Myocardial Creatine Kinase Research Articles

Optical coherence tomography analysis of lesion characteristics and thrombus types in non ST-segment elevation myocardial infarction patients

The precise features of lesions in non-ST-segment elevation myocardial infarction (NSTEMI) patients with total occlusion (TO) of the infarct-related artery (IRA) are still unclear. This study employs optical coherence tomography (OCT) to investigate pathological features in NSTEMI patients with or without IRA TO and explores the relationship between thrombus types and IRA occlusive status. This was a single-center retrospective study. A total of 202 patients diagnosed with NSTEMI were divided into two groups: those with Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 before percutaneous coronary intervention (PCI) (referred to as the TO group, n = 100) and those TIMI flow grade 1–3 (referred to as the Non-TO group, n = 102). Baseline characteristics, coronary angiography findings, and OCT results were collected. Multivariate logistic analysis identified factors influencing TO in NSTEMI. The category of NSTEMI was further subdivided based on the type of electrocardiogram (ECG) into two subgroups: ST segment unoffset myocardial infarction (STUMI) and ST segment depression myocardial infarction (STDMI). This division allows for a more specific classification of NSTEMI cases. The TO group had a younger age, higher male representation, more smokers, lower hypertension and cerebrovascular disease incidence, lower left ventricular ejection fraction (LVEF), and higher creatine kinase myocardial band (CKMB) and creatine kinase (CK) peak levels. In the TO group, LCX served as the main IRA (52.0%), whereas in the Non-TO group, LAD was the predominant IRA (45.1%). Compared to the Non-TO group, OCT findings demonstrated that red thrombus/mixed thrombus was more common in the TO group, along with a lower occurrence of white thrombus (p < 0.001). The TO group exhibited a higher prevalence of STUMI (p = 0.001), whereas STDMI was more commonly observed in the Non-TO group (p = 0.001). NSTEMI presents as STUMI and STDMI distinct entities. Red thrombus/mixed thrombus in IRA often indicates occlusive lesions with STUMI on ECG. White thrombus suggests non-occlusive lesions with STDMI on ECG.

Geomagnetic activity affects animal myocardial ischemia/reperfusion injury: an experimental-simulated study

Numerous studies have shown that geomagnetic activity (GMA) contributes to the development and escalation of cardiovascular disease (CVD), as well as increased morbidity and mortality. However, the underlying molecular mechanisms and approaches for understanding GMA remain unclear. This study aimed to investigate the impact of GMA on oxidative stress and inflammatory responses. Myocardial ischemia/reperfusion injury (MI/RI) rat models were created under various geomagnetic field conditions. The range of cardiac function, markers of myocardial injury, inflammatory factors, and the TLR4/NF-κB signaling pathway were measured after the 24-h period. The findings showed that weak GMA significantly improved cardiac function in the MI/RI rat model and reduced the size of myocardial infarction and creatine kinase (CK) and lactic dehydrogenase (LDH) levels. Additionally, weak GMA enhanced superoxide dismutase (SOD) activity and decreased malondialdehyde (MDA) content. Furthermore, weak GMA significantly reduced the levels of the myocardial inflammatory cytokines interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Conversely, the effects observed under severe GMA conditions were opposite to those observed under weak GMA. Western blot and qPCR analysis demonstrated that weak GMA led to a significant downregulation of TLR4, TRAF6, NF-κB, TNF-α, and MCP-1 in the MI/RI rat models. In contrast to weak GMA, severe GMA increased TLR4, TRAF6, NF-κB, and TNF-α expression. This study suggested that weak GMA had a limiting effect on MI/RI rat models, whereas severe GMA exacerbated injury in MI/RI rats. These effects were associated with oxidative stress and inflammatory responses and might potentially involve the TLR4/NF-κB signaling pathway.

Potential therapeutic effect of Salvia coccinea leaf extract in chronic disorders: Myocardial infarction, cataract, and arthritis in rat

