Isoproterenol-induced Cardiac Injury Research Articles

Neferine Pretreatment Attenuates Isoproterenol-Induced Cardiac Injury Through Modulation of Oxidative Stress, Inflammation, and Apoptosis in Rats.

Heart attacks, also known as myocardial infarctions (MIs), are one of the main reasons people die from cardiovascular diseases (CVDs) worldwide. Neferine, an alkaloid derived from Nelumbo nucifera seeds, has garnered interest due to its purported medicinal effects. In the current research, we induced MI in rats using the β-adrenergic agonist isoproterenol to investigate whether neferine can improve cardiac dysfunction. The rats were separated into four groups: control, isoproterenol (ISO), and two treatment groups received neferine at doses of 10 or 20mg/kg once daily for 28days. On days 27 and 28, the groups undergoing treatment were administered with an ISO injection. Results showed that pretreatment with neferine strongly protected against changes in lipid profiles and cardiac functional markers in ISO-administered rats. Neferine attenuated histopathologic changes, collagen deposition, and myocardial fibrosis in rats administered ISO. Neferine pretreatment significantly inhibited the oxidative stress, inflammatory, and apoptotic markers in the heart of ISO-injected rats. This was achieved through Nrf2/Keap1/ARE signaling stimulation, TLR4/NF-κB/MAPK-mediated signaling inhibition, and activation of the intrinsic apoptotic pathway. Using CB-Dock-2, researchers determined that neferine has a high binding affinity with protein receptors that are pivotal in several biological processes. In conclusion, the study provides strong evidence that pretreatment with neferine protects rats from ISO-induced heart damage.

PGRMC1 Ablation Protects from Energy-Starved Heart Failure by Promoting Fatty Acid/Pyruvate Oxidation.

Heart failure (HF) is an emerging epidemic with a high mortality rate. Apart from conventional treatment methods, such as surgery or use of vasodilation drugs, metabolic therapy has been suggested as a new therapeutic strategy. The heart relies on fatty acid oxidation and glucose (pyruvate) oxidation for ATP-mediated contractility; the former meets most of the energy requirement, but the latter is more efficient. Inhibition of fatty acid oxidation leads to the induction of pyruvate oxidation and provides cardioprotection to failing energy-starved hearts. One of the non-canonical types of sex hormone receptors, progesterone receptor membrane component 1 (Pgrmc1), is a non-genomic progesterone receptor associated with reproduction and fertility. Recent studies revealed that Pgrmc1 regulates glucose and fatty acid synthesis. Notably, Pgrmc1 has also been associated with diabetic cardiomyopathy, as it reduces lipid-mediated toxicity and delays cardiac injury. However, the mechanism by which Pgrmc1 influences the energy-starved failing heart remains unknown. In this study, we found that loss of Pgrmc1 inhibited glycolysis and increased fatty acid/pyruvate oxidation, which is directly associated with ATP production, in starved hearts. Loss of Pgrmc1 during starvation activated the phosphorylation of AMP-activated protein kinase, which induced cardiac ATP production. Pgrmc1 loss increased the cellular respiration of cardiomyocytes under low-glucose conditions. In isoproterenol-induced cardiac injury, Pgrmc1 knockout resulted in less fibrosis and low heart failure marker expression. In summary, our results revealed that Pgrmc1 ablation in energy-deficit conditions increases fatty acid/pyruvate oxidation to protect against cardiac damage via energy starvation. Moreover, Pgrmc1 may be a regulator of cardiac metabolism that switches the dominance of glucose-fatty acid usage according to nutritional status and nutrient availability in the heart.

Melatonin Supplement Plus Exercise Effectively Counteracts the Challenges of Isoproterenol-Induced Cardiac Injury in Rats.

