川芎嗪联用L-精氨酸对缺血/再灌注损伤兔心肌线粒体功能的影响

探讨川芎嗪联用L-精氨酸对心肌缺血／再灌注损伤（MI／RI）时心肌细胞线粒体功能的影响。方法：选用日本大耳白兔50只,随机分为正常对照组（A组）、心肌缺血／再灌注组（B组）、心肌缺血／再灌注＋川芎嗪治疗组（C组）、心肌缺血／再灌注＋L-精氨酸治疗组（D组）和心肌缺血／再灌注＋川芎嗪＋L-精氨酸治疗组（E组）。观察心肌线粒体呼吸功能、Ca^2＋浓度（[Ca^2＋]m）、丙二醛浓度（MDA）、超氧化物歧化酶活性（SOD）和心肌组织三磷酸腺苷（ATP）、能荷（EC）的变化。结果：C、D、E组与B组比较,线粒体呼吸控制率（RCR）、Ⅲ态呼吸速率（ST3）、SOD明显升高,Ⅳ态呼吸速率（ST4）、[Ca^2＋]m、MDA显著降低,心肌组织ATP、EC均明显增高;且与A组比较,E组上述指标均无明显差异。结论：川芎嗪联用L-精氨酸可通过降低氧自由基水平和减轻钙超载,而改善缺血／再灌注损伤心肌的线粒体功能。     

The evolution of meningococcal infection in Mongolia]

On the basis of the generalization and analysis of the results of bacteriological and immunological investigations the epidemic process of meningococcal infection (MI) in Mongolia was found to undergo definite changes during the last 20 years. Group A meningococci prevailing in the etiology of MI were replaced by strains belonging to group B affecting mainly young children (aged up to 3 years). MI morbidity rate caused by group B meningococci was found to be higher in Mongolia than in other countries of the world. These data substantiate the necessity of using more effective remedies for the control of this infection and, in particular, specific immunization with vaccines against group B meningococci; profound study of the properties of the circulating meningococcal strains is to be carried out.     

Effects of the vasopeptidase inhibitor omapatrilat on cardiac endogenous kinins in rats with acute myocardial infarction

The purposes of this study were to evaluate and to compare the effects of simultaneous angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) inhibition by the vasopeptidase inhibitor omapatrilat (1 mg. kg(-1). day(-1)) with those of the selective ACE inhibitor enalapril (1 mg. kg(-1). day(-1)) on survival, cardiac hemodynamics, and bradykinin (BK) and des-Arg(9)-BK levels in cardiac tissues 24 h after myocardial infarction (MI) in rats. The effect of the co-administration of both B(1) and B(2) kinin receptor antagonists (2.5 mg. kg(-1). day(-1) each) with metallopeptidase inhibitors was also evaluated. The pharmacological treatments were infused subcutaneously using micro-osmotic pumps for 5 days starting 4 days before the ligation of the left coronary artery. Immunoreactive kinins were quantified by highly sensitive and specific competitive enzyme immunoassays. The post-MI mortality of untreated rats with a large MI was high; 74% of rats dying prior to the hemodynamic study. Mortality in the other MI groups was not significantly different from that of the untreated MI rats. Cardiac BK levels were not significantly different in the MI vehicle-treated group compared with the sham-operated rats. Both omapatrilat and enalapril treatments of MI rats significantly increased cardiac BK concentrations compared with the sham-operated group (P < 0.05). However, cardiac BK levels were significantly increased only in the MI omapatrilat-treated rats compared with the MI vehicle-treated group (P < 0.01). Cardiac des-Arg(9)-BK concentrations were not significantly modified by MI, and MI with omapatrilat or enalapril treatment compared with the sham-operated group. The co-administration of both kinin receptor antagonists with MI omapatrilat- and enalapril-treated rats had no significant effect on cardiac BK and des-Arg(9)-BK levels. Thus, the significant increase of cardiac BK concentrations by omapatrilat could be related to a biochemical or a cardiac hemodynamic parameter on early (24 h) post-MI state.     