Aqueous extract from Salvia coccinea leaf (AESL) has been shown its unique anti-oxidant effect via Nuclear factor (NF)-kappa (κ)B pathway in human monocytic THP-1 ​cells and pharmacological effect on inflammatory diseases like diabetes in rats. Using AESL, which possess antioxidant activity by scavenging radicals and decreasing oxidative stress, would be a promising strategy for the treatment of other inflammatory disorders like myocardial infarction, arthritis, and cataract. This study was designed to evaluate the ameliorating effects of AESL on isoproterenol (Iso)-induced myocardium infarction (MI), selenite-induced cataractogenesis, and complete Freund's adjuvant-induced arthritis in Wistar rats. In this study, AESL ameliorated pathological changes in Iso-induced MI heart muscles and Electro Cardio Gram pattern, 35–80 ​% protection of the cataractogenesis, and prevented the apoptosis induced by selenite in the rat lens. Both pre and post-treatment of AESL (600 ​mg/kg, bw) showed no swelling of the joint and, 35 days treatment showed significant prevention against bony destruction as depicted by less narrowing of joint spaces and soft tissue swelling when compared with control rats. Oral administration of AESL inhibited the Iso-induced increase in serum and myocardial lipid peroxidation, aspartate transaminase, alanine transaminase, creatine kinase, troponin-I, and troponin-T, and lactate dehydrogenase of myocardium infarction rats. Significant increases in the activity of superoxide dismutase, catalase, glutathione peroxidase, and a reduced level of glutathione, were observed in AESL treated cataract rat lens. The results demonstrate that AESL is useful in, in addition to diabetes, controlling myocardium infarction, cataracts, and arthritis.

Synergistic effect on cardiac energetics by targeting the creatine kinase system: in vivo application of high-resolution 31P-CMRS in the mouse

BackgroundPhosphorus cardiovascular magnetic resonance spectroscopy (31P-CMRS) has emerged as an important tool for the preclinical assessment of myocardial energetics in vivo. However, the high rate and diminutive size of the mouse heart is a challenge, resulting in low resolution and poor signal-to-noise. Here we describe a refined high-resolution 31P-CMRS technique and apply it to a novel double transgenic mouse (dTg) with elevated myocardial creatine and creatine kinase (CK) activity. We hypothesised a synergistic effect to augment energetic status, evidenced by an increase in the ratio of phosphocreatine-to-adenosine-triphosphate (PCr/ATP). Methods and resultsSingle transgenic Creatine Transporter overexpressing (CrT-OE, n = 7) and dTg mice (CrT-OE and CK, n = 6) mice were anaesthetised with isoflurane to acquire 31P-CMRS measurements of the left ventricle (LV) utilising a two-dimensional (2D), threefold under-sampled density-weighted chemical shift imaging (2D-CSI) sequence, which provided high-resolution data with nominal voxel size of 8.5 µl within 70 min. (1H-) cine-CMR data for cardiac function assessment were obtained in the same imaging session. Under a separate examination, mice received invasive haemodynamic assessment, after which tissue was collected for biochemical analysis. Myocardial creatine levels were elevated in all mouse hearts, but only dTg exhibited significantly elevated CK activity, resulting in a 51% higher PCr/ATP ratio in heart (3.01 ± 0.96 vs. 2.04 ± 0.57—mean ± SD; dTg vs. CrT-OE), that was absent from adjacent skeletal muscle. No significant differences were observed for any parameters of LV structure and function, confirming that augmentation of CK activity does not have unforeseen consequences for the heart. ConclusionsWe have developed an improved 31P-CMRS methodology for the in vivo assessment of energetics in the murine heart which enabled high-resolution imaging within acceptable scan times. Mice over-expressing both creatine and CK in the heart exhibited a synergistic elevation in PCr/ATP that can now be tested for therapeutic potential in models of chronic heart failure.

Design and synthesis of DNA hydrogel based on EXPAR and CRISPR/Cas14a for ultrasensitive detection of creatine kinase MB

Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas systems exhibit significant potential in developing biosensing technology due to their collateral cleavage capabilities. Herein, we introduced the collateral cleavage activity of CRISPR/Cas14a to activate DNA hydrogel for ultrasensitive detection of the myocardial infarction biomarker creatine kinase MB (CK-MB). In this strategy, the designed CRISPR/Cas14a system can be activated by introducing complementary DNA (cDNA) derived from competitive dissociation and exponential amplification (EXPAR), which is positively correlated with creatine kinase isoenzyme (CK-MB) concentration. Then the activated Cas14a protein can be utilized to indiscriminately cleave the DNA hydrogel cross-linker strand, leading to the degradation of the gel matrix and thus releasing the pre-encapsulated PtNPs/Cu-TCPP(Fe). PtNPs/Cu-TCPP(Fe) can trigger the TMB reaction, leading to an increase in absorbance value at 450 nm, thus enabling the quantitative detection of CK-MB. The proposed strategy combines CRISPR/Cas14a with DNA hydrogel for the first time, improving the programmability of DNA hydrogel and providing a reliable, sensitive, and versatile detection platform for trace non-nucleic acid targets.

