Increased Infarct Size Research Articles

Exogenous ANP Treatment Ameliorates Myocardial Insulin Resistance and Protects against Ischemia-Reperfusion Injury in Diet-Induced Obesity.

Increasing evidence suggests natriuretic peptides (NPs) coordinate interorgan metabolic crosstalk. We recently reported exogenous ANP treatment ameliorated systemic insulin resistance by inducing adipose tissue browning and attenuating hepatic steatosis in diet-induced obesity (DIO). We herein investigated whether ANP treatment also ameliorates myocardial insulin resistance, leading to cardioprotection during ischemia–reperfusion injury (IRI) in DIO. Mice fed a high-fat diet (HFD) or normal-fat diet for 13 weeks were treated with or without ANP infusion subcutaneously for another 3 weeks. Left ventricular BNP expression was substantially reduced in HFD hearts. Intraperitoneal-insulin-administration-induced Akt phosphorylation was impaired in HFD hearts, which was restored by ANP treatment, suggesting that ANP treatment ameliorated myocardial insulin resistance. After ischemia–reperfusion using the Langendorff model, HFD impaired cardiac functional recovery with a corresponding increased infarct size. However, ANP treatment improved functional recovery and reduced injury while restoring impaired IRI-induced Akt phosphorylation in HFD hearts. Myocardial ultrastructural analyses showed increased peri-mitochondrial lipid droplets with concomitantly decreased ATGL and HSL phosphorylation levels in ANP-treated HFD, suggesting that ANP protects mitochondria from lipid overload by trapping lipids. Accordingly, ANP treatment attenuated mitochondria cristae disruption after IRI in HFD hearts. In summary, exogenous ANP treatment ameliorates myocardial insulin resistance and protects against IRI associated with mitochondrial ultrastructure modifications in DIO. Replenishing biologically active NPs substantially affects HFD hearts in which endogenous NP production is impaired.

Bergapten mediated inflammatory and apoptosis through AMPK/eNOS/AKT signaling pathway of isoproterenol-induced myocardial infarction in Wistar rats.

Bergapten (BeG) is explored for its anti-inflammatory and antioxidant properties. Myocardial infarction (MI) is reported to be one of the leading cardiovascular diseases characterized by mitochondrial dysfunction and apoptosis. The main purpose of this study is to assess the cardiopreventive effects of BeG (50 mg/kg) in isoproterenol (ISO)-induced MI in Wistar rats. The increased infarct size after ISO induction was reduced simultaneously on treatment with BeG. Similarly, augmented levels of cardiac biomarkers, namely cardiac troponin T, creatine kinase (CK), cardiac troponin I, and CK-MB were also suppressed by BeG. The increased rate of lipid hydroperoxidesand thiobarbituric acid reactive substances owingto the oxidative stress caused by free radical generation in ISO-inducedrats were also inhibited by BeG. Antioxidants reduce oxidative stress by scavenging free radicals. ISO induction reduces these antioxidant enzymes glutathione peroxidase, catalase, superoxide dismutase, and glutathione, andlevels causing oxidative cardiac damage to the heart tissue. BeG supplementation improved these enzymes synthesis preventing potential damage to the myocardium. Inflammation caused by ISO pretreatment increased the secretion of proinflammatory cytokines in ISO-inducedrats. Pretreatment with BeG suppressed these inflammatory cytokines to a normal level in ISO + BeG-treated rats. The histopathological examination of the morphological characteristics showed that the intensity of cardiac damage caused by ISO induction was less in BeG pretreated rats with less inflammatory cells and no necrosis. BeG also showed promising results in the molecular alteration of AMP-activated protein kinase/endothelialnitric oxide synthase/protein kinase B signaling molecules. These observations emphasize the cardioprotective effects of BeG and its potential use as a drug in the near future.