Glutaredoxin-1 overexpression enhances neovascularization and diminishes ventricular remodeling in chronic myocardial infarction

Oxidative stress plays a critical role in the pathophysiology of cardiac failure, including the modulation of neovascularization following myocardial infarction (MI). Redox molecules thioredoxin (Trx) and glutaredoxin (Grx) superfamilies actively maintain intracellular thiol-redox homeostasis by scavenging reactive oxygen species. Among these two superfamilies, the pro-angiogenic function of Trx-1 has been reported in chronic MI model whereas similar role of Grx-1 remains uncertain. The present study attempts to establish the role of Grx-1 in neovascularization and ventricular remodeling following MI. Wild-type (WT) and Grx-1 transgenic (Grx-1(Tg/+)) mice were randomized into wild-type sham (WTS), Grx-1(Tg/+) Sham (Grx-1(Tg/+)S), WTMI, Grx-1(Tg/+)MI. MI was induced by permanent occlusion of the LAD coronary artery. Sham groups underwent identical time-matched surgical procedures without LAD ligation. Significant increase in arteriolar density was observed 7 days (d) after surgical intervention in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Further, improvement in myocardial functional parameters 30 d after MI was observed including decreased LVIDs, LVIDd, increased ejection fraction and, fractional shortening was also observed in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Moreover, attenuation of oxidative stress and apoptotic cardiomyocytes was observed in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Increased expression of p-Akt, VEGF, Ang-1, Bcl-2, survivin and DNA binding activity of NF-κB were observed in the Grx-1(Tg/+)MI group when compared to WTMI animals as revealed by Western blot analysis and Gel-shift analysis, respectively. These results are the first to demonstrate that Grx-1 induces angiogenesis and diminishes ventricular remodeling apparently through neovascularization mediated by Akt, VEGF, Ang-1 and NF-κB as well as Bcl-2 and survivin-mediated anti-apoptotic pathway in the infarcted myocardium.     

Effects of Peroxisome Proliferator-Activated Receptor-δ Agonist on Cardiac Healing after Myocardial Infarction

Peroxisome proliferator-activated receptor-delta (PPAR-δ)-dependent signaling is associated with rapid wound healing in the skin. Here, we investigated the therapeutic effects of PPAR-δ-agonist treatment on cardiac healing in post-myocardial infarction (MI) rats. Animals were assigned to the following groups: sham-operated control group, left anterior descending coronary artery ligation (MI) group, or MI with administration of the PPAR-δ agonist GW610742 group. GW610742 (1 mg/kg) was administrated intraperitoneally after the operation and repeated every 3 days. Echocardiographic data showed no differences between the two groups in terms of cardiac function and remodeling until 4 weeks. However, the degrees of angiogenesis and fibrosis after MI were significantly higher in the GW610742-treated rats than in the untreated MI rats at 1 week following MI, which changes were not different at 2 weeks after MI. Naturally, PPAR-δ expression in infarcted myocardium was highest increased in 3 day after MI and then disappeared in 14 day after MI. GW610742 increased myofibroblast differentiation and transforming growth factor-beta 2 expression in the infarct zone at 7 days after MI. GW610742 also increased bone marrow-derived mesenchymal stem cell (MSC) recruitment in whole myocardium, and increased serum platelet-derived growth factor B, stromal-derived factor-1 alpha, and matrix metallopeptidase 9 levels at day 3 after MI. PPAR-δ agonists treatment have the temporal effect on early fibrosis of infarcted myocardium, which might not sustain the functional and structural beneficial effect.     

Changes of collagen metabolism predict the left ventricular remodeling after myocardial infarction

Objectives: To analyze the predictive value of cardiac collagen metabolism “in vivo" in patients with myocardial infarction (MI) treated with percutaneous coronary intervention (PCI). Design: Forty-five patients (age 66 ± 8.27) underwent biochemical analysis for cardiac collagen metabolism (groups A, B and C); 30 patients with their first MI were treated with successful PCI (group A; n = 30), group B (n = 5) were MI patients with unsuccessful PCI. Group C were patients without MI (n = 10), they underwent elective diagnostic coronary angiography only. The collagen metabolism was analyzed in acute and subacute MI phases by using serum blood markers: the carboxy-terminal propeptide of type I procollagen (PICP), amino-terminal propeptide of type III procollagen (PIIINP) and carboxy-terminal telopeptide of type I collagen (ICTP). Furthermore, the ejection fraction (EF) and left ventricular end-diastolic volume maximal changes in the course of 6 months were measured by echocardiography. Results: A significant increase of both PICP and PIIINP on day 4 following MI was detected. Furthermore, PICP and PIIINP level assessed on the 30th day was significantly higher in the PCI unsuccessful group versus successful group. PICP level on day 4 above 110 ug/l and PIIINP level above 4 ug/l was significantly often found in the subgroup of patients with the EF improvement less than 10% or worsening and with significant left ventricular dilatation during 6 months follow-up. Cardiac catheterization itself does not affect collagen metabolism. Conclusion: We concluded that collagen metabolism markers enable to study in vivo the MI healing and to predict left ventricular functional and volume changes.     

