenol in rats

This study was aimed to evaluate the preventive effect of diosgenin and exercise on tissue antioxidant status in isoproterenol-induced myocardial infarction (MI) in male Wistar rats. Levels of lipid peroxides, reduced glutathione (GSH), and the activities of glutathione-dependent antioxidant enzymes (glutathione peroxidise and glutathione reductase) and antiperoxidative enzymes (catalase and superoxide dismutase) in the plasma and the heart tissue of experimental groups of rats were determined. Pretreatment with diosgenin and exercise exerted an antioxidant effect against isoproterenol-induced myocardial infarction by blocking the induction of lipid peroxidation. A tendency to prevent the isoproterenol-induced alterations in the level of GSH, in the activities of glutathione-dependent antioxidant enzymes and antiperoxidative enzymes was also observed. Histopathological findings of the myocardial tissue showed a protective role for combination of diosgenin and exercise in isoproterenol (ISO)-treated rats. Thus, the present study reveals that preconditioning with diosgenin and exercise exerts cardioprotective effect against ISO-induced MI due to its free radical scavenging and antioxidant effects, which maintains the tissue defense system against myocardial damage.     

Protective effects of N-acetyl cysteine on lipid peroxide metabolism on isoproterenol-induced myocardial infarcted rats

The present study was designed to evaluate the preventive effects of N-acetyl cysteine on lipid peroxide metabolism in isoproterenol (ISO) induced myocardial infarcted rats. Male albino Wistar rats were pretreated with N-acetyl cysteine (5 and 10 mg/kg) daily for a period of 14 days. After the pretreatment period, ISO (100 mg/kg) was subcutaneously injected to rats twice at an interval of 24 h. Increased activities of serum creatine kinase, creatine kinase-MB, lactate dehydrogenase, and increased intensities of serum lactate dehydrogenase-isoenzyme bands (LDH-1, LDH-2) were observed in ISO-induced rats. The heart lipid peroxidation products were significantly increased, and the antioxidant system was significantly reduced in ISO-induced rats. Pretreatment with N-acetyl cysteine (5 and 10 mg/kg) to ISO-induced rats showed significant effects on all the biochemical parameters studied. Histopathological findings of the myocardium also showed the protective role of N-acetyl cysteine in ISO-induced rats. Furthermore, in vitro study confirmed the potent-free radical scavenging activity of N-acetyl cysteine. The effect at a dose of 10 mg/kg of N-acetyl cysteine was more pronounced than the dose, 5 mg/kg. The results of our study show that N-acetyl cysteine protects the heart against ISO-induced myocardial infarction by its free radical scavenging effect.     

Inhibition of NADPH oxidase by apocynin promotes myocardial antioxidant response and prevents isoproterenol-induced myocardial oxidative stress in rats

Preventive and/or therapeutic interventions for ischemic heart disease have gained considerable attention worldwide. We investigated the mechanism(s) underlying cardioprotection of apocynin (APO) and whether it attenuates isoproterenol (ISO)-induced myocardial damage in vivo. Thirty-two male Wistar Albino rats were randomised into four groups (n?=?8 for each group): Group I (Control); Group II (ISO), ISO was given intraperitoneally (ip) (150?mg/kg/d) daily for 2 consecutive days; Group III (APO?+?ISO), APO was applied ip 20?mg/kg 30?min before the first ISO administration and continued for the next 2 d after the second ISO administration; Group IV (ISO?+?APO), after the ISO treatment on days 1 and 2, 20?mg/kg APO was given ip on days 3 and 4. Cardioprotective effects of APO were evaluated by biochemical values, histopathological observations and the antiapoptotic relative proteins. Mean blood pressure, heart rate, and electrocardiography (ECG) were also monitored. Malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), total oxidant status (TOS), total antioxidant capacity (TAC), oxidative stress index (OSI), caspase-3 and connexin 43 levels were determined. Major ECG changes were observed in the ISO-treated rats. MDA, TOS, OSI and creatine kinase levels decreased and SOD, CAT, GSH and TAC levels increased, indicating that APO reduced cardiac injury and oxidative stress compared with controls. APO also decreased the number of cardiomyocytes with pyknotic nuclei, inflammatory cell infiltration, intracytoplasmic vacuolisation and myofibrils. APO provides preventive and therapeutic effects on ISO-induced myocardial injury in rats by inhibiting reactive oxygen species production, blocking inflammation and enhancing antioxidant status.     

Apelin protects myocardial injury induced by isoproterenol in rats

We aimed to explore the change in level of apelin and its receptor APJ during myocardial injury and the therapeutic effects of apelin in myocardial injury. Rat myocardial injury was induced by subcutaneous injection of a high dose of isoproterenol (ISO); apelin and APJ mRNA levels were determined by RT-PCR; APJ protein was determined by Western blot; EIA and RIA were used to measure the apelin content and receptor binding, respectively. Plasma lactate dehydrogenase (LDH) activity and myocardial and plasma malondialdehyde (MDA) contents were higher in ISO-treated hearts than that in controls. ISO-treated rats showed lower +/-LV dp/dt(max) values and higher LVEDP value (all P<0.01), which suggested severe heart failure. As well, the apelin content in plasma, atrial and ventricular myocardium was decreased by 27%, 30% and 25% (P<0.01), respectively. The mRNA levels of apelin and APJ in myocardia were also markedly reduced; but the APJ protein level in myocardia was increased. However, administration of apelin significantly ameliorated myocardial injury and ISO-induced heart failure. Compared with the ISO-alone group, the group given low-dosage apelin (5 nmol/kg/day) had 39% and 66% higher +LV dp/dt(max) and -LV dp/dt(max) values, and 40.7% lower LVEDP value (P<0.01), and the leakage of myocardial LDH and increased MDA content were attenuated (all P<0.01). Interestingly, bolus injections of apelin (10 nmol/kg/day) resulted in potent inotropic effects in ISO-treated rats. ISO-induced myocardial injury resulted in hypoexpression of apelin and its receptor APJ, and the administration of exogenous apelin ameliorated heart failure and myocardial injury. Apelin could have a cardioprotective effect, and the apelin-APJ system may be a new therapeutic target in myocardial injury and heart failure.