Red blood cell eNOS is cardioprotective in acute myocardial infarction

Red blood cells (RBCs) were shown to transport and release nitric oxide (NO) bioactivity and carry an endothelial NO synthase (eNOS). However, the pathophysiological significance of RBC eNOS for cardioprotection in vivo is unknown. Here we aimed to analyze the role of RBC eNOS in the regulation of coronary blood flow, cardiac performance, and acute myocardial infarction (AMI) in vivo. To specifically distinguish the role of RBC eNOS from the endothelial cell (EC) eNOS, we generated RBC- and EC-specific knock-out (KO) and knock-in (KI) mice by Cre-induced inactivation or reactivation of eNOS. We found that RBC eNOS KO mice had fully preserved coronary dilatory responses and LV function. Instead, EC eNOS KO mice had a decreased coronary flow response in isolated perfused hearts and an increased LV developed pressure in response to elevated arterial pressure, while stroke volume was preserved. Interestingly, RBC eNOS KO showed a significantly increased infarct size and aggravated LV dysfunction with decreased stroke volume and cardiac output. This is consistent with reduced NO bioavailability and oxygen delivery capacity in RBC eNOS KOs. Crucially, RBC eNOS KI mice had decreased infarct size and preserved LV function after AMI. In contrast, EC eNOS KO and EC eNOS KI had no differences in infarct size or LV dysfunction after AMI, as compared to the controls. These data demonstrate that EC eNOS controls coronary vasodilator function, but does not directly affect infarct size, while RBC eNOS limits infarct size in AMI. Therefore, RBC eNOS signaling may represent a novel target for interventions in ischemia/reperfusion after myocardial infarction.

Indole-3-Carbinol (I3C) Protects the Heart From Ischemia/Reperfusion Injury by Inhibiting Oxidative Stress, Inflammation, and Cellular Apoptosis in Mice.

Strategies for treating myocardial ischemia in the clinic usually include re-canalization of the coronary arteries to restore blood supply to the myocardium. However, myocardial reperfusion insult often leads to oxidative stress and inflammation, which in turn leads to apoptosis and necrosis of myocardial cells, for which there are no standard treatment methods. The aim of this study was to determine the pharmacological effect of indole-3-carbinol (I3C), a phytochemical found in most cruciferous vegetables, in a mouse model of myocardial ischemia/reperfusion injury (MIRI). Our results showed that I3C pretreatment (100 mg/kg, once daily, i. p.) prevented the MIRI-induced increase in infarct size and serum creatine kinase (CK) and lactate dehydrogenase (LDH) in mice. I3C pretreatment also suppressed cardiac apoptosis in MIRI mice by increasing the expression levels of the anti-apoptotic protein Bcl-2 and decreasing the expression levels of several apoptotic proteins, including Bax, caspase-3, and caspase-9. In addition, I3C pretreatment was found to reduce the levels of parameters reflecting oxidative stress, such as dihydroethidium (DHE), malondialdehyde (MDA), reactive oxygen species (ROS), and nitric oxide (NO), while increasing the levels of parameters reflecting anti-oxidation, such as total antioxidant capacity (T-AOC) and glutathione (GSH), in MIRI-induced ischemic heart tissue. I3C pretreatment was also able to remarkably decrease the expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) mRNA in ischemic heart tissue. These results demonstrate that administration of I3C protects the heart from MIRI through its anti-apoptotic, antioxidant, and anti-inflammatory effects.

CARD27: The Effect of Permissive Hypertension on Cerebral Perfusion in VAD Patients with Embolic Stroke

Study: This study aims to investigate the effect of permissive hypertension, a deliberate rise in Mean Arterial Pressure (MAP), on cerebral perfusion in Left Ventricular Assist Device (LVAD) patients with embolic stroke. Methods: A previously published Lumped Parameter Model (LPM) of the human circulation, including pulmonary and systemic circulation, as well as all four cardiac chambers and an LVAD, is divided into circulation of the upper and lower body. The upper circulation is further divided into extracranial and intracranial vessels to study brain perfusion as a function of MAP, as well as peripheral and intracranial resistance. Actual LVAD H-Q characteristic curves model the instantaneous LVAD response to a rise in MAP and the differential increase in resistance between the intracranial region suffering a stroke and the remaining circulation. The resulting changes in intracranial flow rate as MAP increases and vascular resistance is altered are analyzed. Increased resistance in intracranial vasculature is incorporated into a model of a typical embolic stroke, and its influence on cerebral perfusion is studied for a range of LVAD speeds and MAP values. Results: In LVAD patients with embolic stroke, intracranial flow significantly decreases as MAP is allowed to rise. These findings are robust at any LVAD speed, consistent with a significant reduction in LVAD flow with increased afterload. This counterintuitive result of permissive hypertension in LVAD patients is captured by the LPM model of embolic stroke, whereby the increase in intracranial resistance decreases cerebral perfusion even further via a decrease in total cardiac output associated with the increase in MAP. Third-generation LVADs are known to be afterload sensitive. Our results show that a mere increase in MAP from 70 to 80 mmHg decreases cerebral blood flow by a commensurate 15%, thus increasing infarct size, which is quite deleterious (see Fig. 1). Our study confirms there is no role for permissive hypertension in LVAD patients with embolic stroke. Figure 1. Cranial flow rate (Qcranial) as a function of MAP for no embolism (purple) and embolism (teal) cases and for 2400 RPM (circles) and 2800 RPM (squares) LVAD speeds.

