CC类趋化因子亚家族与心肌梗死的研究进展

CC类趋化因子亚家族是趋化因子家族中成员最多、研究最广泛的一大类细胞因子,其主要功能参与炎症细胞激活、迁移、粘附等病理生理过程。大量研究表明,CC类趋化因子亚家族成员参与了心肌梗死后病理过程的各个阶段。其中研究最为深入的为单核细胞趋化蛋白-1（monocyte chemoattractant protein-1,MCP-1）及其受体CC趋化因子受体2（CC chemokine receptor 2,CCR2）,在心肌梗死后炎症期、增殖期及疤痕愈合期都发挥了重要作用从而影响梗死后心室重构。近年来,CC类趋化因子亚家族其他成员亦被逐渐揭示参与了心肌梗死的发展。本文结合以往大量文献将对CC类趋化因子亚家族在心肌梗死各个阶段中尤其是梗死后各期对于心室重构的影响进行综述,以期为今后的实验研究提供方向及疾病的预防和治疗提供药物靶点。     

Increased Eotaxin and MCP-1 Levels in Serum from Individuals with Periodontitis and in Human Gingival Fibroblasts Exposed to Pro-Inflammatory Cytokines

Periodontitis is a chronic inflammatory disease of tooth supporting tissues resulting in periodontal tissue destruction, which may ultimately lead to tooth loss. The disease is characterized by continuous leukocyte infiltration, likely mediated by local chemokine production but the pathogenic mechanisms are not fully elucidated. There are no reliable serologic biomarkers for the diagnosis of periodontitis, which is today based solely on the degree of local tissue destruction, and there is no available biological treatment tool. Prompted by the increasing interest in periodontitis and systemic inflammatory mediators we mapped serum cytokine and chemokine levels from periodontitis subjects and healthy controls. We used multivariate partial least squares (PLS) modeling and identified monocyte chemoattractant protein-1 (MCP-1) and eotaxin as clearly associated with periodontitis along with C-reactive protein (CRP), years of smoking and age, whereas the number of remaining teeth was associated with being healthy. Moreover, body mass index correlated significantly with serum MCP-1 and CRP, but not with eotaxin. We detected higher MCP-1 protein levels in inflamed gingival connective tissue compared to healthy but the eotaxin levels were undetectable. Primary human gingival fibroblasts displayed strongly increased expression of MCP-1 and eotaxin mRNA and protein when challenged with tumor necrosis factor-α (TNF-α and interleukin-1β (IL-1β), key mediators of periodontal inflammation. We also demonstrated that the upregulated chemokine expression was dependent on the NF-κΒ pathway. In summary, we identify higher levels of CRP, eotaxin and MCP-1 in serum of periodontitis patients. This, together with our finding that both CRP and MCP-1 correlates with BMI points towards an increased systemic inflammatory load in patients with periodontitis and high BMI. Targeting eotaxin and MCP-1 in periodontitis may result in reduced leukocyte infiltration and inflammation in periodontitis and maybe prevent tooth loss.     

Differential Cardiovascular Outcomes after Dipeptidyl Peptidase-4 Inhibitor,Sulfonylurea, and Pioglitazone Therapy,All in Combination with Metformin,for Type 2 Diabetes: A Population-Based Cohort Study

Background/ObjectivesData on the comparative effectiveness of oral antidiabetics on cardiovascular outcomes in a clinical practice setting are limited. This study sought to determine whether a differential risk of cardiovascular disease (CVD) exists for the combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor plus metformin versus a sulfonylurea derivative plus metformin or pioglitazone plus metformin.MethodsWe conducted a cohort study of 349,476 patients who received treatment with a DPP-4 inhibitor, sulfonylurea, or pioglitazone plus metformin for type 2 diabetes using the Korean national health insurance claims database. The incidence of total CVD and individual outcomes of myocardial infarction (MI), heart failure (HF), and ischemic stroke (IS) were assessed using the hazard ratios (HRs) estimated from a Cox proportional-hazards model weighted for a propensity score.ResultsDuring follow-up, 3,881 patients developed a CVD, including 428 MIs, 212 HFs, and 1,487 ISs. The adjusted HR with 95% confidence interval (CI) for a sulfonylurea derivative plus metformin compared with a DPP-4 inhibitor plus metformin was 1.20 (1.09-1.32) for total CVD; 1.14 (1.04-1.91) for MI; 1.07 (0.71-1.62) for HF; and 1.51 (1.28-1.79) for IS. The HRs with 95% CI for total CVD, MI, HF, and IS for pioglitazone plus metformin were 0.89 (0.81-0.99), 1.05 (0.76-1.46), 4.81 (3.53-6.56), and 0.81 (0.67-0.99), respectively.ConclusionsCompared with a DPP-4 inhibitor plus metformin, treatment with a sulfonylurea drug plus metformin was associated with increased risks of total CVD, MI, and IS, whereas the use of pioglitazone plus metformin was associated with decreased total CVD and IS risks.     

