Transgenic A1 adenosine receptor overexpression increases myocardial resistance to ischemia

Activation of myocardial A₁ adenosine receptors (A₁AR) protects the heart from ischemic injury. In this study transgenic mice were created using the cardiac-specific α-myosin heavy chain promoter and rat A₁AR cDNA. Heart membranes from two transgene positive lines displayed ≈1,000-fold overexpression of A₁AR (6,574 ± 965 and 10,691 ± 1,002 fmol per mg of protein vs. 8 ± 5 fmol per mg of protein in control hearts). Compared with control hearts, transgenic Langendorff-perfused hearts had a significantly lower intrinsic heart rate (248 beats per min vs. 318 beats per min, P < 0.05), lower developed tension (1.2 g vs. 1.6 g, P < 0.05), and similar coronary resistance. The difference in developed tension was eliminated by pacing. Injury of control hearts during global ischemia, indexed by time-to-ischemic contracture, was accelerated by blocking adenosine receptors with 50 μM 8-(p-sulfophenyl) theophylline but was unaffected by addition of 20 nM N⁶-cyclopentyladenosine, an A₁AR agonist. Thus A₁ARs in ischemic myocardium are presumably saturated by endogenous adenosine. Overexpressing myocardial A₁ARs increased time-to-ischemic contracture and improved functional recovery during reperfusion. The data indicate that A₁AR activation by endogenous adenosine affords protection during ischemia, but that the response is limited by A₁AR number in murine myocardium. Overexpression of A₁AR affords additional protection. These data support the concept that genetic manipulation of A₁AR expression may improve myocardial tolerance to ischemia.     

胰岛素样生长因子-1与冠状动脉病变程度的关系

目的探讨冠心病患者胰岛素样生长因子-1（IGF-1）与冠状动脉病变程度的关系。方法42例冠心病患者分为急性心肌梗死（AMI）组12例，不稳定型心绞痛（UAP）组15例，稳定型心绞痛（SAP）组15例，16例冠状动脉造影（CAG）结果正常者为对照组。采用酶联免疫吸附法（ELISA）测定血清IGF-1水平。结果AMI和UAP组中IGF-1明显高于SAP和对照组（P〈0．01）。SAP组IGF-1明显低于对照组（P〈0．01）；IGF-1在单支病变组、双支病变组、三支病变组均高于对照组（P〈O．05），但单支、双支、三支病变组之间差异无统计学意义（P〉O．05）。结论IGF-1参与动脉硬化粥样斑块的发生发展过程，可作为预测斑块稳定性的标志物。     

Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity

The fibroblast growth factors (FGFs), and the corresponding receptors, are implicated in more than just the regulation of epithelial cell proliferation and differentiation. Specifically, FGF23 is a regulator of serum inorganic phosphate levels, and mice deficient in FGF receptor-4 have altered cholesterol metabolism. The recently described FGF19 is unusual in that it is nonmitogenic and appears to interact only with FGF receptor-4. Here, we report that FGF19 transgenic mice had a significant and specific reduction in fat mass that resulted from an increase in energy expenditure. Further, the FGF19 transgenic mice did not become obese or diabetic on a high fat diet. The FGF19 transgenic mice had increased brown adipose tissue mass and decreased liver expression of acetyl coenzyme A carboxylase 2, providing two mechanisms by which FGF19 may increase energy expenditure. Consistent with the reduction in expression of acetyl CoA carboxylase 2, liver triglyceride levels were reduced.     