Saprirearine protects H9c2 cardiomyocytes against hypoxia/reoxygenation-induced apoptosis by activating Nrf2.

Myocardial infarction is a major cause of mortality and disability worldwide. Ischemia/reperfusion injury is the key factor that results in the increase in infarct size in pathogenesis. To find a novel therapy for myocardial infarction, we have evaluated saprirearine, a natural diterpenoid, using H9c2 cardiomyocytes injured by hypoxia/reoxygenation and explored the possible mechanisms. The results showed that saprirearine improved cell survival by increasing cell viability and blocking the release of lactate dehydrogenase. Meanwhile, saprirearine was found to attenuate mitochondrial dysfunction by inhibiting calcium overload, collapse of the mitochondrial membrane potential, and opening of the mitochondrial permeability transition pore. And oxidative stress resulting from hypoxia/reoxygenation was ameliorated by saprirearine through the reduction of reactive oxygen species and malondialdehyde as well as activation of superoxide dismutase and catalase. Additionally, saprirearine inactivated cysteinyl aspartate-specific proteinase-3, the up-regulated B-cell lymphoma-2 and down-regulated Bcl-2-associated X protein, to inhibit hypoxia/reoxygenation-induced apoptosis. Further research revealed saprirearine-activated nuclear factor E2-related factor-2 in H9c2 cardiomyocytes, which is closely associated with its protective effects. These findings can provide evidence for the discovery of new therapies targeting myocardial infarction and the application of saprirearine in clinical practice.

Nt5e deficiency does not affect post-stroke inflammation and lesion size in a murine ischemia/reperfusion stroke model

SummaryExtracellular ATP released to the ischemic brain parenchyma is quickly metabolized by ectonucleotidases. Among them, the ecto-5′-nucleotidase CD73 encoded by Nt5e generates immunosuppressive adenosine. Genetic deletion of Nt5e led to increased infarct size in the murine photothrombotic stroke model. We aimed at validating this result using the transient middle cerebral artery occlusion (tMCAO) stroke model that represents pathophysiological aspects of penumbra and reperfusion. Three days after tMACO, we did not detect a difference in stroke size between CD73-deficient (CD73−/−) and control mice. Consistent with this finding, CD73−/− and control mice showed comparable numbers and composition of brain-infiltrating leukocytes measured by flow cytometry. Using NanoString technology, we further demonstrated that CD73−/− and control mice do not differ regarding glia cell gene expression profiles. Our findings highlight the potential impact of stroke models on study outcome and the need for cross-validation of originally promising immunomodulatory candidates.

Asporin, an extracellular matrix protein, is a beneficial regulator of cardiac remodeling