Effect of Folic Acid Supplementation on Levels of Circulating Monocyte Chemoattractant Protein-1 and the Presence of Intravascular Ultrasound Derived Virtual Histology Thin-Cap Fibroatheromas in Patients with Stable Angina Pectoris

Background

Virtual Histology Intravascular Ultrasound (VH–IVUS) may be used to detect early signs of unstable coronary artery disease. Monocyte Chemoattractant Protein-1 (MCP-1) is linked with coronary atherosclerosis and plaque instability and could potentially be modified by folic acid treatment.

Methods

In a randomized, prospective study, 102 patients with stable angina pectoris (SAP) received percutaneous coronary intervention and established medical treatment as well as either homocysteine-lowering folic acid/vitamin B₁₂ (±B₆) or placebo (±B₆) for 1 year before VH–IVUS was performed. The presence of VH-Thin-Cap Fibroatheroma (VH-TCFA) in non-intervened coronary vessels was registered and serum levels of MCP-1 were measured. The patients were subsequently followed for incident myocardial infarction (MI).

Results

Patients treated with folic acid/vitamin B₁₂ had a geometric mean (SD) MCP-1 level of 79.95 (1.49) versus 86.00 (1.43) pg/mL for patients receiving placebo (p-value 0.34). VH-TCFA lesions were present in 7.8% of patients and did not differ between intervention arms (p-value 0.47). Serum levels of MCP-1 were 1.46 (95% CI 1.12 to 1.92) times higher in patients with VH-TCFA lesions than in those without (p-value 0.005). Afterwards, patients were followed for median 2.1 years and 3.8% experienced a myocardial infarction (MI), which in post-hoc Cox regression analyses was independently predicted by both MCP-1 (P-value 0.006) and VH-TCFA (p-value 0.01).

Conclusions

In patients with SAP receiving established medical treatment, folic acid supplementation is not associated with either presence of VH-TCFA or levels of MCP-1. MCP-1 is however associated with VH-TCFA, a finding corroborated by increased risk for future MI. ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00354081","term_id":"NCT00354081"}}NCT00354081.     

Irbesartan attenuates ischemic brain damage by inhibition of MCP-1/CCR2 signaling pathway beyond AT₁ receptor blockade

Angiotensin II type 1 (AT(1)) receptor blockers (ARBs) are known to prevent the onset of stroke and to attenuate neural damage. Additional beneficial effects of ARBs, independent of AT(1) receptor blockade, have been highlighted. Irbesartan is reported to act as an antagonist of the monocyte chemoattractant protein-1 (MCP-1) receptor, C-C chemokine receptor 2 (CCR2), due to its molecular structure. We examined the possible synergistic effects of co-administration of irbesartan with propagermanium, a CCR2 antagonist, on ischemic brain damage. Administration of propagermanium decreased ischemic brain area after middle cerebral artery occlusion (MCAO). To study the possible synergistic effects of propagermanium with ARBs, we employed non-effective lower doses of irbesartan and losartan. Administration of irbesartan with propagermanium decreased the ischemic brain area more markedly compared with propagermanium alone, but co-administration of losartan did not. MCP-1 mRNA level was significantly increased on the ipsilateral side after MCAO, and administration of irbesartan with propagermanium decreased the MCP-1 level, whereas co-administration of losartan did not. Similar results were obtained for MCP-1 protein level. CCR2 mRNA expression was significantly elevated on the ipsilateral side; however, no significant difference was observed between each group. mRNA levels of other inflammatory cytokines such as TNF-α and IL-1β also significantly increased on the ipsilateral side, but the expression levels were not changed by each drug treatment. Taking these findings together, irbesartan exerts more beneficial effects on ischemic brain damage with an MCP-1 receptor blocker, at least due to its inhibitory effects on MCP-1/CCR2 signaling beyond AT(1) receptor blockade.     