Activation of myocardial angiogenesis and upregulation of fibroblast growth factor-2 in transmyocardial-revascularization-treated mice

OBJECTIVE: To evaluate the growth factor responses associated with myocardial angiogenesis. DESIGN: Mice were treated with transmyocardial revascularization (TMR) and evaluated for angiogenic and growth factor responses. METHODS: TMR was performed via thoractomy with a 27 g needle. At 2, 5, and 7 days post-treatment, hearts were removed from the TMR treated and control groups, then assayed for angiogenesis, fibroblast growth factor (FGF)-2 expression and vascular endothelial cell growth factor (VEGF) expression. RESULTS: TMR caused an angiogenic reaction in the myocardial blood vessels at 7 days post-TMR treatment. Elevated FGF-2 corresponded with increased TMR related angiogenesis. VEGF levels only increased in hearts that were prewounded then TMR treated. CONCLUSIONS: The data show that TMR stimulates myocardial angiogenesis. The angiogenic reaction is mediated by FGF-2 which increased in most experimental treatment groups. The VEGF response was more specific, requiring prewounding then TMR treatment for a VEGF increase.     

胰岛素样生长因子-1与冠状动脉造影对照研究

目的探讨胰岛素样生长因子-1（IGF-1）与急性冠状动脉综合征（ACS）的关系,并且通过冠状动脉造影研究IGF-1与冠状动脉狭窄及其程度的关系。方法将114例入院患者行冠状动脉造影后分为4组,稳定型心绞痛组（SAP）24例,不稳定型心绞痛组（UAP）33例,急性心肌梗死组（AMI）26例,冠状动脉照影无狭窄或狭窄小于25%者为对照组31例。用ELISA法测定其外周静脉血清IGF-1水平,分析各组IGF-1水平之间的关系以及冠状动脉狭窄程度与IGF-1水平的关系。结果①UAP组、AMI组血清IGF-1浓度较对照组、SAP组明显降低,且差异有统计学意义[（19.02±9.65）μg/L,（16.56±6.64）μg/L和（34.89±7.09）μg/L,（31.06±8.64）μg/L,P〈0.05],SAP组血清IGF-1浓度较对照组降低,但差异无统计学意义[（31.06±8.64）μg/L和（34.89±7.09）μg/L,P〉0.05],AMI组血清IGF-1浓度较UAP组降低,但差异无统计学意义[（16.56±6.64）μg/L和（19.02±9.65）μg/L,P〉0.05];②血清IGF-1浓度与其相应的冠状动脉狭窄积分呈明显负相关（r=-0.659,P〈0.05）。结论血清IGF-1浓度可能作为预测急性冠脉综合征及冠状动脉狭窄程度的参考指标之一。     

Transgenic overexpression of pregnancy-associated plasma protein-A increases the somatic growth and skeletal muscle mass in mice

Although IGFs are indispensable to skeletal muscle development, little information is available regarding the mechanisms regulating the local action of IGFs in skeletal muscle tissues. Here we tested the hypothesis that pregnancy-associated plasma protein-A (PAPP-A), a member of the metalloproteinase superfamily, promotes skeletal muscle formation in vivo through degrading IGF binding proteins (IGFBPs), which increases the bioavailability of IGFs. Expression of PAPP-A is significantly increased in muscle five days after muscle injury in mice. Targeted overexpression of PAPP-A using a muscle-specific promoter significantly increased the prenatal/postnatal growth, skeletal muscle weight, and muscle fiber area in mice. These anabolic effects were reproduced using F2/F3 progeny. Free IGF-I concentration was severalfold higher in the conditioned medium (CM) of ex vivo cultured muscle from the transgenic mice, compared with the wild-type littermate muscle. Accordingly, the proliferation of C2C12 myoblasts was significantly increased in the presence of CM from cultured skeletal muscle of the transgenic mice, compared with the controls. This observed increase in myoblast proliferation was abolished on addition of noncleavable IGFBP-4 peptide, which reduced free IGF-I concentration back to the basal level of the wild-type CM. Furthermore, proliferation and differentiation of C2C12 myoblasts was increased by transient overexpression of proteolytically active PAPP-A but not by inactive mutant PAPP-A (E483/A). Collectively, we identified PAPP-A as a novel regulator of prenatal/postnatal growth and skeletal muscle formation in vivo. Moreover, our studies provide the first experimental evidence that IGFBP degradation is a key determinant in modulating the local action of IGFs in muscle.     