Heart failure is accompanied by adverse cardiac remodeling involving extracellular matrix (ECM). Cardiac ECM acts as a major reservoir for many proteins including growth factors, cytokines, collagens, and proteoglycans. Activated fibroblasts during cardiac injury can alter the composition and activity of these ECM proteins. Through unbiased analysis of a microarray dataset of human heart tissue comparing normal hearts (n = 135) to hearts with ischemic cardiomyopathy (n = 94), we identified Asporin (ASPN) as the top differentially regulated gene (DEG) in ischemic cardiomyopathy; its gene-ontology terms relate closely to fibrosis and cell death. ASPN is a Class I small leucine repeat protein member implicated in cancer, osteoarthritis, and periodontal ligament mineralization. However, its role in cardiac remodeling is still unknown. Here, we initially confirmed our big dataset analysis through cells, mice, and clinical atrial biopsy samples to demonstrate increased Aspn expression after pressure overload or cardiac ischemia/reperfusion injury. We tested the hypothesis that Aspn, being a TGFβ1 inhibitor, can attenuate fibrosis in mouse models of cardiac injury. We found that Aspn is released by cardiac fibroblasts and attenuates TGFβ signaling. Moreover, Aspn−/− mice displayed increased fibrosis and decreased cardiac function after pressure overload by transverse aortic constriction (TAC) in mice. In addition, Aspn protected cardiomyocytes from hypoxia/reoxygenation-induced cell death and regulated mitochondrial bioenergetics in cardiomyocytes. Increased infarct size after ischemia/reperfusion injury in Aspn−/− mice confirmed Aspn's contribution to cardiomyocyte viability. Echocardiography revealed greater reduction in left ventricular systolic function post-I/R in the Aspn−/− animals compared to wild type. Furthermore, we developed an ASPN-mimic peptide using molecular modeling and docking which when administered to mice prevented TAC-induced fibrosis and preserved heart function. The peptide also reduced infarct size after I/R in mice, demonstrating the translational potential of ASPN-based therapy. Thus, we establish the role of ASPN as a critical ECM molecule that regulates cardiac remodeling to preserve heart function.

Cardiac consequences of intermittent hypoxia: a matter of dose? A systematic review and meta-analysis in rodents.

AimIntermittent hypoxia (IH) is considered to be a major contributor to obstructive sleep apnoea-related cardiovascular consequences. The present meta-analysis aimed to assess the effects of IH on cardiac remodelling, function and infarct size after myocardial ischaemia across different rodent species and IH severities.Methods and resultsRelevant articles from PubMed, Embase and Web of Science were screened. We performed a random effect meta-analysis to assess the effect of IH on myocardium in rodents by using standardised mean difference (SMD). Studies using rodents exposed to IH and outcomes related to cardiac remodelling, contractile function and response to myocardial ischaemia–reperfusion were included. 5217 articles were screened and 92 were included, demonstrating that IH exposure induced cardiac remodelling, characterised by cardiomyocyte hypertrophy (cross-sectional area: SMD=2.90, CI (0.82–4.98), I2=94.2%), left ventricular (LV) dilation (LV diameter: SMD=0.64, CI (0.18–1.10), I2=88.04%), interstitial fibrosis (SMD=5.37, CI (3.22–7.53), I2=94.8) and apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labelling: SMD=6.70, CI (2.96–10.44), I2=95.9). These structural changes were accompanied by a decrease in LV ejection fraction (SMD=−1.82, CI (−2.52–−1.12), I2=94.22%). Importantly, most of the utilised IH protocols mimicked extremely severe hypoxic disease. Concerning infarct size, meta-regression analyses highlighted an ambivalent role of IH, depending on its severity. Indeed, IH exposure with inspiratory oxygen fraction (FIO2) <7% was associated with an increase in infarct size, whereas a reduced infarct size was reported for FIO2 levels above 10%. Heterogeneity between studies, small study effect and poor reporting of methods in included articles limited the robustness of the meta-analysis findings.ConclusionThis meta-analysis demonstrated that severe IH systematically induces cardiac remodelling and contractile dysfunction in rodents, which might trigger or aggravate chronic heart failure. Interestingly, this meta-analysis showed that, depending on stimulus severity, IH exhibits both protective and aggravating effects on infarct size after experimental ischaemia–reperfusion procedures.

Characterizing the transition from immune response to tissue repair after myocardial infarction by multiparametric imaging

Persistent inflammation following myocardial infarction (MI) precipitates adverse outcome including acute ventricular rupture and chronic heart failure. Molecular imaging allows longitudinal assessment of immune cell activity in the infarct territory and predicts severity of remodeling. We utilized a multiparametric imaging platform to assess the immune response and cardiac healing following MI in mice. Suppression of circulating macrophages prior to MI paradoxically resulted in higher total leukocyte content in the heart, demonstrated by increased CXC motif chemokine receptor 4 (CXCR4) positron emission tomography imaging. This supported the formation of a thrombus overlying the injured region, as identified by magnetic resonance imaging. The injured and thrombotic region in macrophage depeleted mice subsequently showed active calcification, as evidenced by accumulation of 18F-fluoride and by cardiac computed tomography. Importantly, macrophage suppression triggered a prolonged inflammatory response confirmed by post-mortem tissue analysis that was associated with higher mortality from ventricular rupture early after occlusion and with increased infarct size and worse chronic contractile function at 6 weeks after reperfusion. These findings establish a molecular imaging toolbox for monitoring the interplay between adverse immune response and tissue repair after MI. This may serve as a foundation for development and monitoring of novel targeted therapies that may include immune modulation and endogenous healing support.