间歇有氧运动对MI大鼠肾脏CD40表达的影响及可能机制

目的：探讨间歇有氧运动对心肌梗死（MI）大鼠肾脏CD40表达的影响,揭示运动改善MI肾脏功能的可能机制。方法：36只雄性SD大鼠,随机分为假手术组（Sham）、心肌梗死组（MI）、心梗+间歇运动组（ME）,每组12只。MI组采用心脏左冠状动脉前降支（LAD）结扎法,建立MI模型。Sham组大鼠实施假手术,ME组大鼠在MI手术后1周进行8周跑台运动。运动开始速度为10 m/min运动10 min后,速度逐渐增至25 m/min×7 min,再以15 m/min×3 min运动,之后依次交替进行。每天60 min×1次,每周5 d,共8周。训练结束后次日,各组大鼠评定心功能,腹主动脉取血及获取肾脏组织后,测定肾脏胶原容积百分比（CVF）、CD40、hs-CRP、TNF-α、IL-6、p-NF-κBp65、BUN和sCr等指标变化。结果：与Sham组比较,MI组大鼠LVEDP升高,LVSP和±dp/dt max显著降低,肾脏CVF升高;MI后可见肾脏肾小管细胞胞浆中CD40阳性染色,CD40蛋白和mRNA表达增多,血清及肾脏hs-CRP、TNF-α和IL-6表达升高,同时肾脏p-NF-κBp65蛋白表达增多,血清BUN和sCr表达增高。与MI组比较,ME组大鼠LVEDP降低,LVSP和±dp/dt max升高,肾脏CVF降低;肾脏CD40蛋白和mRNA表达减少,血清及肾脏hs-CRP、TNF-α和IL-6表达降低;同时肾脏p-NF-κBp65蛋白表达降低,血清BUN和sCr表达减少。结论：间歇有氧运动可显著降低心梗大鼠肾脏CD40表达,抑制NF-κB通路,减少血清及肾脏炎症因子表达,改善心梗大鼠肾脏功能。     

Cdc2 and Mos regulate Emi2 stability to promote the meiosis I-meiosis II transition

The transition of oocytes from meiosis I (MI) to meiosis II (MII) requires partial cyclin B degradation to allow MI exit without S phase entry. Rapid reaccumulation of cyclin B allows direct progression into MII, producing a cytostatic factor (CSF)-arrested egg. It has been reported that dampened translation of the anaphase-promoting complex (APC) inhibitor Emi2 at MI allows partial APC activation and MI exit. We have detected active Emi2 translation at MI and show that Emi2 levels in MI are mainly controlled by regulated degradation. Emi2 degradation in MI depends not on Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), but on Cdc2-mediated phosphorylation of multiple sites within Emi2. As in MII, this phosphorylation is antagonized by Mos-mediated recruitment of PP2A to Emi2. Higher Cdc2 kinase activity in MI than MII allows sufficient Emi2 phosphorylation to destabilize Emi2 in MI. At MI anaphase, APC-mediated degradation of cyclin B decreases Cdc2 activity, enabling Cdc2-mediated Emi2 phosphorylation to be successfully antagonized by Mos-mediated PP2A recruitment. These data suggest a model of APC autoinhibition mediated by stabilization of Emi2; Emi2 proteins accumulate at MI exit and inhibit APC activity sufficiently to prevent complete degradation of cyclin B, allowing MI exit while preventing interphase before MII entry.     

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.     