To explore the combined effects of exercise and melatonin supplement against the challenges of isoproterenol-induced cardiac oxidative stress and injury in rats., the expression of peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α), mitochondrial biogenesis, and adenosine triphosphate (ATP) was up-regulated in cardiac muscle in normal rats and in a melatonin and exercise regimented group. Cardiac injury was induced by two subcutaneous injections of isoproterenol in the rats. The combination of exercise and melatonin supplement successfully counteracted the isoproterenol-induced cardiac injury, which is reflected by the improved hemodynamic parameters, reduction in oxidative stress markers, and cardiac injury serum markers (cardiac troponin-I and creatine kinase-MB). The cardiac tissue level of ATP, expression of PGC-1α and mitochondrial biogenesis-related genes, mitochondrial membrane potential, and the activities of typical antioxidants (glutathione, superoxide dismutase) were preserved, whereas the levels of reactive oxygen species, lipid peroxidation, and inflammatory cytokines were suppressed in the melatonin and exercise regimented (MEI) group compared to the group treated with isoproterenol alone. Furthermore, the expression of endoplasmic reticular stress- and apoptosis-related proteins (Bax, Bcl2, and caspase-3) was also effectively suppressed in the MEI group. Therefore, the present study suggests that melatonin supplement in combination with exercise prevents cardiac injury, possibly through the preservation of mitochondrial function and inhibition of oxidative stress in rats.

6-Shogaol protects against isoproterenol-induced cardiac injury in rats through attenutating oxidative stress, inflammation, apoptosis and activating nuclear respiratory factor-2/heme oxygenase-1 signaling pathway.

The current study investigated the preventive effect of 6-Shogaol on isoproterenol hydrochloride (ISO)-induced myocardial cardiac injury. 6-Shogaol (50 mg/kg b.w.) was administered for 14 days at pretreatment and ISO-induction (85 mg/kg b.w.) for the last two days (13th and 14th days) by subcutaneous injection. Cardiac markers in serum like creatine kinase (CK), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), cardiac troponins T (cTn T) and I (cTn I) increased in ISO-induced rats. Moreover, lipid peroxidative markers like thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides (LOOH) were raised, and the activities/level of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH) were diminished in ISO-treated heart tissue. In addition, inflammatory and nuclear respiratory factor (Nrf)-2 signalling molecules were upregulated in ISO-induced ischemic rats. 6-Shogaol pretreatment decreased the activities of cardiac and lipid peroxidative markers and enhanced the antioxidant status in ISO-induced cardiac injury rats. Further, 6-Shogaol pretreatment inhibited serum inflammatory markers: tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), nuclear factor-kappaB (NF-κB), Nrf-2 molecule and heme oxygenase (HO)-1 in ISO-induced cardial damage rats. We noticed the effect of 6-Shogaol inhibited pro-apoptotic genes like B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Fas, caspase-3, -8, -9, cytochrome C, and inflammatory genes and increased Bcl-2 expression in ISO-treated rats. The cardioprotective activity of 6-Shogaol in rats with ISO-induced myocardial damage may be due to its ability to reduce oxidative stress, inflammation, and apoptosis, perhaps via the Nrf-2/HO-1 signalling pathway.

The protective effect of rivaroxaban with or without aspirin on inflammation, oxidative stress, and platelet reactivity in isoproterenol-induced cardiac injury in rats.

Coronary artery diseases are principal sources of mortality and disability in global human population. Progressively, rivaroxaban is being evaluated for the prevention of atherosclerotic thrombi, particularly with anti-platelet agents. Hence, the current report aimed to investigate the cardioprotective effect of rivaroxaban on isoproterenol (ISO)-induced cardiac injury model in rats and the possible synergistic effect when combined with aspirin. Male Wistar rats were randomly assigned into five different groups. Cardiac injury was induced by subcutaneous injection of ISO (85mg/kg) for 2 consecutive days. Rat tail bleeding time was performed prior to sacrifice. Cardiac enzymes, platelet activity, inflammatory, and oxidative stress biomarkers levels were measured using enzyme-linked immunoassay (ELISA). Pre-administration of rivaroxaban alone and on combination with aspirin prevented ISO-induced increase in cardiac thiobarbituric acid reactive substances (TBARS), interleukin 6 (IL-6), and thromboxane B2 (TXB2) levels. Moreover, a significant prolongation of bleeding time was demonstrated among aspirin, rivaroxaban, and aspirin plus rivaroxaban treated groups. On the other hand, the combination treatment of aspirin plus rivaroxaban showed no marked difference in these biomarkers and bleeding time relative to either drug administered separately. However, a prominent decrease of cardiac 6-keto prostaglandin F1α (6-Keto-PGF1α) level was displayed in the combination treatment when compared with ISO and rivaroxaban-treated groups, whereas no significant improvement was seen in cardiac glycoprotein V (GPV) levels except in aspirin-treated group. The study results demonstrated that rivaroxaban decreases cardiac oxidative stress, inflammation, and platelets reactivity. However, the addition of rivaroxaban to aspirin did not seem to show synergistic antioxidant, anti-inflammatory, or antiplatelet effect.