Chemokines and their receptors in the brain: pathophysiological roles in ischemic brain injury

Chemokines constitute a large family of structurally-related small cytokines originally identified as factors regulating the migration of leukocytes in inflammatory and immune responses. Production of chemokines and their receptors in the brain has been reported under various pathological conditions. We revealed that mRNA expression for monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha), members of the CC chemokines, was induced in the rat brain after focal cerebral ischemia, and that intracerebroventricular injection of viral macrophage inflammatory protein-II (vMIP-II), a broad-spectrum chemokine receptor antagonist, reduced infarct volume in a dose-dependent manner. These findings suggest that brain chemokines are involved in ischemic injury, and that chemokine receptors are potential targets for therapeutic intervention in stroke. Another potential target to suppress the harmful effect of chemokines is the signal transmission system(s) regulating the chemokine production. However, very little is known about how the production of chemokines is regulated in the ischemic brain. We examined the induction of MCP-1 production by excitotoxic injury via activation of NMDA receptors in the cortico-striatal slice cultures, and found that excitotoxic injury induced MCP-1 production in the slice culture. Almost all of the MCP-1 immunoreactivity was located on astrocytes. On the other hand, NMDA-treatment failed to increase the MCP-1 production in the enriched astrocyte cultures, indicating that NMDA dose not directly act on astrocytes. Some signal(s) is likely sent from the injured neurons to astrocytes to induce the MCP-1 production. These results showed that organotypic slice cultures are useful to investigate the molecular mechanism regulating the chemokine production in the injured brain.     

Correlation between MMP-9 and extracellular cytokine HMGB1 in prediction of human ischemic stroke outcome

Ischemic stroke (IS) outcome predictors include clinical features, biochemical parameters and some risk factors. The relations between two main players in the ischemic brain, MMPs and HMGB1, were estimated in the plasma of ischemic stroke patients stratified according to the Glasgow Outcome Scale and the Oxfordshire Community Stroke Project classification. IS patients exhibited higher plasma concentration of MMP-9 and the inflammatory cytokine HMGB1 compared with healthy controls. A full-blown correlation between MMP-9 activation and increased plasma MMP-9 concentration was observed in case of IS patients. A similar activity of MMP-2 and MMP-12 was characteristic of healthy volunteers and IS patients. In patients with ischemic stroke increased plasma levels of MMP-9 and HMGB1 are associated with a poor functional outcome and are significantly correlated with each other (P = 0.0054). We suggest that diagnostic benefits will be obtained if plasma HMGB1 levels are measured for IS patients in addition to MMP-9.     

Nootkatone attenuates myocardial oxidative damage,inflammation, and apoptosis in isoproterenol-induced myocardial infarction in rats

BackgroundMyocardial infarction (MI) is a lethal manifestation of cardiovascular diseases. Oxidative stress, inflammation, and subsequent cell death are known to play crucial roles in the pathogenesis of MI. Despite tremendous developments in interventional cardiology, there is need for novel drugs for the prevention and treatment of MI. For the development of novel drugs, usage of natural products has gained attention as a therapeutic approach for ischemic myocardial injury. Among many popular plant-derived compounds, Nootkatone (NKT), a natural bioactive sesquiterpene, abundantly found in grapefruit, has attracted attention for its plausible health benefits and pharmacological properties.PurposeThe present study investigated the cardioprotective effects of NKT in rats against MI induced by isoproterenol (ISO), a synthetic catecholamine and β-adrenergic agonist that produces MI in a physiologically relevant manner.MethodsMI was induced in male Wistar albino rats by subcutaneous injection of ISO (85 mg/kg body weight) on 9^th and 10^th day. Rats were pre- and co-treated with NKT (10 mg/kg) through daily oral administration for eleven days.ResultsISO-induced MI was characterized by a significant decline in cardiac function, increased serum levels of cardiomyocyte injury markers, enhanced oxidative stress, and altered PI3K/Akt and NrF2/Keap1/HO-1 signaling pathways. ISO also elevated the levels of myocardial pro-inflammatory cytokines, promoted lysosomal dysfunction, altered TLR4-NFκB/MAPK signaling, and triggered intrinsic apoptotic pathway in heart tissues. However, NKT administration significantly restored or modulated majority of the altered biochemical and molecular parameters in ISO-treated rats. Furthermore, histopathological observations confirmed the myocardial restoring effect of NKT.ConclusionThe present study concludes the cardioprotective effects and underlying mechanisms of NKT against ISO-induced MI in rats, and suggests that NKT or plants containing NKT could be an alternative to cardioprotective agents in ischemic heart diseases.     