Silencing of ATP2B1‐AS1 contributes to protection against myocardial infarction in mouse via blocking NFKBIA‐mediated NF‐κB signalling pathway

Myocardial infarction (MI) is an acute coronary syndrome that refers to tissue infarction of the myocardium. This study aimed to investigate the effect of long intergenic non‐protein‐coding RNA (lincRNA) ATPase plasma membrane Ca²⁺ transporting 1 antisense RNA 1 (ATP2B1‐AS1) against MI by targeting nuclear factor‐kappa‐B inhibitor alpha (NFKBIA) and mediating the nuclear factor‐kappa‐B (NF‐κB) signalling pathway. An MI mouse model was established and idenepsied by cardiac function evaluation. It was determined that ATP2B1‐AS1 was highly expressed, while NFKBIA was poorly expressed and NF‐κB signalling pathway was activated in MI mice. Cardiomyocytes were extracted from mice and introduced with a series of mouse ATP2B1‐AS1 vector, NFKBIA vector, siRNA‐mouse ATP2B1‐AS1 and siRNA‐NFKBIA. The expression of NF‐κBp50, NF‐κBp65 and IKKβ was determined to idenepsy whether ATP2B1‐AS1 and NFKBIA affect the NF‐κB signalling pathway, the results of which suggested that ATP2B1‐AS1 down‐regulated the expression of NFKBIA and activated the NF‐κB signalling pathway in MI mice. Based on the data from assessment of cell viability, cell cycle, apoptosis and levels of inflammatory cytokines, either silencing of mouse ATP2B1‐AS1 or overexpression of NFKBIA was suggested to result in reduced cardiomyocyte apoptosis and expression of inflammatory cytokines, as well as enhanced cardiomyocyte viability. Our study provided evidence that mouse ATP2B1‐AS1 silencing may have the potency to protect against MI in mice through inhibiting cardiomyocyte apoptosis and inflammation, highlighting a great promise as a novel therapeutic target for MI.     

Clinical significance of matrix metalloproteinases activity in acute myocardial infarction

Matrix metalloproteinases (MMP) degrade myocardial fibrillar collagen in acute myocardial infarction (MI) patients. Their activity is tightly controlled in normal myocardium by a family of closely related tissue inhibitors known as TIMP. An imbalance in their activity might contribute to post-MI remodeling. Plasma levels of MMP-1, TIMP-1 and MMP-1/TIMP-1 complex were measured, using relevant ELISA kits, in 24 (22 males-2 females), acute MI patients with a mean age 59 +/- 14 years. Blood samples were taken on admission (0 h), and 3 h, 6 h, 9 h, 18 h, 24 h, 36 h, 48 h, 3rd, 4th, 5th, 7th, 15th, 30th days after MI. All patients underwent coronary arteriography with ventriculography for estimation of left ventricular ejection fraction (LVEF) and extent of coronary artery diseases, and echocardiographic study for measuring end-diastolic diameter (EDD). Ten patients with an LVEF < 45%, an EDD > 47.5 mm, and heart failure symptoms were included in group A and compared against 12 patients with an LVEF > 45% an EDD < 47.5 mm in group B. Mean plasma concentrations of MMP-1 were higher by 21% in group A (1.3 +/- 0.2 ng/mL) compared to group B (1 +/- 0.1 ng/mL) over the total study period. TIMP-1 plasma concentrations showed very little difference between the 2 groups, (704 +/- 213 ng/mL versus 691 +/- 165 ng/mL, (6%)). Finally, plasma concentrations of MMP-1/TIMP-1 complex were lower by -36% in group A with a mean value of 2.7 +/- 0.6 ng/mL versus 3.7 +/- 0.5 ng/mL in group B. Mean values for the differences were significant at time points 0, 6, 18, 24 and 48 hours for MMP-1 (p < 0.036), and on 48 h and the 4th day for MMP-1/TIMP-1 complex (p < 0.031). Moreover, a good correlation was found between plasma concentrations of creatine kinase (CK) and MMP-1 at 18 h (r = 0.422, p = 0.041) and on the 4th day (r = 0.67, p = 0.046), and TIMP-1 on the 4th day (r = 0.67, p = 0.047). Additionally, mean values for LVEF were 35.8 +/- 8.8% in group A versus 51.2 +/- 1.8% (p = 0.00014) in group B. Also, the EDD in-group A was 52.1 +/- 6.9 mm versus 42.9 +/- 3.2 mm in group B (p = 0.00013). In acute MI patients, increased MMP-1, with no change in TIMP-1, is associated with left ventricular dysfunction and dilatation, suggesting that increased collagenolytic activity contributes to loss of LV function.     