Association of greenness exposure with coronary artery stenosis and biomarkers of myocardial injury in patients with myocardial infarction

BackgroundGreenness has been linked to cardiovascular health; however, limited evidence is available regarding its association with coronary artery stenosis and biomarkers of myocardial injury. We aimed to assess these associations and examine their modification and mediation effects in patients with myocardial infarction (MI). MethodsThis study included 2030 patients with MI. The normalized difference vegetation index (NDVI) was used to characterize greenness exposure. We used a logistic regression model to explore the relationship between coronary artery stenosis and residential greenness, and applied linear regression models to assess the association of greenness with biomarkers of myocardial injury. The bootstrap method was used to explore whether potential variables mediated the associations. To further investigate the exposure-response curve describing these relationships, we developed restricted cubic spline models. ResultCompared to the lowest quartile of NDVI, the odds ratio (OR) (95 % confidence interval [CI]) for severe stenosis (≥75 % stenosis) was 0.68 (95 % CI: 0.47 to 0.98) for the third quartile. Participants in the highest greenness exposure quartile had lower levels of cardiac troponin I (cTnI), creatine kinase (CK), and creatine kinase isoenzyme (CKMB) than those in the lowest quartile (β = −0.22, 95 % CI: −0.40 to −0.05; β = −0.13, 95 % CI: −0.22 to −0.04; β = −0.07, 95 % CI: −0.14 to −0.003). The association between residential greenness and myocardial injury biomarkers was stronger in men and older participants. Mediation analyses revealed that the effects of greenness on coronary stenosis, cTnI, CK, and CKMB were mediated by systolic blood pressure (SBP) and diastolic blood pressure (DBP). ConclusionHigher greenness exposure was associated with coronary artery stenosis and reduced levels of myocardial injury biomarkers, including cTnI, CK, and CKMB. These associations may be partially mediated by SBP and DBP levels.

Cardiac Protection of a Novel Lupane-Type Triterpenoid from Injuries Induced by Hypoxia-Reperfusion.

Myocardial ischemia–reperfusion injury (MIRI) leads to cardiac remodeling and heart failure associated with acute myocardial infarction, which is one of the leading causes of death worldwide. Betulinic acid (BA), a widely distributed lupane-type triterpenoid, has been reported to possess antioxidative activity and inhibit apoptosis in MIRI. Due to the low bioavailability and water insolubility of BA, a previous study found a series of BA-derivative compounds by microbial transformation. In this study, we observe whether there are anti-MIRI effects of BTA07, a BA derivative, on cardiac injuries induced by hypoxia/reoxygenation (H/R) in adult rat cardiomyocytes in vitro and in Langendorff-perfused hearts ex vivo, and further explore its mechanism of cardioprotection to find more efficient BA derivatives. The hemodynamic parameters of isolated hearts were monitored and recorded by a Lab Chart system. The markers of oxidative stress and apoptosis in isolated hearts and adult rat cardiomyocytes (ARCMs) were evaluated. The expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X (Bax), protein kinase B (Akt) and phospho-Akt (pAkt, Ser473) induced by H/R were detected via Western blot. The Langendorff experiments showed that BTA07 improves hemodynamic parameters, reduces myocardium damage and infarct size, inhibits levels of myocardial tissue enzymes lactate dehydrogenase (LDH) and creatine kinase (CK) in the coronary outflow and reduces oxidative stress and the activation of caspase-3 in the myocardium. In vitro, BTA07 reduced cell death and caspase-3 activation and inhibited reactive oxygen species (ROS) generation. Furthermore, the protective effects of BTA07 were attenuated by inhibition of the PI3K/Akt signaling pathway with LY294002 in ARCMs. BTA07 protects ARCMs and isolated hearts from hypoxia–reperfusion partly by inhibiting oxidative stress and cardiomyocyte apoptosis.

Normothermic blood polarizing versus depolarizing cardioplegia in a porcine model of cardiopulmonary bypass.