Cardioprotective Effect of Taxifolin against Isoproterenol-Induced Cardiac Injury through Decreasing Oxidative Stress, Inflammation, and Cell Death, and Activating Nrf2/HO-1 in Mice.

Oxidative stress and inflammation are key components in cardiovascular diseases and heart dysfunction. Herein, we evaluated the protective effects of (+)-taxifolin (TAX), a potent flavonoid with significant antioxidant and anti-inflammatory actions, on myocardial oxidative tissue injury, inflammation, and cell death, using a mouse model of isoproterenol (ISO)-induced acute myocardial injury. Mice were given TAX (25 and 50 mg/kg, orally) for 14 days before receiving two subsequent injections of ISO (100 mg/kg, s.c.) at an interval of 24 h on the 15th and 16th days. The ISO-induced cardiac tissue injury was evidenced by increased serum creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), and lactate dehydrogenase (LDH), along with several histopathological changes. The ISO also induced increased malondialdehyde (MDA) with concomitant declined myocardial glutathione level and antioxidant enzymes activities. Moreover, ISO-induced heart injury was accompained with elevated cardiac NF-κB p65, TNF-α, IL-1β, Bax, and caspase-3, as well as decreased Bcl-2, Nrf2, and HO-1. Remarkably, TAX reduced the severity of cardiac injury, oxidative stress, inflammation, and cell death, while enhancing antioxidants, Bcl-2, and Nrf2/HO-1 signaling in ISO-injected mice. In conclusion, TAX protects against ISO-induced acute myocardial injury via activating the Nrf2/HO-1 signaling pathway and attenuating the oxidative tissue injury and key regulators of inflammatory response and apoptosis. Thus, our findings imply that TAX may constitute a new cardioprotective therapy against acute MI, which undoubtedly deserves further exploration in upcoming human trials.

Cardioprotective effects of alantolactone on isoproterenol-induced cardiac injury and cobalt chloride-induced cardiomyocyte injury.

ObjectivesAlantolactone (AL) is a compound extracted from the roots of Inula Racemosa that has shown beneficial effects in cardiovascular disease. However, the cardioprotective mechanism of AL against hypoxic/ischemic (H/I) injury is still unclear. This research aimed to determine AL’s ability to protect the heart against isoproterenol (ISO)-induced MI injury in vivo and cobalt chloride (CoCl2) induced H/I injury in vitro.MethodsElectrocardiography (ECG), lactate dehydrogenase (LDH), creatine kinase (CK), and cardiac troponin I (cTnI) assays in addition to histological analysis of the myocardium were used to investigate the effects of AL in vivo. Influences of AL on L-type Ca2+ current (ICa-L) in isolated rat myocytes were observed by the patch-clamp technique. Furthermore, cell viability, apoptosis, oxidative stress injury, mitochondrial membrane potential, and intracellular Ca2+ concentration were examined in vitro.ResultsThe results indicated that AL treatment ameliorated the morphological and ECG changes associated with MI, and decreased levels of LDH, CK, and cTnI. Furthermore, pretreatment with AL elevated antioxidant enzyme activity and suppressed ROS production. AL prevented H/I-induced apoptosis, mitochondria damage, and calcium overload while reducing ICa-L in a concentration and time dependent fashion. The 50% inhibiting concentration (IC50) and maximal inhibitory effect (Emax) of AL were 17.29 μmol/L and 57.73 ± 1.05%, respectively.ConclusionAL attenuated MI-related injury by reducing oxidative stress, apoptosis, calcium overload, and mitochondria damage. These cardioprotective effects may be related to the direct inhibition of ICa-L.