Identification of LRP1B-interacting proteins and inhibition of protein kinase Cα-phosphorylation of LRP1B by association with PICK1

Recent studies show LDL receptor-related protein 1B, LRP1B as a transducer of extracellular signals. Here, we identify six interacting partners of the LRP1B cytoplasmic region by yeast two-hybrid screen and confirmed their in vivo binding by immunoprecipitation. One of the partners, PICK1 recognizes the C-terminus of LRP1B and LRP1. The cytoplasmic domains of LRP1B are phosphorylated by PKCα about 100 times more efficiently than LRP1. Binding of PICK1 inhibits phosphorylation of LRP1B, but does not affect LRP1 phosphorylation.This study presents the possibility that LRP1B participates in signal transduction which PICK1 may regulate by inhibiting PKCα phosphorylation of LRP1B.

Structured summary

MINT-6801075: Lrp1b (uniprotkb:Q9JI18) physically interacts (MI:0218) with SNTG2 (uniprotkb:Q925E0) by two hybrid (MI:0018)MINT-6801030, MINT-6801468: Lrp1b (uniprotkb:Q9JI18) physically interacts (MI:0218) with Pick1 (uniprotkb:Q80VC8) by two hybrid (MI:0018)MINT-6801284: LRP1B4 (uniprotkb:Q9JI18) physically interacts (MI:0218) with RanBPM (uniprotkb:P69566) by anti tag coimmunoprecipitation (MI:0007)MINT-6801108: Lrp1b (uniprotkb:Q9JI18) physically interacts (MI:0218) with Grb7 (uniprotkb:Q03160) by two hybrid (MI:0018)MINT-6801090: Lrp1b (uniprotkb:Q9JI18) physically interacts (MI:0218) with RanBPM (uniprotkb:P69566) by two hybrid (MI:0018)MINT-6801008: Lrp1b (uniprotkb:Q9JI18) physically interacts (MI:0218) with Jip-1b (uniprotkb:Q9WVI9-1) by two hybrid (MI:0018)MINT-6801052: Lrp1b (uniprotkb:Q9JI18) physically interacts (MI:0218) with Jip-2 (uniprotkb:Q9ERE9) by two hybrid (MI:0018)MINT-6801258, MINT-6801271: LRP1B4 (uniprotkb:Q9JI18) physically interacts (MI:0218) with Pick1 (uniprotkb:Q80VC8) by anti tag coimmunoprecipitation (MI:0007)MINT-6801244: RanBPM (uniprotkb:P69566) physically interacts (MI:0218) with mLRP4 (uniprotkb:Q8VI56) by anti tag coimmunoprecipitation (MI:0007)MINT-6801131, MINT-6801158: LRP1B4 (uniprotkb:Q9JI18) physically interacts (MI:0218) with Jip-1b (uniprotkb:Q9WVI9-1) by anti tag coimmunoprecipitation (MI:0007)MINT-6801231: PICK1 (uniprotkb:Q80VC8) physically interacts (MI:0218) with mLRP4 (uniprotkb:Q8VI56) by anti tag coimmunoprecipitation (MI:0007)MINT-6801173: Jip-1b (uniprotkb:Q9WVI9-1) physically interacts (MI:0218) with mLRP4 (uniprotkb:Q8VI56) by anti tag coimmunoprecipitation (MI:0007)     

Evaluation of endothelin-1-induced pulmonary vasoconstriction following myocardial infarction