OBJECTIVESWe have previously demonstrated beneficial cardiac protection with hypothermic polarizing cardioplegia compared to a hyperkalemic depolarizing cardioplegia. In this study, a porcine model of cardiopulmonary bypass was used to compare the protective effects of normothermic blood-based polarizing and depolarizing cardioplegia during cardiac arrest.METHODSThirteen pigs were randomized to receive either normothermic polarizing (n = 8) or depolarizing (n = 5) blood-based cardioplegia. After initiation of cardiopulmonary bypass, normothermic arrest (34°C, 60 min) was followed by 60 min of on-pump and 90 min of off-pump reperfusion. Primary outcome was myocardial injury measured as arterial myocardial creatine kinase concentration. Secondary outcome was haemodynamic function and the energy state of the hearts.RESULTSDuring reperfusion, release of myocardial creatine kinase was comparable between groups (P = 0.36). In addition, most haemodynamic parameters showed comparable results between groups, but stroke volume (P = 0.03) was significantly lower in the polarizing group. Adenosine triphosphate levels were significantly (18.41 ± 3.86 vs 22.97 ± 2.73 nmol/mg; P = 0.03) lower in polarizing hearts, and the requirement for noradrenaline administration (P = 0.002) and temporary pacing (6 vs 0; P = 0.02) during reperfusion were significantly higher in polarizing hearts.CONCLUSIONSUnder normothermic conditions, polarizing blood cardioplegia was associated with similar myocardial injury to depolarizing blood cardioplegia. Reduced haemodynamic and metabolic outcome and a higher need for temporary pacing with polarized arrest may be associated with the blood-based dilution of this solution.

Effects of dezocine combined with dexmedetomidine on adverse reactions and inflammatory factors in patients undergoing HIPEC after intestinal surgery and its protective effect on the heart in the perioperative period.

The aim of this study was to explore the effects of dezocine combined with dexmedetomidine on adverse reactions and inflammatory factors in patients undergoing hyperthermic intraperitoneal chemotherapy (HIPEC) after intestinal surgery and its protective effect on the heart in the perioperative period. A total of 80 patients treated with HIPEC after intestinal surgery in our hospital from September 2018 to December 2019 were enrolled as research subjects. All patients were evenly divided into two groups using a random number table. As to analgesia and sedation during treatment, dezocine was injected intramuscularly at 30 min before treatment in the control group. Meanwhile, dezocine combined with dexmedetomidine was given in the same way in the observation group. Adverse reactions and changes in numeric rating scale (NRS) pain score during intervention were compared between the two groups. The changes in the levels of inflammatory and myocardial injury-related factors, and vascular endothelial function and regeneration ability among cardiovascular indicators at 12 h after intervention were compared as well. Additionally, the correlations of left ventricular mass index (LVMI) with the changes in the levels of inflammatory factor high-sensitivity C-reactive protein (hs-CRP), myocardial injury-related factor lactic dehydrogenase (LDH), vascular endothelial function indicator endothelin-1 (ET-1) and cardiovascular regeneration ability index vascular endothelial growth factor (VEGF) were analyzed. Compared with control group, the total prevalence rate of severe pain, respiratory depression, nausea and vomiting, diarrhea, and muscle rigidity during intervention was significantly reduced in the observation group (p<0.05). NRS pain score at 1, 4, 8 and 12 h after intervention decreased remarkably in the observation group compared with the control group (p<0.05). Meanwhile, the levels of inflammatory factors tumor necrosis factor-α (TNF-α) and hs-CRP, and myocardial injury-related factors LDH and creatine kinase MB (CKMB) as well as ET-1 at 12 h after intervention declined remarkably in observation group compared with control group (p<0.05). However, the levels of nitric oxide (NO), VEGF and basic fibroblast growth factor (bFGF) rose significantly in the observation group (p<0.05). Besides, LVMI was positively correlated with hs-CRP and LDH, whereas was negatively associated with ET-1 and VEGF (p<0.05). In HIPEC, dezocine combined with dexmedetomidine used for sedation and analgesia is able to effectively reduce adverse reactions and relieve inflammatory responses in vivo, exerting a cardio-protective effect.

Influences of ALDH2 on Cardiomyocyte Apoptosis in Heart Failure Rats Through Regulating PINK1-Parkin Signaling Pathway-Mediated Mitophagy