The Uremic Toxin Adsorbent AST-120 Abrogates Cardiorenal Injury Following Myocardial Infarction

An accelerated progressive decline in renal function is a frequent accompaniment of myocardial infarction (MI). Indoxyl sulfate (IS), a uremic toxin that accumulates from the early stages of chronic kidney disease (CKD), is contributory to both renal and cardiac fibrosis. IS levels can be reduced by administration of the oral adsorbent AST-120, which has been shown to ameliorate pathological renal and cardiac fibrosis in moderate to severe CKD. However, the cardiorenal effect of AST-120 on less severe renal dysfunction in the post-MI setting has not previously been well studied. MI-induced Sprague-Dawley rats were randomized to receive either AST-120 (MI+AST-120) or were untreated (MI+Vehicle) for 16 weeks. Serum IS levels were measured at baseline, 8 and 16 weeks. Echocardiography and glomerular filtration rate (GFR) were assessed prior to sacrifice. Renal and cardiac tissues were assessed for pathological changes using histological and immunohistochemical methods, Western blot analysis and real-time PCR. Compared with sham, MI+Vehicle animals had a significant reduction in left ventricular ejection fraction (by 42%, p<0.001) and fractional shortening (by 52%, p<0.001) as well as lower GFR (p<0.05) and increased serum IS levels (p<0.05). A significant increase in interstitial fibrosis in the renal cortex was demonstrated in MI+Vehicle animals (p<0.001). Compared with MI+Vehicle, MI+AST-120 animals had increased GFR (by 13.35%, p<0.05) and reduced serum IS (p<0.001), renal interstitial fibrosis (p<0.05), and renal KIM-1, collagen-IV and TIMP-1 expression (p<0.05). Cardiac function did not change with AST-120 treatment, however gene expression of TGF-β1 and TNF-α as well as collagen-I and TIMP-1 protein expression was decreased in the non-infarcted myocardium (p<0.05). In conclusion, reduction of IS attenuates cardio-renal fibrotic processes in the post-MI kidney. KIM-1 appears to be a sensitive renal injury biomarker in this setting and is correlated with serum IS levels.     

Irbesartan attenuates ischemic brain damage by inhibition of MCP-1/CCR2 signaling pathway beyond AT1 receptor blockade

Angiotensin II type 1 (AT₁) receptor blockers (ARBs) are known to prevent the onset of stroke and to attenuate neural damage. Additional beneficial effects of ARBs, independent of AT₁ receptor blockade, have been highlighted. Irbesartan is reported to act as an antagonist of the monocyte chemoattractant protein-1 (MCP-1) receptor, C–C chemokine receptor 2 (CCR2), due to its molecular structure. We examined the possible synergistic effects of co-administration of irbesartan with propagermanium, a CCR2 antagonist, on ischemic brain damage. Administration of propagermanium decreased ischemic brain area after middle cerebral artery occlusion (MCAO). To study the possible synergistic effects of propagermanium with ARBs, we employed non-effective lower doses of irbesartan and losartan. Administration of irbesartan with propagermanium decreased the ischemic brain area more markedly compared with propagermanium alone, but co-administration of losartan did not. MCP-1 mRNA level was significantly increased on the ipsilateral side after MCAO, and administration of irbesartan with propagermanium decreased the MCP-1 level, whereas co-administration of losartan did not. Similar results were obtained for MCP-1 protein level. CCR2 mRNA expression was significantly elevated on the ipsilateral side; however, no significant difference was observed between each group. mRNA levels of other inflammatory cytokines such as TNF-α and IL-1β also significantly increased on the ipsilateral side, but the expression levels were not changed by each drug treatment. Taking these findings together, irbesartan exerts more beneficial effects on ischemic brain damage with an MCP-1 receptor blocker, at least due to its inhibitory effects on MCP-1/CCR2 signaling beyond AT₁ receptor blockade.     