Endothelin (ET) levels are elevated in congestive heart failure secondary to myocardial infarction (MI) and correlate well with the severity of pulmonary hypertension (PH), suggesting that the ET peptide could contribute to the pathophysiology of venous PH. Alterations of pulmonary vasoreactivity to ET after MI and the respective roles of the ET(A) and ET(B) receptors (ET(A)-R and ET(B)-R) have never been evaluated, to our knowledge. MI was induced in rats. Three weeks later, small pulmonary resistance arteries were mounted on a microvascular myograph. Cumulative concentration-response curves to ET-1 and sarafotoxin 6c (S6c) were performed. Response to ET was also assessed in the presence of ET-R antagonists. Heterodimerization of receptors was evaluated by immunoprecipitation of the ET(B)-R, followed by western blotting for the expression of the ET(A)-R. Maximal vasoconstriction and sensitivity to ET-1 were similar in sham and MI with values of 88 +/- 3.9% and 80 +/- 3.8%, respectively. The response to S6c was similarly less in both sham (67 +/- 5.7%) and MI groups (60 +/- 6.6%). When administered alone, the ET(A)-R antagonist (10 nM A-147627.1) and the ET(B)-R antagonist (1 microM A-192621.1) had no significant effect. However, their combination markedly reduced vaso-constriction (52 +/- 5.3%; P < 0.001). The endothelial and medial distribution of ET-Rs was similar in sham and MI groups. In vitro studies demonstrated co-immunoprecipitation of the ET(A)-R and ET(B)-R. Vasoconstriction of isolated resistance pulmonary arteries to ET agonists is not altered after MI. Dual antagonism results in optimal blockade of vasoconstriction, possibly because the ET(A)-R and ET(B)-R can form functional heterodimers.     

Training-induced changes in skeletal muscle Na+-K+ pump number and isoform expression in rats with chronic heart failure.

The mechanisms responsible for the decrements in exercise performance in chronic heart failure (CHF) remain poorly understood, but it has been suggested that sarcolemmal alterations could contribute to the early onset of muscular fatigue. Previously, our laboratory demonstrated that the maximal number of ouabain binding sites (B(max)) is reduced in the skeletal muscle of rats with CHF (Musch TI, Wolfram S, Hageman KS, and Pickar JG. J Appl Physiol 92: 2326-2334, 2002). These reductions may coincide with changes in the Na(+)-K(+)-ATPase isoform (alpha and beta) expression. In the present study, we tested the hypothesis that reductions in B(max) would coincide with alterations in the alpha- and beta-subunit expression of the sarcolemmal Na(+)-K(+)-ATPase of rats with CHF. Moreover, we tested the hypothesis that exercise training would increase B(max) along with producing significant changes in alpha- and beta-subunit expression. Rats underwent a sham operation (sham; n = 10) or a surgically induced myocardial infarction followed by random assignment to either a control (MI; n = 16) or exercise training group (MI-T; n = 16). The MI-T rats performed exercise training (ET) for 6-8 wk. Hemodynamic indexes demonstrated that MI and MI-T rats suffered from severe left ventricular dysfunction and congestive CHF. Maximal oxygen uptake (Vo(2 max)) and endurance capacity (run time to fatigue) were reduced in MI rats compared with sham. B(max) in the soleus and plantaris muscles and the expression of the alpha(2)-isoform of the Na(+)-K(+)-ATPase in the red portion of the gastrocnemius (gastrocnemius(red)) muscle were reduced in MI rats. After ET, Vo(2 max) and run time to fatigue were increased in the MI-T group of rats. This coincided with increases in soleus and plantaris B(max) and the expression of the alpha(2)-isoform in the gastrocnemius(red) muscle. In addition, the expression of the beta(2)-isoform of the gastrocnemius(red) muscle was increased in the MI-T rats compared with their sedentary counterparts. This study demonstrates that CHF-induced alterations in skeletal muscle Na(+)-K(+)-ATPase, including B(max) and isoform expression, can be partially reversed by ET.     

Adipose stromal vascular fraction cell construct sustains coronary microvascular function after acute myocardial infarction

A three-dimensional tissue construct was created using adipose-derived stromal vascular fraction (SVF) cells and evaluated as a microvascular protection treatment in a myocardial infarction (MI) model. This study evaluated coronary blood flow (BF) and global left ventricular function after MI with and without the SVF construct. Fischer-344 rats were separated into four groups: sham operation (sham), MI, MI Vicryl patch (no cells), and MI SVF construct (MI SVF). SVF cells were labeled with green fluorescent protein (GFP). Immediately postinfarct, constructs were implanted onto the epicardium at the site of ischemia. Four weeks postsurgery, the coronary BF reserve was significantly decreased by 67% in the MI group and 75% in the MI Vicryl group compared with the sham group. The coronary BF reserve of the sham and MI SVF groups in the area at risk was not significantly different (sham group: 83 ± 22% and MI SVF group: 57 ± 22%). Griffonia simplicifolia I and GFP-positive SVF immunostaining revealed engrafted SVF cells around microvessels in the infarct region 4 wk postimplant. Overall heart function, specifically ejection fraction, was significantly greater in MI SVF hearts compared with MI and MI Vicryl hearts (MI SVF: 66 ± 4%, MI: 37 ± 8%, and MI Vicryl: 29 ± 6%). In conclusion, adipose-derived SVF cells can be used to construct a novel therapeutic modality for treating microvascular instability and ischemia through implantation on the epicardial surface of the heart. The SVF construct implanted immediately after MI not only maintains heart function but also sustains microvascular perfusion and function in the infarct area by sustaining the coronary BF reserve.     