Quantitative Proteomics Reveal That Metabolic Improvement Contributes to the Cardioprotective Effect of T89 on Isoproterenol-Induced Cardiac Injury.

BackgroundT89, a traditional Chinese medicine, has passed phase II, and is undergoing phase III clinical trials for treatment of ischemic cardiovascular disease by the US FDA. However, the role of T89 on isoproterenol (ISO)-induced cardiac injury is unknown. The present study aimed to explore the effect and underlying mechanism of T89 on ISO-induced cardiac injury.MethodsMale Sprague-Dawley rats received subcutaneous injection of ISO saline solution at 24 h intervals for the first 3 days and then at 48 h intervals for the next 12 days. T89 at dose of 111.6 and 167.4 mg/kg was administrated by gavage for 15 consecutive days. Rat survival rate, cardiac function evaluation, morphological observation, quantitative proteomics, and Western blotting analysis were performed.ResultsT89 obviously improved ISO-induced low survival rate, attenuated ISO-evoked cardiac injury, as evidenced by myocardial blood flow, heart function, and morphology. Quantitative proteomics revealed that the cardioprotective effect of T89 relied on the regulation of metabolic pathways, including glycolipid metabolism and energy metabolism. T89 inhibited the enhancement of glycolysis, promoted fatty acid oxidation, and restored mitochondrial oxidative phosphorylation by regulating Eno1, Mcee, Bdh1, Ces1c, Apoc2, Decr1, Acaa2, Cbr4, ND2, Cox 6a, Cox17, ATP5g, and ATP5j, thus alleviated oxidative stress and energy metabolism disorder and ameliorated cardiac injury after ISO. The present study also verified that T89 significantly restrained ISO-induced increase of HSP70/HSP40 and suppressed the phosphorylation of ERK, further restored the expression of CX43, confirming the protective role of T89 in cardiac hypertrophy. Proteomics data are available via ProteomeXchange with identifier PXD024641.ConclusionT89 reduced mortality and improves outcome in the model of ISO-induced cardiac injury and the cardioprotective role of T89 is correlated with the regulation of glycolipid metabolism, recovery of mitochondrial function, and improvement of myocardial energy.

Lycorine ameliorates isoproterenol-induced cardiac dysfunction mainly via inhibiting inflammation, fibrosis, oxidative stress and apoptosis

ABSTRACT Alleviating cardiac dysfunction improves the prognosis of heart failure patients. Lycorine is an alkaloid with several beneficial biological properties. Here, we used mice to evaluate the effect of lycorine on cardiac dysfunction elicited by isoproterenol. Mice were divided into four groups: control, lycorine, isoproterenol, and isoproterenol + lycorine. Mice in the combined group were treated daily with 10 mg/kg isoproterenol intraperitoneally for 2 weeks and 5 mg/kg lycorine was given simultaneously intraperitoneally for 4 weeks. Cardiac structure and function were assessed by echocardiography, hematoxylin and eosin staining, and Masson’s trichrome staining. Isoproterenol-induced cardiac dysfunction and histopathological injury that was significantly improved by treatment with lycorine. Western blotting and the quantitative real-time polymerase chain reaction were used to explore the molecular mechanisms of these effects. Levels of the inflammatory cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, were increased by treatment with isoproterenol; these increases were significantly reduced by lycorine, with involvement of the NF-κB signaling pathway. The fibrotic factors, collagen I and collagen III, were increased by isoproterenol and decreased by treatment with lycorine through inhibiting activation of the Smad signaling pathway. In addition, lycorine alleviated oxidative stress as evidenced by a reduction in total reactive oxygen species in the isoproterenol + lycorine group compared to the isoproterenol group. Lycorine exerted an anti-apoptotic effect as evidenced by upregulating Bcl-2 and downregulating Bax. Overall, our findings demonstrate that lycorine protects against cardiac dysfunction induced by isoproterenol by inhibiting inflammation, fibrosis, oxidative stress, and apoptosis.