Hypothermia for Cardioprotection in Patients with St-Elevation Myocardial Infarction: Do Not Give It the Cold Shoulder Yet!

The timely revascularization of an occluded coronary artery is the cornerstone of treatment in patients with ST-elevation myocardial infarction (STEMI). As essential as this treatment is, it can also cause additional damage to cardiomyocytes that were still viable before reperfusion, increasing infarct size. This has been termed “myocardial reperfusion injury”. To date, there is still no effective treatment for myocardial reperfusion injury in patients with STEMI. While numerous attempts have been made to overcome this hurdle with various experimental therapies, the common denominator of these therapies is that, although they often work in the preclinical setting, they fail to demonstrate the same results in human trials. Hypothermia is an example of such a therapy. Although promising results were derived from experimental studies, multiple randomized controlled trials failed to do the same. This review includes a discussion of hypothermia as a potential treatment for myocardial reperfusion injury, including lessons learned from previous (negative) trials, advanced techniques and materials in current hypothermic treatment, and the possible future of hypothermia for cardioprotection in patients with STEMI.

Neuronal GPR81 regulates developmental brain angiogenesis and promotes brain recovery after a hypoxic ischemic insult

Perinatal hypoxic/ischemic (HI) brain injury is a major clinical problem with devastating neurodevelopmental outcomes in neonates. During HI brain injury, dysregulated factor production contributes to microvascular impairment. Glycolysis-derived lactate accumulated during ischemia has been proposed to protect against ischemic injury, but its mechanism of action is poorly understood. Herein, we hypothesize that lactate via its G-protein coupled receptor (GPR81) controls postnatal brain angiogenesis and plays a protective role after HI injury. We show that GPR81 is predominantly expressed in neurons of the cerebral cortex and hippocampus. GPR81-null mice displayed a delay in cerebral microvascular development linked to reduced levels of various major angiogenic factors and augmented expression of anti-angiogenic Thrombospondin-1 (TSP-1) in comparison to their WT littermates. Coherently, lactate stimulation induced an increase in growth factors (VEGF, Ang1 and 2, PDGF) and reduced TSP-1 expression in neurons, which contributed to accelerating angiogenesis. HI injury in GPR81-null animals curtailed vascular density and consequently increased infarct size compared to changes seen in WT mice; conversely intracerebroventricular lactate injection increased vascular density and diminished infarct size in WT but not in GPR81-null mice. Collectively, we show that lactate acting via GPR81 participates in developmental brain angiogenesis, and attenuates HI injury by restoring compromised microvasculature.

Abstract WP255: Cyfip2 Genotype Contributes To Variation In Stroke Vulnerability Among C57BL/6 Mouse Substrains

C57BL/6 mouse substrains of the N lineage derived from the NIH colony later than the separation of the Bailey line in the early 1960s show increased stroke vulnerability relative to C57BL/6J. A missense mutation in Cyfip2 , encoding cytoplasmic FMR1 interacting protein 2, is one of several known variants with a corresponding substrain distribution. This study evaluated reciprocal mouse lines in which the N Cyfip2 variant had been either introduced into C57BL/6J (J- Cyfip2 &lt;N&gt;) or corrected in C57BL/6NJ (NJ- Cyfip2 &lt;J&gt;) by CRISPR-Cas9 editing. Stroke was produced by permanent surgical occlusion of the middle cerebral and ipsilateral common carotid arteries under isoflurane anesthesia, and infarct volume was measured as the region of pallor in brain slices incubated with triphenyltetrazolium chloride at 24 hours. Figure illustrates mean ± SEM (group sizes in parentheses) for mice of the current study, along with prior data for parent substrains. Introduction of the N-lineage mutation markedly increased infarct size in both males and females (†) while maintaining the sex difference seen in J mice (*). Correction of the mutation in NJ had no significant effect. At face value these results establish Cyfip2 genotype as an important determinant of stroke vulnerability since the variant alone is sufficient to increase infarct volume in the J background. However, it is not the sole basis for differing stroke outcome among substrains, and at least one other variant must underlie the heterogeneity in sex difference. Cyfip2 encodes a protein with recognized functional roles in brain and the immune system, but the precise intersection with stroke pathology remains to be established.