Serum MMP-9 activity as a diagnosing marker for the developing heart failure of post MI patients

Myocardial infarction (MI) is the result, in mostly cases, of the destabilization and rupture of atherosclerotic lesions. The destruction of cardiac tissue resulting from myocardial ischemia could further result in heart failure. It has been suggested that plaque instability may be mediated by matrix metalloproteinase (MMP) family. Studies have identified increased MMP-2 and MMP-9 in human platelets, and acute myocardial infarction patients with elevated MMP-2 and MMP-9 levels. However, the alteration of MMP-2 and MMP-9 from post MI left ventricle remodeling to heart failure remains to be clarified. The purpose of this study is to investigate the serum concentrations and activities of MMP-2 and MMP-9 in the developing heart failure from post MI patients. Twenty eight patients with MI without heart failure (Killip FC I) (group A; compensated) and twenty seven MI patients with heart failure (Killip II-III) (group B; decompensated) were collected to evaluate the serum levels and activities of MMP-2 and MMP-9 by ELISA and Zymography, respectively. It was observed that the both serum levels and activities of MMP-9 significantly increased (P < 0.01) in decompensated group compared to compensated group, but there was no significant difference of serum MMP-2 levels and activities between two groups. The highly elevated serum MMP-9 concentration of decompensated patients is not related with inflammatory or localized infarct area of myocardium and the real mechanisms remain to be revealed. We suggest that the increase of MMP-9 levels and activity may be used as a new marker to diagnose the development of heart failure in patients with post MI, and provide the therapeutic implications in the future.     

High plasma levels of MCP-1 and eotaxin provide evidence for an immunological basis of fibromyalgia

Fibromyalgia (FMS), a predominantly female (85%) syndrome, affects an estimated 2% of the US population with skeletal muscle ache, fatigue, headache, and sleep disorder. The pathogenesis of FMS is unknown and there is no laboratory test for diagnosis. In this study, plasma levels of 25 cytokines and chemokines in 92 female patients with FMS and 69 family members were measured compared to 77 controls. Trans-endothelial migration of normal leukocytes in response to FMS plasma and the cytokine profile of human myoblasts were analyzed. High levels of MCP-1 (P < 0.001) and eotaxin (P < 0.01) were found in patients and family members compared to controls. Patients (56/92) treated with the single agent guaifenesin (>3 months) had higher levels of eotaxin than those not treated (P < 0.01). Diluted plasma from patients increased the migration of normal eosinophils and monocytes, but not neutrophils, through an endothelial/Matrigel barrier only when mast cells are included in the lower wells (P < 0.05). Furthermore, myoblasts can secrete MCP-1, eotaxin, and IP-10, while treatment with MCP-1 caused secretion of IL-1beta, eotaxin and IP-10. FMS is associated with inflammatory chemokines, that MCP-1 and eotaxin may contribute to the symptoms of FMS, and that similar cytokine profiles found in family members support the idea that FMS has a genetic component. Furthermore, the chemokine profile associated with FMS has direct effects on the migration of eosinophils and monocytes in the presence of mast cells, and skeletal muscle itself may secrete.     

LncRNA NONRATT021972 involved the pathophysiologic processes mediated by P2X<Subscript>7</Subscript> receptors in stellate ganglia after myocardial ischemic injury