In vitro and in vivo cardioprotective and metabolic efficacy of vitamin E TPGS/Apelin

AimsApelin and vitamin E have been proposed as signaling molecules, but their synergistic role is unknown. The aim of this work was to develop vitamin E TPGS/Apelin system to test their cardioprotective and metabolic efficacy in vitro and in vivo. MethodsFDA-approved surfactant D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS-1000) and Apelin complex were characterized by physico-chemical methods (CMC determination, dynamic light scattering and circular dichroism). In vitro studies were carried out on H9C2 cardiomyoblasts and isolated murine cardiomyocytes. In vivo studies were performed in isoproterenol- and high-fat diet-induced cardiac remodeling models in mice. ResultsWe found that vitamin E TPGS/Apelin provide cardioprotective and metabolic efficacy in vitro and in vivo. In vitro studies revealed that vitamin E TPGS/Apelin reduces hypoxia-induced mitochondrial ROS production in cultured cardiomyocytes and H9C2 cardiomyoblasts. In addition, vitamin E TPGS/Apelin confers apoptotic response to hypoxic stress in cells. In a mouse model of isoproterenol-induced cardiac injury, TPGS is not able to affect cardiac remodeling, however combination of vitamin E TPGS and Apelin counteracts myocardial apoptosis, oxidative stress, hypertrophy and fibrosis. Furthermore, combination treatment attenuated obesity-induced cardiometabolic and fibrotic remodeling in mice. ConclusionTogether, our data demonstrated the therapeutic benefits of vitamin E TPGS/Apelin complex to combat cardiovascular and metabolic disorders.

Combination of vitamin E and L-carnitine is superior in protection against isoproterenol-induced cardiac injury: histopathological evidence.

L-carnitine and vitamin E have antioxidant properties. This study aimed to assess the effectiveness of L-carnitine, vitamin E and their combination in protection against isoproterenol (ISO)-induced biochemical and histopathological changes in rat heart. Fifty male Wistar rats assigned to five groups; control, ISO-treated group (100 mg/kg), ISO + vitamin E-treated group (100 IU/kg), ISO + L-carnitine (100 mg/kg) and ISO + vitamin E + L-carnitine treated group. At the end of the experiment, serum cardiac enzyme as well as the cardiac level malondi- aldehyde (MDA), antioxidant enzymes and inflammatory cytokines interleukin-6, tumour necrosis factor alpha (TNF-a) were assessed. Histopathological changes in the left ventricle wall were assessed using the light and electron microscopy. Treating rats with vitamin E and L-carnitine could alleviate ISO-induced changes as it significantly reduced the serum level cardiac enzymes, MDA and IL-6, TNF-a and improved the antioxidants enzymes (SOD, GSPxase and GSRase). Histopathologically, they improved cardiac fibres atrophy, haemorrhages between cardiac fibres, lost striations, and disturbed sarcomere structure. The combined ef- fect of vitamin E and L-carnitine was more superior compared to the other groups. Combined administration of vitamin E, L-carnitine ameliorated the biochemical and histopathological cardiac injury induced by ISO. The effect seemed to be mediated through the antioxidant and anti-inflammatory effect of vitamin E, L-carnitine. Administration of these two elements is recommended for patient at risk for myocardial infarction.

α-Lipoic acid and amlodipine/perindopril combination potentiate the therapeutic effect of mesenchymal stem cells on isoproterenol induced cardiac injury in rats

Cardiac injury is a dangerous disease and become a greater issue in the forthcoming decades. The ultimate goal is to prevent the progression of heart failure and apoptotic processes. Cardiac tissue may regenerate itself but to certain extent depending on the number of resident stem cells that is limited. Thus, research had been focused on bone marrow derived stem cells (BM-MSCs) as a promising therapy in different types of tissues, including the heart. This study is designed not only to assess the therapeutic effect of BM-MSCs but also to improve their therapeutic effect in combination with antioxidant α-lipoic acid (ALA) and antihypertensive therapeutic drug form (AP) against isoproterenol-induced cardiac injury and compared with that of BM-MSCs alone. Cardiac injury was induced in 70 male rats by Isoproterenol (ISO was injected s.c. for four consecutive days). Experimental animals were divided into six ISO-treated groups beside a control non treated one. The six ISO-treated groups were divided into: ISO group, ISO+BM-MSCs group, ISO+ALA group, ISO+AP group, ISO+ALA+AP group and ISO+ALA+AP+BM-MSCs group, the last five groups were treated with the examined materials after one week of ISO injection. Isoproterenol significantly increased serum CK-MB, LDH activities, Troponin1 and TNF-α. Oxidative stress is evidenced by the increased MDA, NO and Caspase-3 activity associated with significant reduction of GSH content and SOD activity in cardiac tissue. Furthermore, mRNA expression of NFκB and iNOS were significantly up regulated and eNOS mRNA expression was down regulated. Administration of BM-MSCs, ALA and AP alone significantly mitigated the induced cardiac injury. Concomitant administration of ALA and AP after BM-MSCs induced a more pronounced improving effect on cardiac functions. In conclusion, the concomitant administration of ALA and AP after BM-MSCs infusion increases the cellular antioxidant levels of cardiac tissue that improves the repairing function of BM-MSCs.