Effect of simvastatin on collagen I deposition in non-infarcted myocardium: role of NF-κB and osteopontin

The novel biological effect of statins in alleviating myocardium fibrosis following infarction has been increasingly recognized, yet the underlying mechanisms are not fully understood. The purpose of this study was to characterize the effect of simvastatin on myocardial fibrosis and collagen I deposition in the non-infarcted region after myocardial infarction (MI) and to identify the role of NF-κB and osteopontin in simvastatin-mediated inhibition of post-MI collagen over-expression. A rat model of MI was generated by ligating the left anterior descending coronary artery. The rats surviving the MI operation were randomly divided into the following 3 groups: myocardial infarction (MI, vehicle), simvastatin (Sim, 30 mg·kg-1·day-1), and pyrrolidine dithiocarbamate (PDTC, an inhibitor of NF-κB, 100 mg·kg-1·day-1). Four weeks after MI, cardiac function, mRNAs, and protein expression in non-infarcted myocardium were analyzed. Myocardial fibrosis and collagen I over-expression were observed following MI, accompanied by an increase of NF-κB and osteopontin. Simvastatin improved post-MI left ventricular dysfunction and ameliorated post-MI associated changes to several cardiac parameters, including the left ventricular end diastolic pressure (LVEDP), the maximal rate of pressure development (+dP/dtmax), and the maximal rate of pressure decline (-dP/dtmax). Concurrently, simvastatin significantly suppressed the over-expression of NF-κB, osteopontin, and collagen I in the non-infarcted region following MI. Inhibition of NF-κB by PDTC also reduced osteopontin over-expression and excessive collagen I production and improved the above functional myocardial parameters. These results show that post-MI myocardial fibrosis and collagen I over-expression in the non-infarcted region is associated with activation of NF-κB and osteopontin up-regulation. The anti-fibrotic effect of simvastatin following MI is associated with the attenuation of the expression of osteopontin and NF-κB. The inhibition of NF-κB activation could be the process upstream of osteopontin suppression in the simvastatin-mediated effect.     

Heterogeneity in MT1-MMP activity with ischemia-reperfusion and previous myocardial infarction: relation to regional myocardial function

After a myocardial infarction (MI), an episode of ischemia-reperfusion (I/R) can result in a greater impairment of left ventricular (LV) regional function (LVRF) than that caused by an initial I/R episode in the absence of MI. Membrane type-I matrix metalloproteinase (MT1-MMP) proteolytically processes the myocardial matrix and is upregulated in LV failure. This study tested the central hypothesis that a differential induction of MT1-MMP occurs and is related to LVRF after I/R in the context of a previous MI. Pigs with a previous MI [3 wk postligation of the left circumflex artery (LCx)] or no MI were randomized to undergo I/R [60-min/120-min left anterior descending coronary artery (LAD) occlusion] or no I/R as follows: no MI and no I/R (n = 6), no MI and I/R (n = 8), MI and no I/R (n = 8), and MI and I/R (n = 8). Baseline LVRF (regional stroke work, sonomicrometry) was lower in the LAD region in the MI group compared with no MI (103 ± 12 vs. 188 ± 26 mmHg·mm, P < 0.05) and remained lower with peak ischemia (35 ± 8 vs. 88 ± 17 mmHg·mm, P < 0.05). Using a novel interstitial microdialysis method, MT1-MMP was directly measured and was over threefold higher in the LCx region and over twofold higher in the LAD region in the MI group compared with the no MI group at baseline. MT1-MMP fluorogenic activity was persistently elevated in the LCx region in the MI and I/R group but remained unchanged in the LAD region. In contrast, no changes in MT1-MMP occurred in the LCx region in the no MI and I/R group but increased in the LAD region. MT1-MMP mRNA was increased by over threefold in the MI region in the MI and I/R group. In conclusion, these findings demonstrate that a heterogeneous response in MT1-MMP activity likely contributes to regional dysfunction with I/R and that a subsequent episode of I/R activates a proteolytic cascade within the MI region that may contribute to a continued adverse remodeling process.     