ADAMTS9-AS2 Promotes Angiogenesis of Brain Microvascular Endothelial Cells Through Regulating miR-185-5p/IGFBP-2 Axis in Ischemic Stroke.

Ischemic stroke is a common disease threatening human health. ADAMTS9-AS2 is a lncRNA that has been widely studied in tumors, but not in ischemic stroke. The purpose of this study was to investigate the role and potential molecular mechanism of ADAMTS9-AS2 in endothelial cell function after ischemic stroke in vivo and in vitro. The results showed that ADAMTS9-AS2 was decreased in the plasma of acute ischemic stroke (AIS) patients and in the brain tissue and plasma of MCAO mice, and the low expression of ADAMTS9-AS2 was associated with the increase in infarct size. Besides, compared with the control group, MCAO treatment slightly promoted angiogenesis, which was enhanced by the overexpression of ADAMTS9-AS2. Molecular mechanism results indicated that ADAMTS9-AS2 and miR-185-5p affected the pathological process of ischemic stroke through ceRNA mechanism, and IGFBP-2 was a downstream target gene of miR-185-5p. These findings demonstrated that ADAMTS9-AS2 promoted angiogenesis through regulating miR-185-5p/IGFBP-2 axis, suggesting that ADAMTS9-AS2 may be a potential marker for the diagnosis and treatment of neurological diseases.

The nuclear receptor co-repressor 1 is a novel cardioprotective factor against acute myocardial ischemia-reperfusion injury

Acute myocardial ischemia/reperfusion (MI/R) is a major determinant of prognosis in myocardial infarction patients, while effective therapies are currently lacking. Nuclear receptor co-repressor 1 (NCoR1) is emerging as a critical regulator of cell survival and death signaling in mammals. However, the role of NCoR1 in the pathogenesis of acute MI/R injury remains unknown. Here, we observed that NCoR1 was highly expressed in the mouse heart and significantly downregulated after acute MI/R injury. Cardiomyocyte-specific NCoR1 deletion led to significantly increased infarct size and exacerbated cardiac dysfunction compared to wild-type littermates. Moreover, cardiomyocyte-specific NCoR1 deficiency exacerbated MI/R-induced mitochondrial dysfunction and apoptotic pathway activation. Transcriptomic profiling results indicated that cardiomyocyte-specific NCoR1 deficiency pivotally promoted activation of inflammatory pathways. Through integrated omics analysis, signal transducer and activator of transcription 1 (STAT1) was identified as a downstream target trans-repressed by NCoR1. STAT1 activation played a key mediating role in the detrimental effects of NCoR1 deficiency in MI/R injury. Collectively, our findings provided the first evidence that cardiomyocyte-expressed NCoR1 functioned as a crucial cardioprotective factor against acute MI/R injury by targeting the STAT1 pathway in heart.

THE NEUROPROTECTIVE EFFECT OF TOCILIZUMAB IN BRAIN ISCHEMIA REPERFUSION INJURY.

The aim: This research was conducted to assess the possible neuroprotective effect of Tocilizumab in brain ischemic reperfusion injury in rats. Materials and methods: 24 adult Sprague-Dawley rats were divided into four groups randomly. The sham group was given anesthesia at the same time as the other groups and was in the same condition as the other groups. Control group: 1 h of ischemia followed by 4 h of reperfusion. The vehicle group was the same as the control, but they were given the vehicle intraperitoneally (1 ml/kg of 0.9 % NaCl) for 7 days before the ischemia. The treatment group as the control group, but they were given tocilizumab (8 mg/ kg) intraperitoneally for 7 days before ischemia. Results: control group, inducing ischemia/reperfusion increased infarction size considerably (p<0.001), when comparison to the control and vehicle groups, tocilizumab at dose (8 mg/kg) showed a significantly (p<0.001) smaller infraction area. Conclusions: In a cerebral ischemia/reperfusion, a reduction in infarction area in injected with Tocilizumab medication was considered neuroprotective for cerebral ischemia/reperfusion.

