Cerebral ischemia-reperfusion injury (CIRI), a prevalent stroke-related complication, can lead to severe brain damage. Inflammation is a crucial factor in CIRI pathogenesis, and the complement ...component 3a receptor (C3aR) could be a key mediator in the post-CIRI inflammatory cascade. In this study, the role of C3aR in CIRI was investigated utilizing a middle cerebral artery occlusion (MCAO) model in C3aR knockout (KO) mice. Magnetic resonance imaging (MRI) and neurofunctional assessments revealed that C3aR KO mice exhibited significantly diminished cerebral infarction and improved neurological impairments. Consequently, the focus shifted to searching for a small molecule antagonist of C3aR. JR14a, a new potent thiophene antagonist of C3aR, was injected intraperitoneally into mice 1-h post-MCAO model implementation. The mass spectrometry (MS) results indicated the ability of JR14a to penetrate the blood-brain barrier. Subsequent TTC staining and neurofunctional assessments revealed the efficacy of JR14a in reducing cerebral infarct volume and neurological impairment following MCAO. In addition, immunofluorescence (IF) and immunohistochemistry (IHC) demonstrated attenuated microglial activation, neutrophil infiltration, and blood-brain barrier disruption by JR14a in the MCAO model. Furthermore, enzyme-linked immunosorbent assay (ELISA) and Western blotting supported the role of JR14a in downregulating the expression levels of C3aR, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), as well as the phosphorylation of p65. In conclusion, the findings suggested that C3aR could be a potential therapeutic target for CIRI, and JR14a emerged as a promising treatment candidate.
•Deletion of C3aR mitigates cerebral ischemia-reperfusion injury in mice.•JR14a, a C3aR antagonist, attenuates cerebral ischemia-reperfusion injury.•JR14a diminishes the inflammatory response via suppressing the activation of NF-κB.•JR14a alleviates microglial activation, neutrophil infiltration, and BBB disruption.
Evidences shows that socioeconomic status is reversely associated with the risk of morbidity and mortality for people with cardiovascular disease via pro-inflammation mechanism, but the population ...profile is not deeply defined on. We aimed to investigate the impact of medical insurance coverage on postoperative systemic inflammatory reaction in two kinds of disease populations undergoing distinct cardiac procedures.
A total of 515 patients receiving open mitral valve procedure with high-total expense from May 2013 through May 2021 in Sichuan Provincial People's Hospital were retrospectively collected and stratified according to medical insurance reimbursement: low coverage with high out-pocket (< 30%), medium coverage (≤ 60%, but ≥ 30%), and high coverage (> 60%). Another 118 cases undergoing atrium septum defect (ASD) or patent foramen ovale (PFO) occlusion and taking on consistent low-total expense and low-coverage (< 30%) were also classified according to their insured conditions. The postoperative systemic inflammatory response indexes were high sensitivity C-reactive protein (hs-CRP) and the neutrophil-lymphocyte ratio (NLR).
Low insurance reimbursement population undergoing open mitral valve procedure had a higher level of hs-CRP and NLR but not troponin I protein or lactate within 48 h postoperatively, and higher thoracic drainage, longer ventilation use and stay in intensive care unit. No significant difference in inflammatory indexes existed among diverse medical insurance coverage in population undergoing ASD/PFO occlusion.
Higher inflammatory reaction and weaker clinical recovery was associated with lower insurance coverage population undergoing open mitral valve procedure but not ASD/PFO interventional occlusion procedure.
This study aimed to explore the effects of dexamethasone (DEX) and its combination with luteolin (LUT) on cardiac function during myocardial infarction (MI) in a mouse model. We evaluated whether the ...Keap1/Nrf2 pathway mediates the cardioprotective function of DEX both in vivo and in vitro. The MI mouse model was established by ligation of the left anterior descending coronary artery of wild-type (WT) and Nrf2 knockout mice. After recovery for 21 days, DEX or its combination with LUT was intraperitoneally administered at different doses to WT or Nrf2 knockout mice daily for 7 consecutive days. Mice treated with DEX at a low dose (50 μg/kg/day) showed better cardiac function, fewer cardiac lesions, and smaller infarct sizes compared with MI model mice. DEX (50 μg/kg/day) administration also significantly decreased the production of reactive oxygen species (ROS) and pro-inflammatory cytokines, increased the expression of antioxidative enzymes, and activated the Keap1/Nrf2/HO-1 pathway. However, in Nrf2 knockout mice, DEX treatment did not influence cardiac function, inflammation, the oxidative response, or Keap1/Nrf2/HO-1 activation. In the MI cell model, low concentrations of DEX attenuated the H2O2-induced decreases in cell viability and antioxidative enzyme levels and activated the Keap1/Nrf2/HO-1 pathway. Low doses of DEX exerted protective effects in MIR mice and MI cell models by improving cardiac function, eliminating ROS, inhibiting inflammatory responses, and activating antioxidative responses. The protective effects of DEX on myocardial tissues were mediated by the Keap1/Nrf2/HO-1 pathway.