Adenosine triphosphate (ATP) acts on P2X receptors to initiate signal transmission. P2X₇ receptors play a role in the pathophysiological process of myocardial ischemic injury. Long noncoding RNAs (lncRNAs) participate in numerous biological functions independent of protein translation. LncRNAs are implicated in nervous system diseases. This study investigated the effects of NONRATT021972 small interference RNA (siRNA) on the pathophysiologic processes mediated by P2X₇ receptors in stellate ganglia (SG) after myocardial ischemic injury. Our results demonstrated that the expression of NONRATT021972 in SG was significantly higher in the myocardial ischemic (MI) group than in the control group. Treatment of MI rats with NONRATT021972 siRNA, the P2X₇ antagonist brilliant blue G (BBG), or P2X₇ siRNA improved the histology of injured ischemic cardiac tissues and decreased the elevated concentrations of serum myocardial enzymes, creatine kinase (CK), CK isoform MB (CK-MB), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) compared to the MI rats. NONRATT021972 siRNA, BBG, or P2X₇ siRNA treatment in MI rats decreased the expression levels of P2X₇ immunoreactivity, P2X₇ messenger RNA (mRNA), and P2X₇ protein, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) in the SG compared to MI rats. NONRATT021972 siRNA treatment prevented the pathophysiologic processes mediated by P2X₇ receptors in the SG after myocardial ischemic injury.     

Chemokines in proliferative diabetic retinopathy and proliferative vitreoretinopathy

PURPOSE: To determine levels of the chemokines CCL1/I-309, CCL2/MCP-1, CCL3/MIP-1alpha, CCL4/MIP-1beta, CCL7/MCP-3, CCL8/MCP-2, CXCL5/ENA-78, CXCL6/GCP-2, CXCL10/IP-10, and CXCL11/I-TAC in the vitreous humor and serum, from patients with proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR), and rhegmatogenous retinal detachment with no PVR (RD), and to investigate the expression of MCP-1, CXCL12/SDF-1, and the chemokine receptor CXCR3 in epiretinal membranes. METHODS: Paired vitreous humor and serum samples were obtained from patients undergoing vitrectomy for the treatment of RD (57 specimens), PVR (32 specimens), and PDR (88 specimens). The levels of chemokines were measured by enzyme-linked immunosorbent assays. Eighteen PDR and 5 PVR membranes were studied by immunohistochemical techniques. RESULTS: Of all the chemokines studied, only MCP-1 and IP-10 were detected in vitreous humor samples. MCP-1 levels in vitreous humor samples were significantly higher than in serum samples (p < 0.001). MCP-1 levels were significantly higher in vitreous humor samples from patients with PVR and PDR compared with RD (p = 0.0002). MCP-1 levels in vitreous humor samples from patients with active PDR were significantly higher than in inactive PDR cases (p = 0.0224). IP-10 levels in vitreous humor samples were significantly higher than in serum samples (p = 0.0035). IP-10 levels were significantly higher in vitreous humor samples from patients with PVR and PDR compared with RD (p = 0.0083). The incidence of IP-10 detection in vitreous humor samples was significantly higher in active PDR cases compared with inactive cases (p = 0.0214). There was a significant association between the incidence of IP-10 detection and increased levels of MCP-1 in vitreous humor samples from all patients, and patients with RD and PDR (p < 0.001 for all comparisons). MCP-1, and SDF-1 were localized in myofibroblasts in PVR and PDR membranes and in vascular endothelial cells in PDR membranes. CXCR3 was expressed by vascular endothelial cells in PDR membranes. CONCLUSION: MCP-1, IP-10 and SDF-1 may participate in pathogenesis of PVR and PDR. Myofibroblasts and vascular endothelial cells are the major cell types expressing MCP-1, SDF-1, and CXCR3 in epiretinal membranes.     

Post-infarct treatment with [Pyr1]-apelin-13 reduces myocardial damage through reduction of oxidative injury and nitric oxide enhancement in the rat model of myocardial infarction

Apelin is a newly discovered peptide that has been recently shown to have cardioprotective effects in the animal model of myocardial infarction (MI) and ischemia/reperfusion (I/R) injuries. The aim of the present study was to investigate the long term cardioprotective effect of [Pyr1]-apelin-13 in the rat model of MI. Male Wistar rats (n = 22) were randomly divided into three groups: (1) sham operated group (2) control MI group and (3) MI treated with apelin (MI-AP group). MI animals were subjected to 30 min of left anterior descending coronary artery (LAD) ligation and 14 days of reperfusion. 24 h after LAD ligation, apelin (10 nmol/kg/day) was administered i.p. for 5 days. Blood sampling was performed at days 1, 3, 5 and 7 after MI for determination of serum changes of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), malondialdehyde (MDA) and nitric oxide (NO). Myocardial infarct size (IS) and hemodynamic function were also measured at the end of the study at day 14. We found out that post infarct treatment with apelin decreases infarct size, serum levels of LDH, CK-MB and MDA and increases heart rate and serum level of NO in the consecutive days, but there were no significant differences in blood pressure in the MI-AP group in comparison with MI. In conclusion, apelin has long term cardioprotective effects against myocardial infarction through attenuation of cardiac tissue injury and lipid peroxidation and enhancement of NO production.     