Impaired vessel relaxation response and increased infarct size in smooth muscle cannabinoid receptor 1 knockout mice.

Cannabinoids are reported to regulate cardiovascular functions. Cannabinoid receptors 1 (CB1Rs) are widely expressed in both the neuronal system and vascular system, but the contribution of CB1Rs in vascular smooth muscle (CB1RSM) to cardiovascular functions is not clear yet. In this research, we analyzed the effects of CB1RSM on blood pressure, vasoconstriction, and vasodilation abilities by using conditionally CB1R knockout mice (CB1RSMKO). The results show no significant difference in basal blood pressure between the conscious CB1RSMKO and control mice, indicating that CB1RSM is not essential for basal blood pressure maintenance. The constriction of the CB1RSMKO mesenteric artery in vitro was not significantly altered compared with that of the control mice. In contrast, the relaxation to CB1R agonist 2-AG or WIN55212-2 was decreased in CB1RSMKO vessels, suggesting that activation of CB1RSM mediates the vasodilation effect of cannabinoids. Ischemia stroke mouse model was used to further identify the potential function of CB1RSM in pathological conditions, and the results showed that the infarct volume in CB1RSMKO mice is significantly increased compared with the control littermates. These results suggest that vascular CB1R may not play a central role in basal vascular health maintenance but is protective in ischemia states, such as stroke. The protection function may be mediated, at least partly, by the relaxation effect of CB1RSM-dependent activities of endocannabinoids.

Neuroprotection of chromobox 7 knockout in the mouse after cerebral ischemia-reperfusion injury via nuclear factor E2-related factor 2/hemeoxygenase-1 signaling pathway.

To explore the mechanism of chromobox 7 (CBX7)-mediated nuclear factor E2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) signaling pathway in the cerebral ischemia/reperfusion (I/R) injury. The experimental wild-type (WT) and CBX7-/- mice were used to establish cerebral I/R models using the middle cerebral artery occlusion (MCAO) surgery to determine CBX7 levels at different time points after MCAO injury. For all mice, neurological behavior, infarct size, water content, and oxidative stress-related indicators were determined, and transferase (TdT)-mediated dUTP-biotin nick-end labeling (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL)) staining method was employed to observe cell apoptosis, while Western blot to measure the expression of CBX7 and Nrf/HO-1 pathway-related proteins. At 6h, 12h, 24h, 3days, and 7days after mice with MCAO, CBX7 expression was gradually up-regulated and the peak level was reached at 24h. Mice in the WT + MCAO group had increased infarct size, with significant increases in the modified neurological severity scores and water content in the brain, as well as the quantity of TUNEL-positive cells. For the oxidative stress-indicators, an increase was seen in the content of MDA (malondial dehyde), but the activity of SOD (superoxide dismutase) and content of GSH-PX (glutathione peroxidase) and CAT (catalase) were decreased; meanwhile, the protein expression of CBX7, HO-1, and nuclear Nrf2 was up-regulated, while the cytoplasmic Nrf2 was down-regulated. Moreover, CBX7 knockout attenuated I/R injury in mice. Knockout of CBX7 may protect mice from cerebral I/R injury by reducing cell apoptosis and oxidative stress, possibly via activating the Nrf2/HO-1 pathway.

Collateral cardiovascular damage during the COVID-19 pandemic.

Care pathways for ST-segment elevation myocardial infarction (STEMI) were interrupted during the coronavirus disease 2019 (COVID-19) pandemic. A new cardiac MRI study has revealed that increased total ischaemic time for patients with STEMI during major public health restrictions was associated with increased infarct size and other markers of myocardial damage.

High levels of interleukin-6 are associated with final infarct size and adverse clinical events in patients with STEMI

ObjectiveInflammation has emerged as a new treatment target in patients with coronary artery disease and inflammation seems to play an important role in ischaemia/reperfusion injury that follows ST-elevation myocardial infarction...