Discovery of a Novel Small-Molecule Modulator of C-X-C Chemokine Receptor Type 7 as a Treatment for Cardiac Fibrosis.

C-X-C chemokine receptor type 7 (CXCR7) is involved in cardiac and immune pathophysiology. We report the discovery of a novel 1,4-diazepine CXCR7 modulator, demonstrating for the first time the role of pharmacological CXCR7 intervention in cardiac repair. Structure-activity-relationship (SAR) studies demonstrated that a net reduction in lipophilicity (log D) and an incorporation of saturated ring systems yielded compounds with good CXCR7 potencies and improvements in oxidative metabolic stability in human-liver microsomes (HLM). Tethering an ethylene amide further improved the selectivity profile (e.g., for compound 18, CXCR7 Ki = 13 nM, adrenergic α 1a Kb > 10 000 nM, and adrenergic β 2 Kb > 10 000 nM). The subcutaneous administration of 18 in mice led to a statistically significant increase in circulating concentrations of plasma stromal-cell-derived factor 1α (SDF-1α) of approximately 2-fold. Chronic dosing of compound 18 in a mouse model of isoproterenol-induced cardiac injury further resulted in a statistically significant reduction of cardiac fibrosis.

Possible protective mechanisms exerted by metformin or metformin and vitamin E in isoproterenol-induced cardiac injury.

Several studies have reported that metformin is cardioprotective for diabetic and non-diabetic ischemic hearts through mechanisms that cannot be entirely attributed to its anti-hyperglycemic effect. This study was designed to investigate the cardioprotective effects of metformin with and without vitamin E after induction myocardial infarction (MI) in rats, using isoproterenol. Administration of metformin or vitamin E significantly reduced the cardiac mass index (P < 0.01), ameliorated the changes to cardiac biomarkers, and attenuated oxidative stress levels compared to the isoproterenol group. Interestingly, combination therapy showed a slight synergistic effect. Histopathological analysis suggested that metformin treatment reduced NF-κB expression and protected against isoproterenol-induced MI. Our results indicate that metformin mediates a cardioprotective effect against isoproterenol-induced MI via antioxidant activity and modulation of the NF-κB signaling pathway. This suggests that metformin would be beneficial in MI treatment.

Protective effects of high-intensity versus low-intensity interval training on isoproterenol-induced cardiac injury in wistar rats