•Dexamethasone (DEX) at low dose exerts cardio-protective function during myocardial infarction (MI) in a mouse model.•In Nrf2 knockout mice, DEX treatment did not cause any changes in cardiac function improvement.•Combination administration of DEX and luteolin (LUT) further improved heart function restoration in MI mouse model.•DEX restored H2O2-induced decreased cell viability and antioxidative enzyme levels and activated the Keap1/Nrf2/HO-1 pathway in a MI cell model.
Mesenchymal stem cell (MSC) transplantation is regarded as a promising candidate for the treatment of ischaemic heart disease. The major hurdles for successful clinical translation of MSC therapy are ...poor survival, retention, and engraftment in the infarcted heart. Stromal cell-derived factor-1/chemokine receptor 4 (SDF-1/CXCR4) constitutes one of the most efficient chemokine/chemokine receptor pairs regarding cell homing. In this review, we mainly focused on previous studies on how to regulate the SDF-1/CXCR4 interaction through various priming strategies to maximize the efficacy of mesenchymal stem cell transplantation on ischaemic hearts or to facilitate the required effects. The strengthened measures for enhancing the therapeutic efficacy of the SDF-1/CXCR4 interaction for mesenchymal stem cell transplantation included the combination of chemokines and cytokines, hormones and drugs, biomaterials, gene engineering, and hypoxia. The priming strategies on recipients for stem cell transplantation included ischaemic conditioning and device techniques.
Totally video-guided thorascopic cardiac surgery (TVTCS) represents one of the most minimally invasive access routes to the heart. Its feasibility and safety can be guaranteed by an experienced ...surgeon with skilled operative techniques under the guidance of a video signal via thoracoscopy and the imaging from transesophageal echocardiography. At present, this surgical approach has been applied for atrioventricular valve disease, atrial septum defects plus and partial anomalous pulmonary venous drainage, cardiac tumors, hypertrophic obstructive cardiomyopathy, aortic valve disease, and atrial fibrillation. Multimodality cardiovascular imaging, including echocardiography, X-ray, computed tomography (CT), magnetic resonance imaging (MRI) and cardiac catheterization, provides morphologic characteristics and function status of the cardiovascular system and a comprehensive view of the target anatomy. In this review, the benefits of multimodality cardiovascular imaging are summarized for the clinical practice of TVTCS, including the preoperative preparation, intraoperative guidance and postoperative supervision. The disease categories are also individually reviewed on the basis of multimodality cardiovascular imaging, to ensure the feasibility and safety for TVTCS. Cardiovascular imaging technologies not only confirm who is a candidate for this surgical technique, but also provide technical support during the procedure and for postop follow to assess the clinical outcomes. Multimodality cardiovascular imaging is instrumental to provide the requirements to solve the problems for conduction of TVTCS; and to provide individualized protocols with high-resolution and real-time dynamic imaging fusion.
Sympathetic neural remodeling, which involves the inflammatory response, plays an important role in ventricular arrhythmias (VAs) after myocardial infarction (MI). Adrenergic receptors on macrophages ...potentially modulate the inflammatory response. We hypothesized that the increased level of catecholamines activates macrophages and regulates sympathetic neural remodeling after MI. We treated MI mice with either clodronate or metoprolol for 5 days following coronary artery ligation. Mice without treatment after MI and sham-operation mice served as the positive control and negative control, respectively. The norepinephrine levels in plasma and the peri-infarct myocardium increased by almost two-fold in the MI mice compared with the sham-operation mice. Both in vivo and ex vivo electrophysiology examinations showed that the vulnerability to VAs induced by MI was alleviated by macrophage depletion with clodronate and β1-adrenergic blockade with metoprolol, which was in line with circulating and peri-infarct norepinephrine levels, sympathetic reinnervation, and the expression of nerve growth factor (NGF) 7 days after surgery. To further verify the interaction between catecholamines and macrophages, we preconditioned lipopolysaccharide-stimulated RAW 264.7 cells using epinephrine or epinephrine with selective adrenergic antagonists. The expression and release of inflammatory factors including NGF were enhanced by epinephrine. This effect was inhibited by metoprolol but not by other subtype antagonists. Our data suggested that the increased level of catecholamines, traditionally known as positive inotropes secreted from sympathetic nerve endings, might regulate cardiac sympathetic neural remodeling through β1-adrenergic receptors on macrophages, subsequently inducing VAs after MI.