Selective pressure-regulated retroinfusion of fibroblast growth factor-2 into the coronary vein enhances regional myocardial blood flow and function in pigs with chronic myocardial ischemia

OBJECTIVES: We sought to improve regional myocardial delivery and subsequent collateral perfusion induced by basic fibroblast growth factor-2 (FGF-2) using selective pressure-regulated retroinfusion of coronary veins for delivery. This hypothesis was tested in a newly developed pig model with percutaneous induction of chronic ischemia. BACKGROUND: Selective pressure-regulated retroinfusion of coronary veins is a catheter-based procedure that has been shown to provide effective regional delivery of drugs and gene vectors into ischemic myocardium. METHODS: A high-grade stenosis with subsequent progression to total occlusion within 28 days was induced by implanting a reduction stent graft into the left anterior descending artery (LAD). After seven days, a 30-min retroinfusion (anterior cardiac vein) was performed with (n = 7) or without (n = 7) 150 microg FGF-2 and compared with a 30-min antegrade infusion of 150 microg FGF-2 into the LAD (n = 7). Sonomicrometry to assess regional myocardial function at rest and during pacing, and microspheres to assess regional myocardial blood flow, were performed 28 days after implantation of the reduction stent. RESULTS: Retroinfusion of FGF-2 compared favorably with controls and with antegrade infusion of FGF-2 with regard to regional myocardial function at rest (18.5 +/- 4.1% vs. 5.7 +/- 2.9% vs. 7.9 +/- 1.8%, respectively, p < 0.05) and during pacing. Regional myocardial blood flow was also higher in the LAD territory after retroinfusion of FGF-2 (1.07 +/- 0.14 vs. 0.66 +/- 0.07 vs. 0.72 +/- 0.17 ml x min(-1) x g(-1), p < 0.05). CONCLUSIONS: Selective pressure-regulated retroinfusion increased tissue binding of FGF-2 and enhanced functionally relevant collateral perfusion compared with antegrade intracoronary delivery in pigs with chronic myocardial ischemia.     

急性心肌梗死患者经皮冠状动脉介入术后血清成纤维细胞生长因子21和髓过氧化物酶水平与预后的关系

目的探究急性心肌梗死(AMI)患者经皮冠状动脉介入术(PCI)后血清成纤维细胞生长因子21(FGF-21)、髓过氧化物酶(MPO)水平与预后的关系。方法选择2016年1月至2018年12月在我院接受PCI术治疗的108例AMI患者作为研究对象。根据随访过程中是否发生主要不良心血管事件(MACE),病人分为预后不良组(25例)和预后良好组(83例)。采用酶联免疫吸附法检测受试者血清FGF-21水平,采用胶体金免疫层析法检测受试者血清MPO水平。分析FGF-21、MPO与AMI患者PCI术后MACE发生的关系及诊断MACE发生的效能。结果预后不良组血清FGF-21、MPO水平均高于预后良好组,差异均有统计学意义(P0.05)。FGF-21+MPO诊断AMI患者PCI术后MACE发生的ROC曲线下面积(AUC)为0.860,高于FGF-21、MPO单独诊断AMI患者PCI术后MACE发生的AUC。FGF-21140.41 ng/L和FGF-21≤140.41 ng/L的患者,MACE发生率分别为39.58%和10.00%,差异有统计学意义(P0.001)。MPO419.42μg/L和MPO≤419.42μg/L的患者,MACE发生率分别为35.00%和8.33%,差异有统计学意义(P=0.001)。Cox单因素及Cox多因素分析显示FGF-21、MPO与AMI患者PCI术后MACE发生密切相关(均P0.05)。结论 AMI患者PCI术后血清FGF-21、MPO水平与预后有关。高水平的FGF-21、MPO与MACE发生密切相关。     

Insulin-like growth factor-1 attenuates the detrimental impact of nonocclusive coronary artery constriction on the heart.