Background: Cardiovascular diseases are among the major causes of mortality in industrialized countries. Prevention of cardio- vascular diseases and increasing stress tolerance are two of the main goals of physical training. Objectives: This study was designed to compare the effects of two exercise programs of different intensities on rat hearts with isoproterenol-induced myocardial injuries. Methods: Animals were randomly divided into four groups (n = 8 per group): control group (CTL); ISO group, administered iso- proterenol (85 mg/kg subcutaneously) for two consecutive days; low-intensity interval training + isoproterenol group (LIIT+ ISO: 5 minutes warm up at 40% VO2 max,5 x 10 minutes at50% -60% VO2 max [about 20-24 m/min]); and high-intensity interval training + isoproterenol group (HIIT+ ISO: 5 minutes warm-up at 40% VO2 max, 5 x 5 min at 95% -105% VO2 max [45 -50 m/min]). The train- ing groups performed high- and low-intensity interval training programs (5 days/week) on a motor-driven treadmill for 16 weeks. Seventy-two hours after the last training session, isoproterenol (85 mg/kg) was injected on two consecutive days. On the third day, hemodynamic parameters were recorded, blood samples were taken, and hearts were removed for laboratory analysis. Results: ISO-induced heart injury raised cardiac troponin I levels, significantly decreased + dp/dt max(P< 0.05) and-dp/dt max(P < 0.05), and significantly increased serum CTnI and tissue TNF α levels (P < 0.05). Exercise training had no significant effects on HR, LVSP, and LVEDP. Impairments of + dp/dt max and-dp/dt max were significantly improved in the HIIT+ ISO and LIIT+ISO groups (P < 0.05 for both groups versus ISO). In addition, exercise training groups especially HIIT + ISO to some reduce exacerbated the myocardial lesions induced by ISO (P < 0.05). Conclusions: These biochemical and histopathological findings suggest there is a protective role provided by both high- and low- intensity interval training protocols on ischemic hearts.

MiR-208a as a Biomarker of Isoproterenol-induced Cardiac Injury in Sod2+/− and C57BL/6J Wild-type Mice

This investigation examined microRNA-208a (miR-208a) as a potential biomarker of isoproterenol (ISO)-induced cardiac injury in superoxide dismutase-2 (Sod2(+/-) ) and the wild-type mice, and the potential sensitivity of Sod2(+/-) mice to ISO-induced toxicity. A single intraperitoneal injection of ISO was administered to age-matched wild-type and Sod2(+/-) mice at 0, 80, or 160 mg/kg. Plasma miR-208a, cardiac troponin I (cTnI), and ISO systemic exposure were measured at various time points postdose. Hearts were collected for histopathology examination and for tissue expression of miR-208a and myosin heavy chain 7. ISO administration caused increases in cTnI and miR-208a plasma levels that correlated with myocardial damage; however, the magnitude of increase differed according to the types of mice. At similar ISO systemic exposure, the magnitude of cTnI was greater in wild-type mice compared to Sod2(+/) (-) mice; however, the magnitude of miR-208a was greater in Sod2(+/-) mice than that of the wild-type mice. Myocardial degeneration occurred at ≥3 hr in the wild-type and ≥6 hr in Sod2(+/) (-) mice. At ≥24 hr after ISO administration, miR-208a appeared superior to cTnI in indicating myocardial injury in both wild-type and Sod2(+/-) mice. Sod2(+/-) mice were not more sensitive than wild-type mice to ISO-induced toxicity.

Cardioprotective potential of Korean Red Ginseng extract on isoproterenol-induced cardiac injury in rats

The present study was designed to investigate the cardioprotective effects of Korean Red Ginseng extract (KRG) on isoproterenol (ISO)-induced cardiac injury in rats, particularly in regards to electrocardiographic changes, hemodynamics, cardiac function, serum cardiac enzymes, components of the myocardial antioxidant defense system, as well as inflammatory markers and histopathological changes in heart tissue. ISO (150 mg/kg, subcutaneous, two doses administered at 24-hour intervals) treatment induced significant decreases in P waves and QRS complexes (p<0.01), as well as a significant increase in ST segments. Moreover, ISO-treated rats exhibited decreases in left-ventricular systolic pressure, maximal rate of developed left ventricular pressure (+dP/dtmax) and minimal rate of developed left ventricular pressure (−dP/dtmax), in addition to significant increases in lactate dehydrogenase, aspartate transaminase, alanine transaminase and creatine kinase activity. Heart rate, however, was not significantly altered. And the activities of superoxide dismutase, catalase and glutathione peroxidase were decreased, whereas the activity of malondialdehyde was increased in the ISO-treated group. ISO-treated group also showed increased caspase-3 level, release of inflammatory markers and neutrophil infiltration in heart tissue. KRG pretreatment (250 and 500 mg/kg, respectively) significantly ameliorated almost all of the parameters of heart failure and myocardial injury induced by ISO. The protective effect of KRG on ISO-induced cardiac injury was further confirmed by histopathological study. In this regard, ISO treatment induced fewer morphological changes in rats pretreated with 250 or 500 mg/kg of KRG. Compared with the control group, all indexes in rats administered KRG (500 mg/kg) alone were unaltered (p>0.05). Our results suggest that KRG significantly protects against cardiac injury and ISO-induced cardiac infarction by bolstering antioxidant action in myocardial tissue.