The study aimed to investigate the influences of aldehyde dehydrogenase 2 (ALDH2) on cardiomyocyte apoptosis in heart failure (HF) rats through regulating the PTEN induced putative kinase 1 (PINK1)-Parkin signaling pathway-mediated mitophagy. The rat model of HF was established, and the rats were randomly divided into model group (HF model, n=20) and ALDH2 group (intervention with ALDH2, n=20), with a normal group (n=20) set. After successful modeling, MRI and ECG were applied to detect the cardiac function indexes of the rats. The myocardial function index creatine kinase (CK) was measured, the status of myocardial tissue injury was determined using hematoxylin and eosin staining, and the apoptosis was observed via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. The activity of ALDH2 was detected, and the expression levels of genes and proteins were measured through quantitative polymerase chain reaction (qPCR) and Western blotting assay. The model group had notably decreased fractional shortening (FS) and ejection fraction (EF) and remarkably increased left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) compared with the normal group (p<0.05). The activity of ALDH2 declined obviously in the model group. The myocardial tissue injury was severer in the model group, and the number of apoptotic cells in myocardial tissues was greater in the model group than that in other groups (p<0.05). The model group manifested higher expression levels of Caspase-3 and light chain 3 (LC3) than the ALDH2 group (p<0.05) but significantly lower expression levels of PINK1, Parkin and B-cell lymphoma-2 (Bcl-2) (p<0.05). In comparison with those in the model group, the protein expression levels of PINK1, Parkin and Bcl-2 in myocardial tissues were prominently higher in the ALDH2 group (p<0.05). ALDH2 can inhibit cardiomyocyte apoptosis in HF rats by activating the PINK1-Parkin signaling pathway-mediated mitophagy, which is conducive to the recovery of HF.

Taurine Has Potential Protective Effects against the Chronic Cardiotoxicity Induced by Doxorubicin in Mice.

Doxorubicin (DOX) is an effective anticancer anthracycline drug; however, the cardiotoxicity limits its application. The aim of the present study was to investigate the potential protective effect of taurine against DOX-induced chronic cardiotoxicity in mice. We found that exogenous supplementation of taurine can inhibit the weight loss of mice caused by DOX. The increased activity of myocardial enzymes creatine kinase (CK) and lactate dehydrogenase (LDH) in response to DOX treatment were significantly hampered. In addition, taurine supplementation alleviated the decrease in superoxide dismutase (SOD) activity, glutathione (GSH) content, glutathione peroxidase 4 (Gpx4) expression, and the increase in malondialdehyde (MDA) content caused by DOX. Besides, taurine alleviated myocardial myofibrillar disruption and mitochondrial edema. Furthermore, our results showed that taurine decreased the expressions of cleaved caspase-3 and Bax/Bcl2, thereby inhibiting apoptosis. These collective data demonstrated that exogenous taurine supplementation has a potentially protective effect against the myocardial damage caused by doxorubicin in mice by enhancing antioxidant capacity and reducing oxidative damage and apoptosis.

Protective effects of 18β-Glycyrrhetinic acid against myocardial infarction: Involvement of PI3K/Akt pathway activation and inhibiting Ca2+ influx via L-type Ca2+ channels.

18β‐Glycyrrhetinic acid (18β‐GA) is a component extracted from licorice. This study aimed to evaluate the effects of 18β‐GA on isoproterenol (ISO)‐induced acute myocardial infarction in rats and mice. Two consecutive days of subcutaneous injection of ISO (85 mg/kg/day) resulted in acute myocardial infarction. We examined the pathological changes, oxidative stress, inflammatory response, and expression of apoptosis in mouse hearts. The expressions of phosphoinositol‐3‐kinase (PI3K), protein kinase B (Akt), and the phosphorylation levels of PI3K (p‐PI3K) and Akt (p‐Akt) were determined by western blotting. The whole‐cell patch‐clamp technique was applied to observe the L‐type Ca2+ currents, and the Ion Optix detection system was used for cell contraction and Ca2+ transient in isolated rat cardiac ventricular myocytes. In ISO‐induced myocardial infarction, the J‐point, heart rate, creatine kinase, lactate dehydrogenase, superoxide dismutase, catalase, malondialdehyde, glutathion, and reactive oxygen species decreased in mice after 18β‐GA treatment. 18β‐GA improved ISO‐induced morphologic pathology, inhibited the inflammatory pathway response and cardiomyocyte apoptosis, and inhibited PI3K/Akt signaling. 18β‐GA could significantly inhibit ICa‐L, myocardial contraction, and Ca2+ transient. This study demonstrates that 18β‐GA has cardioprotective effects on acute myocardial infarction, which may be related to inhibiting oxidative stress, inflammation, apoptosis via the PI3K/Akt pathway, and reducing cell contractility and Ca2+ concentration via L‐type Ca2+ channels.

Evaluating the effects of carbon monoxide releasing molecule-2 against myocardial ischemia-reperfusion injury in ovariectomized female rats.