Validation of the wall motion score and myocardial performance indexes as novel techniques to assess cardiac function in mice after myocardial infarction

The aim of this study was to determine the feasibility and accuracy of wall motion score index (WMSI) and myocardial performance index (MPI) for measuring regional and global left ventricular (LV) function with use of high-resolution echocardiography after myocardial infarction (MI) in mice. In 48 mice, myocardial infarction was induced by ligation in the middle of the left anterior descending coronary artery. Echocardiography was performed under anesthesia at baseline and 1 mo after MI. WMSI was analyzed by a 16-segment model on short-axis views, and wall motion was scored as 1 for normal, 2 for hypokinetic, 3 for akinetic, 4 for dyskinetic, and 5 for aneurysmal. WMSI was calculated as the sum of scores divided by the total number of segments. MPI was calculated on the basis of isovolumetric contraction time (IVCT), isovolumetric relaxation time (IVRT), and ejection time (ET): MPI = (IVCT + IVRT)/ET. We measured LV ejection fraction (LVEF), end-systolic and end-diastolic volumes (ESV and EDV), fractional shortening (FS), and infarct size (IS). LVEF at 4 wk after MI was reduced at 32.8 +/- 9.0%. Linear correlation analyses showed that WMSI (1.6 +/- 0.3) correlated with LVEF (r = -0.84, P < 0.0005), FS (r = -0.43, P = 0.003), and IS (34.3 +/- 15.3%, r = 0.86, P < 0.0005). MPI (0.67 +/- 0.09) correlated with LVEF (r = -0.67, P < 0.0005) and IS (r = 0.72, P < 0.0005). MPI also correlated with mitral inflow velocity (r = -0.68, P < 0.0005) and deceleration time (r = -0.42, P = 0.003). Stepwise regression analysis revealed that WMSI was independently associated with IS. IS, FS, mitral inflow velocity, and deceleration time were independent determinants of MPI. In conclusion, echocardiographic assessments of WMSI and MPI in mice are feasible and correlate strongly with two-dimensional measurement of LV function and IS. These novel parameters provide additional noninvasive assessment of regional and global LV function in mice after MI.     

Etanercept Attenuates Myocardial Ischemia/Reperfusion Injury by Decreasing Inflammation and Oxidative Stress

The protective role of etanercept in myocardial ischemia/reperfusion is not well understood. The aim of this study was to investigate whether etanercept modulates neutrophil accumulation, TNF-α induction and oxidative stress in an ischemia/reperfusion injured rat heart model. Rats were randomly exposed to sham operation, myocardial ischemia/reperfusion (MI/R) alone, MI/R+ etanercept. The results demonstrated that compared to MI/R, etanercept reduced myocardial infarction area, myocardial myeloperoxidase (MPO) levels, serum creatinine kinase (CK) and lactate dehydrogenase (LDH) levels, and both serum and myocardial TNF-α production. Etanercept also markedly enhanced the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), and reduced the level of malondialdehyde (MDA) in MI/R rats. In summary, our data suggested that etanercept has protective effects against MI/R injury in rats, which may be attributed to attenuating inflammation and oxidative stress.     

Mineral Metabolism Markers Are Associated with Myocardial Infarction and Hemorrhagic Stroke but Not Ischemic Stroke in Hemodialysis Patients: A Longitudinal Study

Background/Aims

The associations between phosphate, calcium, and intact parathyroid hormone (PTH) levels and composite cardiovascular end points have been studied. This study examined the associations of these markers with myocardial infarction (MI) and stroke separately.