Coronary artery narrowing (CAN) induces tissue injury, which may involve myocyte necrosis and apoptosis. Insulin-like growth factor (IGF)-1 may counteract cell death, modifying the detrimental effects of myocardial ischemia. On this basis, CAN was produced in female FVB.Igf+/- mice and nontransgenic littermates, and the animals were euthanized 7 days later. CAN consisted of an 82% reduction in the vessel luminal cross-sectional area in both groups of mice. Severe left ventricular dysfunction was present in CAN nontransgenic and transgenic mice, but heart and left ventricular weights increased more in littermates than in FVB.Igf+/- mice. Similarly, the changes in chamber volume and diastolic wall stress were greater in nontransgenic mice. Subacute tissue injury, represented by foci of replacement fibrosis, was 2.6-fold higher in CAN littermates than in FVB.Igf+/- mice. Ongoing myocyte necrosis was 5-fold greater in nontransgenic mice, whereas apoptosis was low and did not differ in the 2 groups of mice. In CAN nontransgenic mice, myocyte necrosis was 12-fold more frequent than apoptosis but, in CAN transgenic mice, these 2 types of cell death were comparable. alpha-Myosin and beta-myosin isoform mRNAs were affected by CAN, but alpha-myosin mRNA was reduced more in nontransgenic mice. In conclusion, myocyte necrosis and replacement fibrosis are the prevailing forms of myocardial damage induced by CAN. Constitutive overexpression of IGF-1 attenuates myocyte necrosis and tissue injury, having no effect on cell apoptosis. These factors limit ventricular dilation, myocardial loading, cardiac hypertrophy, and alterations in alpha- and beta-myosin isoform expression.     

Insulin like growth factor-1 increases fatty liver preservation in IGL-1 solution

AIM: To investigate the benefits of insulin like growth factor-1 (IGF-1) supplementation to serum-free institut georges lopez-1 (IGL-1) solution to protect fatty liver against cold ischemia reperfusion injury. METHODS: Steatotic livers were preserved for 24 h in IGL-1  solution supplemented with or without IGF-1 and then perfused "ex vivo " for 2 h at 37℃. We examined the effects of IGF-1 on hepatic damage and function (transaminases, percentage of sulfobromophthalein clearance in bile and vascular resistance). We also studied other factors associated with the poor tolerance of fatty livers to cold ischemia reperfusion injury such as mitochondrial damage, oxidative stress, nitric oxide, tumor necrosis factor-α (TNF-α) and mitogen-activated protein kinases.RESULTS: Steatotic livers preserved in IGL-1 solutionsupplemented with IGF-1 showed lower transaminase levels, increased bile clearance and a reduction in vascular resistance when compared to those preserved in IGL-1solution alone. These benefits are mediated by activation of AKT and constitutive endothelial nitric oxide synthase (eNOS), as well as the inhibition of inflammatory cytokines such as TNF-α. Mitochondrial damage and oxidative stress were also prevented.CONCLUSION: IGL-1  enrichment with IGF-1 increasedfatty liver graft preservation through AKT and eNOS activation, and prevented TNF-α release during normothermic reperfusion.     

血清TGF-β1和IGF-1水平对冠心病患者心功能的影响

目的探讨血清转化生长因子(TGF-β1)和胰岛素样生长因子(IGF-1)水平对冠心病患者心功能的影响.方法选择因胸痛住院患者88例分为急性心肌梗死(AMI)组、心绞痛(AP)组和对照组,填调查表,入院择日行选择性冠状动脉造影术,术前采股动脉血,以ABC双抗体夹心ELISA法检测血清TGF-β1和IGF-1浓度,入院2周内完成超声心动图,所有资料用SPSS10.0软件处理.结果AMI患者与AP患者相比,血清TGF-β1浓度较低(P<0.05),IGF-1血清浓度较低(P<0.001);冠心病患者血清IGF-1水平与EF(P<0.05)和FS(P<0.02)正相关.结论TGF-β1和IGF-1对冠心病患者具有某种保护作用,其中IGF-1能保护冠心病患者的心功能.     