Cardioprotective effect of carbon monoxide, a gasotransmitter against myocardial ischemia-reperfusion injury (I/R), is well established in preclinical studies with male rats. However, its ischemic tolerance in post-menopausal animals has not been examined due to functional perturbations at the cellular level. The protective role of carbon monoxide releasing molecule-2 (CORM-2) on myocardial I/R was studied in female Wistar rats using the Langendorff apparatus. The animals were randomly divided into normal and ovariectomized (Ovx) female rats and were maintained 2months post-surgery. Each group was further divided into 4 subgroups (n = 6/subgroup): normal, I/R, CORM-2-control (20μmol/L), and CORM-2-I/R. The cardiac injury was estimated via myocardial infarct size, lactate dehydrogenase, and creatine kinase levels in coronary effluent and cardiac hemodynamic indices. Mitochondrial functional activity was assessed by measuring mitochondrial electron transport chain enzyme activities, swelling behavior, mitochondrial membrane potential, and oxidative stress. Hemodynamic indices were significantly lower in ovariectomized rat hearts than in normal rat hearts. Sixty minutes of reperfusion of ischemic heart exhibited deteriorated cardiac physiological recovery in both ovariectomized and normal groups, where prominent decline was observed in ovariectomized rat. However, preconditioning the isolated heart with CORM-2 improved hemodynamics parameters significantly in both ovariectomized and normal rat hearts challenged with I/R, but with a limited degree of protection in ovariectomized rat hearts. The protective effect of CORM-2 was further confirmed via a reduction in cardiac injury, preservation of mitochondrial enzymes, and reduction in oxidative stress in all groups. CORM-2 administration significantly attenuated myocardial I/R injury in ovariectomized rat hearts by attenuating I/R-associated mitochondrial perturbations and reducing oxidative stress.

Pharmacological Inhibition of S-Nitrosoglutathione Reductase Reduces Cardiac Damage Induced by Ischemia-Reperfusion.

The cardioprotective effects of nitric oxide (NO) have been described through S-nitrosylation of several important proteins in the mitochondria of the cardiomyocyte. S-nitrosoglutathione reductase (GSNOR) is an enzyme involved in the metabolism of S-nitrosothiols by producing denitrosylation, thus limiting the cardioprotective effect of NO. The effect of GSNOR inhibition on the damage by cardiac ischemia–reperfusion is still unclear. We tested the hypothesis that pharmacological inhibition of GSNOR promotes cardioprotection by increasing the levels of protein S-nitrosylation. In a model of ischemia–reperfusion in isolated rat heart, the effect of a GSNOR inhibitor, 5-chloro-3-(2-[4-ethoxyphenyl) (ethyl) amino]-2-oxoethyl)-1H-indole-2-carboxylic acid (C2), was investigated. Ventricular function and hemodynamics were determined, in addition to tissue damage and S-nitrosylation of mitochondrial proteins. Hearts treated with C2 showed a lower release of myocardial damage marker creatine kinase and a reduction in the infarcted area. It also improved post-ischemia ventricular function compared to controls. These results were associated with increasing protein S-nitrosylation, specifically of the mitochondrial complexes III and V. The pharmacological inhibition of GSNOR showed a concentration-dependent cardioprotective effect, being observed in functional parameters and myocardial damage, which was maximal at 1 µmol/L, associated with increased S-nitrosylation of mitochondrial proteins. These data suggest that GSNOR is an interesting pharmacological target for cardiac reperfusion injury.

Fisetin Attenuates Myocardial Ischemia-Reperfusion Injury by Activating the Reperfusion Injury Salvage Kinase (RISK) Signaling Pathway.

Ischemia-reperfusion (I/R) injury is an unavoidable injury that occurs during revascularization procedures. In the previous study, we reported that fisetin is a natural flavonoid that attenuates I/R injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction. Though fisetin is reported as a GSK3β inhibitor, it remains unclear whether it attenuates myocardial ischemia by activating the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, thereby inhibiting the downstream GSK3β, or by directly interacting with GSK3β while rendering its cardioprotection. In this study, the research team investigates the possible mechanism of action of fisetin while rendering its cardioprotective effect against myocardial I/R injury in rats. For this investigation, the team utilized two myocardial I/R models: Ligation of the left anterior descending artery and Langendorff isolated heart perfusion system. The latter has no neurohormonal influences. The PI3K inhibitor (Wortmannin, 0.015 mg/kg), GSK3β inhibitor (SB216763, 0.7 mg/kg), and fisetin (20 mg/kg) were administered intraperitoneally before inducing myocardial I/R. The result of this study reveals that the administration of fisetin decreases the myocardial infarct size, apoptosis, lactate dehydrogenase, and creatine kinase in serum\\perfusate of the rat hearts subjected to I/R. However, the inhibition of PI3K with Wortmannin significantly reduced the cardioprotective effect of fisetin both in the ex vivo and vivo models. The administration of GSK3β inhibitor after the administration of fisetin and Wortmannin, re-establishing the cardioprotection, indicates the major role of PI3K in fisetin action. Changes in myocardial oxidative stress (level) and mitochondrial functional preservation of interfibrillar and subsarcolemmal mitochondria support the above findings. Hence, the team here reports that fisetin conferred its cardioprotection against I/R injury by activating the PI3K/Akt/GSK3β signaling pathway in rat hearts.