Granulocyte colony-stimulating factor improves early remodeling in isoproterenol-induced cardiac injury in rats

BackgroundGranulocyte colony-stimulating factor (G-CSF) has been used in some animal models and humans with wellestablished cardiovascular diseases. However, its effects in the initial stage of progressive non-ischemic heart failure are unknown. MethodsWistar rats (260–300g) were divided into three groups: control (without any intervention), ISO (150mg/kg isoproterenol hydrochloride sc, once a day for two consecutive days), and ISO-GCSF (50μg/kg/d G-CSF for 7 days beginning 24h after the last administration of ISO). Echocardiography was performed at baseline and after 30 days of follow-up. Subsequently, animals were anesthetized for hemodynamic analysis. The left ventricle was removed for analysis of interstitial collagen deposition and cardiomyocyte hypertrophy. ResultsIsoproterenol led to left ventricular dilation (control, 7.7±0.14mm; ISO, 8.7±0.16mm; ISO-GCSF 7.8±0.09mm; p<0.05), myocardial fibrosis (control, 2.0±0.18%; ISO, 9.1±0.81%; ISO-GCSF 5.9±0.58%; p<0.05) and cardiomyocyte hypertrophy (control, 303±10μm2; ISO, 356±18μm2; ISO-GCSF 338±11μm2; p<0.05). However, G-CSF partially prevented collagen deposition and left ventricular enlargement, with a slight effect on hypertrophy. Characterizing a compensated stage of disease, hemodynamic analysis did not change. ConclusionsG-CSF administered for 7 days was effective in preventing the onset of ventricular remodeling induced by high-dose isoproterenol with decreased collagen deposition and chamber preservation.

Cardiovascular effects of black tea and nicotine alone or in combination against experimental induced heart injury

The present study was designed to elucidate the outcome of subchronic co-administration of black tea and nicotine on cardiovascular performance and whether these substances could modulate the isoproterenol-induced cardiac injury. Animal groups were control, black tea, nicotine and black tea plus nicotine. Test groups received nicotine (2 mg/kg s.c.) and black tea brewed (p.o.) each alone and in combination for 4 weeks. On the 28th day, myocardial damage was induced by isoproterenol (50 mg/kg i.p.), and blood samples were taken. On day 29, after hemodynamic parameters recording, hearts were removed for histopathological evaluation. Tea or nicotine consumption had no significant effects on hemodynamic indices of animals without heart damage. When the cardiac injury was induced, tea consumption maintained the maximum dp/dt, and nicotine significantly decreased the pressure-rate product. Moreover, severity of heart lesions was lower in the presence of nicotine or black tea. Concomitant use of these materials did not show extra effects on mentioned parameters more than the effect of each of them alone. The results suggest that subchronic administration of black tea or nicotine for a period of 4 weeks may have a mild cardioprotective effect, while concomitant use of these materials cannot intensify this beneficial effect.

Cardiac Troponin I in Isoproterenol-Induced Cardiac Injury in the Hanover Wistar Rat: Studies on Low Dose Levels and Routes of Administration

The current studies demonstrate the effect of low-dose intraperitoneal (IP) administration of isoprotenerol (ISO) and subcutaneous (SC) versus IP routes of administration of ISO on serum cardiac troponin I (cTnI) levels in female Hanover Wistar rats, providing additional evidence to support acceptance of cTnI as a cardiac biomarker. At 2 hr postdosing with 0-500 microg/kg ISO, mean serum cTnI levels were increased in a dose-related fashion at > or =10 microg/kg with no evidence of cardiac pathology. At 24 h, cTnI concentrations were generally at control levels, but histologic cardiomyocyte injury was evident in a proportion of the animals given > or =10 microg/kg. In a second experiment, rats given SC ISO at 5,000 microg/kg and necropsied at 0, 1, 2, and 4 hr postdosing had higher levels of serum cTnI than animals given the same dose IP.