Methods

This is a longitudinal study on 65,849 hemodialysis patients from the Japan Renal Data Registry. Patients with prior events at baseline were excluded. Predictors were phosphate, albumin-corrected calcium, intact PTH, and calcium times phosphate product levels. Outcome was the first episode of MI or stroke during a 1-year observation period. Data were analyzed using multiple logistic regression analyses, adjusted for potential confounders.

Results

There were 1,048, 651, and 2,089 events of incident MI, hemorrhagic, and ischemic stroke, respectively. Incident MI was associated with phosphate levels ≥6.5 mg/dL (odds ratio 1.49; confidence interval 1.23–1.80) compared with phosphate levels of 4.7–5.4 mg/dL and intact PTH levels>500 pg/mL (1.35; 1.03–1.79) compared with intact PTH levels of 151–300 pg/mL. Higher albumin-corrected calcium level was positively associated with MI (p = 0.04 by trend analysis). Hemorrhagic stroke was associated only with intact PTH levels>500 pg/mL (1.54; 1.10–2.17). Incident ischemic stroke had no association with phosphate, calcium, or intact PTH levels. The association of calcium times phosphate product with outcomes was essentially the same pattern as that of phosphate and outcomes.

Conclusions

MI was associated with phosphate, calcium, and intact PTH levels, whereas hemorrhagic stroke was associated only with intact PTH. Ischemic stroke was not associated with any of them. The potential distinct beneficial effect on MI and stroke by managing bone and mineral disease should be investigated in future studies.     

Sensory–sympathetic coupling in superior cervical ganglia after myocardial ischemic injury facilitates sympathoexcitatory action via P2X7 receptor

P2X receptors participate in cardiovascular regulation and disease. After myocardial ischemic injury, sensory–sympathetic coupling between rat cervical DRG nerves and superior cervical ganglia (SCG) facilitated sympathoexcitatory action via P2X₇ receptor. The results showed that after myocardial ischemic injury, the systolic blood pressure, heart rate, serum cardiac enzymes, IL-6, and TNF-α were increased, while the levels of P2X₇ mRNA and protein in SCG were also upregulated. However, these alterations diminished after treatment of myocardial ischemic (MI) rats with the P2X₇ antagonist oxATP. After siRNA P2X₇ in MI rats, the systolic blood pressure, heart rate, serum cardiac enzymes, the expression levels of the satellite glial cell (SGC) or P2X₇ were significantly lower than those in MI group. The phosphorylation of ERK 1/2 in SCG participated in the molecular mechanism of the sympathoexcitatory action induced by the myocardial ischemic injury. Retrograde tracing test revealed the sprouting of CGRP or SP sensory nerves (the markers of sensory afferent fibers) from DRG to SCG neurons. The upregulated P2X₇ receptor promoted the activation of SGCs in SCG, resulting in the formation of sensory–sympathetic coupling which facilitated the sympathoexcitatory action. P2X₇ antagonist oxATP could inhibit the activation of SGCs and interrupt the formation of sensory–sympathetic coupling in SCG after the myocardial ischemic injury. Our findings may benefit the treatment of coronary heart disease and other cardiovascular diseases.     

Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population

Cardiovascular diseases, including myocardial infarction (MI) and stroke, most often occur on the background of atherosclerosis, a condition attributed to the interactions between multiple genetic and environmental risk factors. We recently reported a linkage and association study of MI and stroke that yielded a genetic variant, HapA, in the gene encoding 5-lipoxygenase-activating protein (ALOX5AP), that associates with both diseases in Iceland. We also described another ALOX5AP variant, HapB, that associates with MI in England. To further assess the contribution of the ALOX5AP variants to cardiovascular diseases in a population outside Iceland, we genotyped seven single-nucleotide polymorphisms that define both HapA and HapB from 450 patients with ischemic stroke and 710 controls from Aberdeenshire, Scotland. The Icelandic at-risk haplotype, HapA, had significantly greater frequency in Scottish patients than in controls. The carrier frequency in patients and controls was 33.4% and 26.4%, respectively, which resulted in a relative risk of 1.36, under the assumption of a multiplicative model (P=.007). We did not detect association between HapB and ischemic stroke in the Scottish cohort. However, we observed that HapB was overrepresented in male patients. This replication of haplotype association with stroke in a population outside Iceland further supports a role for ALOX5AP in cardiovascular diseases.