This cohort study aims to assess the connection between cytochrome P450 family 2 subfamily C member 19 (CYP2C19) genotyping, platelet aggregability following oral clopidogrel administration, and the ...occurrence of postoperative atrial fibrillation (POAF) after off‐pump coronary artery bypass graft (CABG) surgery. From May 2017 to November 2022, a total of 258 patients undergoing elective first‐time CABG surgery, receiving 100 mg/day oral aspirin and 75 mg/day oral clopidogrel postoperatively, was included for analysis. These patients were categorized based on CYP2C19 genotyping. Platelet aggregability was assessed serially using multiple‐electrode aggregometry before CABG, 1 and 5 days after the procedure, and before discharge. The incidences of POAF were compared using the log‐rank test for cumulative risk. CYP2C19 genotyping led to categorization into CYP2C19*1*1 (WT group, n = 123) and CYP2C19*2 or *3 (LOF group, n = 135). Baseline characteristics and operative data showed no significant differences between the two groups. The incidence of POAF after CABG was 42.2% in the LOF group, contrasting with 22.8% in the WT group (hazard risk HR: 2.061; 95% confidence interval CI: 1.347, 3.153; p = 0.0013). Adenosine diphosphate‐stimulated platelet aggregation was notably higher in the LOF group compared to the WT group 5 days after CABG (30.4% ± 6.5% vs. 17.9% ± 4.1%, p < 0.001), remaining a similar higher level at hospital discharge (25.6% ± 6.1% vs. 12.2% ± 3.5%, p < 0.001). The presence of CYP2C19 LOF was linked to a higher incidence of POAF and relatively elevated platelet aggregation after CABG surgery under the same oral clopidogrel regimen.
Background. To study the expression and clinical significance of long noncoding RNA- (lncRNA-) MIAT in patients with coronary atherosclerotic heart disease (CAD). Methods. Serum MIAT, interleukin-6 ...(IL-6), and tumor necrosis factor-α (TNF-α) in 106 CAD patients and 89 healthy donors were detected. Correlations between serum MIAT and serum IL-6 and TNF-α were analyzed. Risk factors for patients with CAD were analyzed by multiple factor analysis. Results. Compared with healthy donors, serum lncRNA-MIAT was significantly increased in CAD patients. Serum MIAT was positively correlated with serum IL-6 and TNF-α in CAD. Multivariate analysis found that hypertension (OR (95% CI) = 3.471 (2.180–4.091), P=0.011), diabetes (OR (95% CI) = 3.682 (1.698–4.897), P=0.003), HDL-C (OR (95% CI) = 3.372 (1.760–6.920), P=0.001), and serum MIAT expression (OR (95% CI) = 2.687 (1.683–7.468), P=0.001) were independent risk factors for CAD. Conclusions. Serum lncRNA-MIAT in CAD patients was significantly increased, which may be a potential marker for diagnosis and prognosis of CAD.
Remote Ischemic postconditioning (RIPoC) is a cardioprotective strategy for alleviating the reperfusion injury. We hypothesized that RIPoC or ischemic postconditioning (IPoC) could protect the ...engrafted mesenchymal stem cells (MSCs) in reperfusion myocardium.
Female Sprague-Dawley rats were subject to 30 minutes of occlusion of left anterior descending (LAD). Ischemia reperfusion (IR) received reperfusion without interruption after ischemia. RIPoC received 3 cycles of 30 seconds reperfusion and re-occlusion on the limb at the onset of reperfusion. IPoC received 3 cycles of 30 seconds reperfusion and re-occlusion on the LAD at the same time. Male MSCs were intramyocardially administered after ischemia.
Compared with that in IR group, ischemic myocardium in RIPoC+IPoC group, RIPoC group and IPoC group were found to have higher anti-oxidative stress and mitochondrial function level, lower lipid peroxidation and inflammational injury level, higher level of stromal cell derived factor-1 alpha and vascular endothelium growth factor gene expression at 3 days later. By immunohistochemical examination and quantitative polymerase chain reaction, more engrafted MSCs, better cardiac function and less cardiac fibrosis in RIPoC+IPoC group, RIPoC group and IPoC group were detected at 3 weeks after delivery. There were no significant differences between RIPoC and RIPoC+IPoC group.
Combination therapy using intramyocardial MSCs transplantation with RIPoC enhanced transplantation efficiency and cardiac function, and reduced cardiac fibrosis. These beneficial effects were mainly attributed to hospitable milieu for engrafted cells. IPoC could not render additional effect on MSCs engraftment elicited by RIPoC.
Atrial fibrillation (AF) is the most common arrhythmia. Patients with valvular heart disease (VHD) frequently have AF. Growing evidence demonstrates that a specifically altered pattern of microRNA ...(miRNA) expression is related to valvular heart disease with atrial fibrillation (AF-VHD) processes. However, the combinatorial regulation by multiple miRNAs in inducing AF-VHD remains largely unknown.
The work identified AF-VHD-specific miRNAs and their combinations through mapping miRNA expression profile into differential co-expression network. The expressions of some dysregulated miRNAs were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The regulations of signaling pathways by the combinatorial miRNAs were predicted by enrichment analysis tools.
Thirty-two differentially expressed (DE) miRNAs were identified to be AF-VHD-specific, some of which were new findings. These miRNAs interacted to form 5 combinations. qRT-PCR confirmed the different expression of several identified miRNAs, which illustrated the reliability and biomarker potentials of 32 dysregulation miRNAs. The biological characteristics of combinatorial miRNAs related to AF-VHD were highlighted. Twelve signaling pathways regulated by combinatorial miRNAs were predicted to be possibly associated with AF-VHD.
The AF-VHD-related signaling pathways regulated by combinatorial miRNAs may play an important role in the occurrence of AF-VHD. The work brings new insights into biomarkers and miRNA combination regulation mechanism in AF-VHD as well as further biological experiments.
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