Combination of ponatinib with deferoxamine synergistically mitigates ischemic heart injury via simultaneous prevention of necroptosis and ferroptosis

Necroptosis, ferroptosis and cyclophilin D (Cyp D)-dependent necrosis contribute to myocardial ischemia/reperfusion (I/R) injury, and ponatinib, deferoxamine and cyclosporine are reported to inhibit necroptosis, ferroptosis and Cyp D-dependent necrosis, respectively. This study aims to explore whether the any two combination between ponatinib, deferoxamine and cyclosporine exerts a better cardioprotective effect on I/R injury than single medicine does. The H9c2 cells were subjected to 10 h of hypoxia (H) plus 4 h of reoxygenation (R) to establish H/R injury model. The effects of any two combination between ponatinib, deferoxamine and cyclosporine on H/R injury were examined. On this basis, a I/R injury model in rat hearts was established to focus on the effect of ponatinib, deferoxamine and their combination on myocardial I/R injury and the underlying mechanisms. In H/R-treated H9c2 cells, all three medicines can attenuate H/R injury (decrease in LDH release and necrosis percent). However, only the combination of ponatinib with deferoxamine exerted synergistic effect on reducing H/R injury, showing simultaneous suppression of necroptosis and ferroptosis. Expectedly, administration of ponatinib or deferoxamine either before or after ischemia could suppress necroptosis or ferroptosis in the I/R-treated rat hearts as they did in vitro, concomitant with a decrease in myocardial infarct size and creatine kinase release, and the combination therapy is more efficient than single medication. Based on these observations, we conclude that the combination of ponatinib with deferoxamine reduces myocardial I/R injury via simultaneous inhibition of necroptosis and ferroptosis.

Betulin Alleviates Myocardial Ischemia-Reperfusion Injury in Rats via Regulating the Siti1/NLRP3/NF-κB Signaling Pathway.

To study the effects of betulin (BE) on myocardial ischemia-reperfusion (I/R) injury in rats, electrocardiogram (ECG) was detected by an electrocardiograph; myocardial infarction was evaluated by triphenyltetrazolium (TTC) staining, serum biochemical indicators myocardial enzymes creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), serum superoxide dismutase (SOD), glutathione (GSH), nitric oxide (NO), and malondialdehyde (MDA); and inflammatory cytokines were tested by using commercial kits. The expression of the Siti1/NLRP3/NF-κB signaling pathway was detected by western blotting and immunohistochemistry experiments. BE improved ECG; reduced myocardial infarction area; decreased CK, LDH, AST, MDA, NO, and inflammatory cytokines; and increased SOD and GSH in I/R rats. In addition, BE also increased Siti1 and decreased the NLRP3/NF-κB signaling pathway in I/R rats. This study shows that the protection of BE is associated with changes in the Siti1/NLRP3/NF-κB pathway.

Cardiac expression and location of hexokinase changes in a mouse model of pure creatine deficiency.

Creatine kinase (CK) is considered the main phosphotransfer system in the heart, important for overcoming diffusion restrictions and regulating mitochondrial respiration. It is substrate limited in creatine-deficient mice lacking l-arginine:glycine amidinotransferase (AGAT) or guanidinoacetate N-methyltranferase (GAMT). Our aim was to determine the expression, activity, and mitochondrial coupling of hexokinase (HK) and adenylate kinase (AK), as these represent alternative energy transfer systems. In permeabilized cardiomyocytes, we assessed how much endogenous ADP generated by HK, AK, or CK stimulated mitochondrial respiration and how much was channeled to mitochondria. In whole heart homogenates, and cytosolic and mitochondrial fractions, we measured the activities of AK, CK, and HK. Lastly, we assessed the expression of the major HK, AK, and CK isoforms. Overall, respiration stimulated by HK, AK, and CK was ∼25, 90, and 80%, respectively, of the maximal respiration rate, and ∼20, 0, and 25%, respectively, was channeled to the mitochondria. The activity, distribution, and expression of HK, AK, and CK did not change in GAMT knockout (KO) mice. In AGAT KO mice, we found no changes in AK, but we found a higher HK activity in the mitochondrial fraction, greater expression of HK I, but a lower stimulation of respiration by HK. Our findings suggest that mouse hearts depend less on phosphotransfer systems to facilitate ADP flux across the mitochondrial membrane. In AGAT KO mice, which are a model of pure creatine deficiency, the changes in HK may reflect changes in metabolism as well as influence mitochondrial regulation and reactive oxygen species production.NEW & NOTEWORTHY In creatine-deficient AGAT-/- and GAMT-/- mice, the myocardial creatine kinase system is substrate limited. It is unknown whether subcellular localization and mitochondrial ADP channeling by hexokinase and adenylate kinase may compensate as alternative phosphotransfer systems. Our results show no changes in adenylate kinase, which is the main alternative to creatine kinase in heart. However, we found increased expression and activity of hexokinase I in AGAT-/- cardiomyocytes. This could affect mitochondrial regulation and reactive oxygen species production.