Modulation of smooth muscle proliferation in rat carotid artery by platelet-derived mediators and fibroblast growth factor-2

Endothelial denuding injury to the rat carotid artery stimulates smooth muscle cell proliferation in the tunica media. Fibroblast growth factor-2 (FGF2) is responsible for a significant portion of this proliferation but other factors may contribute, particularly those released from adherent platelets. We therefore tested the effects of a range of platelet-derived factors. After filament injury, which minimises FGF2 release, the proliferation rate in thrombocytopaenic rats was decreased by 74% ( P < 0.02). After balloon injury, antibody neutralisation of platelet-derived growth factor (PDGF) caused a 27% decrease in proliferation ( P < 0.05), while inhibition of histamine H 1 receptors caused a 53% increase ( P < 0.05). When filament injury was performed 1 h after FGF2 injection, the proliferation rate increased from 2.3 - 0.7 to 32.8 - 2.7% ( P < 0.001), while filament injury alone caused a proliferation rate of only 18.3 - 2.9% ( P < 0.01 versus filament plus FGF2). These data suggest that platelet-derived factors interact with FGF2 that is adsorbed to the vessel wall in the control of smooth muscle cell proliferation, and that the net effect of platelets is to stimulate smooth muscle cell proliferation. PDGF, but no other platelet agonist tested, contributes to that stimulation.     

莫诺苷对急性心肌梗死大鼠梗死心肌周边组织中Ang-1及FGF-2表达的影响

目的 观察莫诺苷对急性心肌梗死大鼠梗死心肌周边组织中血管生成素（Ang）-1及成纤维细胞生长因子（FGF）-2表达的影响。 方法 选取体质量（260～280）g的雄性SD大鼠20只，采用结扎冠状动脉左前降支的方法制备AMI大鼠模型。造模成功后的大鼠随机分为假手术组、模型组、莫诺苷低剂量组（45 mg/kg）、莫诺苷中剂量组（90 mg/kg）和莫诺苷高剂量组（180 mg/kg）。从造模后第1天开始，采用灌胃方式每天定时给药，假手术组和模型组给予等量的蒸馏水。造模大鼠在连续给药7 d后处死取材，Western blot检测梗死心肌周边组织中Ang-1及FGF-2的蛋白表达量。 结果 与假手术组相比，模型组Ang-1的蛋白表达量明显升高（P<0.01），而FGF-2表达量有升高趋势，但无显著性差异；与模型组相比，莫诺苷高剂量组Ang-1、FGF-2蛋白表达量显著提高（P<0.01，P<0.05）。 结论 莫诺苷能上调急性心肌梗死大鼠梗死心肌周边组织中Ang-1及FGF-2表达，促进血管新生。     

Single coronary artery anomaly: branching of left coronary artery from right coronary artery with 2 distinct patterns

Normal coronary vasculature has a left coronary artery arising from the left coronary cusp and a right coronary artery arising from the right coronary cusp. In about 0.024% of cases in the general population, there is no left main coronary artery. In fact, there is a single coronary artery, which arises from the right coronary cusp. We encountered 2 such cases with distinct patterns. The first case was a patient with angina who had an abnormal stress test for which he underwent coronary angiography. This revealed a single coronary artery arising from the right coronary cusp. This vessel gave rise to the right coronary artery, which had a varicose anatomy, with a critical lesion in the posterior descending artery. The left coronary artery passed anteriorly to the pulmonary artery with a critical lesion in the circumflex artery. In the second case, the patient also had angina with a normal noninvasive work-up but due to his persistent symptoms, coronary angiography was performed. This revealed a single coronary artery arising from the right coronary cusp. Subsequent CT angiography revealed that the left coronary artery coursed in between the aorta and pulmonary artery without critical lesions. In both cases, the patients underwent coronary artery bypass grafting.