Nootkatone, a Dietary Fragrant Bioactive Compound, Attenuates Dyslipidemia and Intramyocardial Lipid Accumulation and Favorably Alters Lipid Metabolism in a Rat Model of Myocardial Injury: An In Vivo and In Vitro Study.

In the present study, we assessed whether nootkatone (NKT), a sesquiterpene in edible plants, can provide protection against dyslipidemia, intramyocardial lipid accumulation, and altered lipid metabolism in a rat model of myocardial infarction (MI) induced by subcutaneous injections of isoproterenol (ISO, 85 mg/kg) on days 9 and 10. The rats were pre- and co-treated with NKT (10 mg/kg, p.o.) administered daily for 11 days. A significant reduction in the activities of myocardial creatine kinase and lactate dehydrogenase, as well as non-enzymatic antioxidants, and alterations in lipids and lipoproteins, along with a rise in plasma lipid peroxidation and intramyocardial lipid accumulation, were observed in ISO-treated rats. ISO administration induced alterations in the activities of enzymes/expressions that played a significant role in altering lipid metabolism. However, NKT treatment favorably modulated all biochemical and molecular parameters altered by ISO and showed protective effects against oxidative stress, dyslipidemia, and altered lipid metabolism, attributed to its free-radical-scavenging and antihyperlipidemic activities in rats with ISO-induced MI. Additionally, NKT decreased the accumulation of lipids in the myocardium as evidenced from Oil red O staining. Furthermore, the in vitro observations demonstrate the potent antioxidant property of NKT. The present study findings are suggestive of the protective effects of NKT on dyslipidemia and the underlying mechanisms. Based on our findings, it can be suggested that NKT or plants rich in NKT can be promising for use as a phytopharmaceutical or nutraceutical in protecting the heart and correcting lipid abnormalities and dyslipidemia, which are risk factors for ischemic heart diseases.

Efficacy and Safety of Abbreviated Eptifibatide Treatment in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

The glycoprotein IIb/IIIa inhibitor eptifibatide, administered as bolus followed by infusion, is an adjunctive antithrombotic treatment during primary percutaneous coronary intervention (PCI) in selected patients with ST-segment elevation myocardial infarction (STEMI). Whether both bolus and infusion are necessary to improve outcomes is unknown. We hypothesized that primary PCI with eptifibatide bolus only is non-inferior to the conventional treatment (bolus and infusion) with regard to infarct size, while reducing bleeding complications. We analyzed 720 consecutive STEMI patients receiving eptifibatide bolus only or conventional treatment in an observational case-control study utilizing propensity score matching of clinical and intervention-specific confounders. Infarct size was estimated based on myocardial bound creatine kinase, creatine kinase (CK), and CK area under the curve values, with a prespecified non-inferiority margin of 20%. Major bleeding was defined as type 2, 3, or 5 on the Bleeding Academic Research Consortium classification. Eptifibatide bolus only was administered to 147 patients (20%), which were matched 1:1 to patients receiving conventional treatment. Based on peak myocardial bound creatine kinase, CK and CK area under the curve values, infarct size was -8.4% (95% CI [-31.2%, 14.4%]), -11.6% (95% CI [-33.5%, 10.3%]), and -13.9% (95% CI [-34.1%, 6.2%]) after eptifibatide bolus, respectively, reaching prespecified noninferiority compared with conventional treatment. Bolus treatment significantly reduced major bleeding complications (OR 0.48, 95% CI [0.30, 0.79]). In conclusion, eptifibatide given as abbreviated bolus only to selected STEMI patients who underwent primary PCI was noninferior regarding infarct size and resulted in less bleeding complications compared with conventional bolus and infusion treatment.