基于三维超声心动图对比分析扩张型心肌病与二尖瓣关闭不全左室构型和收缩功能的研究

摘要 目的：基于三维超声心动图对比分析扩张型心肌病（DCM）与二尖瓣关闭不全（MI）左室构型和收缩功能的研究。方法：收集我院2018年1月至2021年7月就诊患有左心室（LV）扩张的患者100例,其中DCM患者57例,MI患者43例。LV大小大致相仿,DCM组（43±5）mm/m²,MI组（42±5）mm/m²。另选取同时期50例健康受试者作为对照组。所有患者均进行常规超声心动图及三维超声心动图检查,测量指标主要包括左室大小（LVID）、左室后壁厚度（PWT）、左室舒张末期内径（LVEDD）、左室舒张末期室间间隔厚度（IVS）、左室舒张末期容积（LVEDV）、收缩末期容积（LVESV）、相对室壁厚度（RWT）、LV质量指数（LVMI）、三维左室射血分数（3D-LVEF）、三维舒张末期血流速度（3D-EDV）、二维或三维超声心动图球形指数（2D-SI/3D-SI）。结果：DCM组和MI组LVEDD均大于对照组,差异有统计学意义（P＜0.05）。DCM组比MI组患者心功能分级III/IV和心力衰竭的发生率更高,差异有统计学意义（P＜0.05）。DCM组和MI组患者的LVEDD、LVEDD指数、LVEDV、LVEDV指数、3D-EDV、3D-EDV指数均高于对照组,差异有统计学意义（P＜0.05）;但DCM组和MI组对比差异无统计学意义（P＞0.05）。DCM组和MI组患者的LV长度、LV长度指数、LVMI均高于对照组,差异有统计学意义（P＜0.05）;且MI组高于DCM组,差异有统计学意义（P＜0.05）。DCM组和MI组患者的LVESV、LVESV指数、2D-SI、3D-SI均高于对照组,差异有统计学意义（P＜0.05）;且DCM组高于MI组,差异有统计学意义（P＜0.05）。DCM组3D-LVEF、RWT均低于对照组和MI组,差异有统计学意义（P＜0.05）。ROC分析显示,3D-SI在评估左室扩大患者的左室重构方面优于其他变量,3D-SI的ROC曲线下面积为0.875,95%CI为0.816-0.920,3D-SI>0.62对于DCM和MI区分左室构型的特异性（81.66%）和敏感性（92.09%）较高。DCM和MI患者的3D-LVEF和3D-SI均呈线性负相关（r=-0.719,P=0.000;r=-0.682,P=0.000）。DCM和MI患者3D-SI检测心力衰竭的ROC曲线下面积均大于3D-LVEF的ROC曲线下面积,差异有统计学意义（P=0.000）。结论：与MI患者相比,尽管LV大小大致相仿,但DCM患者的左室几何形状更接近球形,且收缩功能更差。收缩功能与3D-SI显著相关,3D-SI较好地描述了左室重构,可能是LV扩张患者心力衰竭的较强指标。     

黄连素对小鼠心肌梗死后心室重构的作用研究

目的:探讨黄连素(Berberine,BBR)在小鼠心肌梗死(myocardial infarction,MI)后心室重构中的作用,并比较BBR预处理(BBR pre-treatment,preBBR)和BBR后处理(BBR post-treatment,postBBR)给药的效果。方法:将60只C57BL/6小鼠随机分为4组,分别为假手术组、单纯MI对照组、MI+preBBR组及MI+postBBR组,每组15只。MI模型采用前降支结扎法制备。MI+preBBR组在MI模型制备前2周开始用BBR(100 mg·kg~(-1)·d~(-1))每天灌胃,持续至MI后28 d;MI+postBBR组在MI模型制备后4 h开始用BBR(100 mg·kg~(-1)·d~(-1))每天灌胃,持续至MI后28 d。记录实验期间小鼠生存情况。MI后28天采用小动物超声测定左心室收缩功能;取心脏组织,测定心脏大小和重量;ELISA方法测定血浆BNP水平;Masson染色评价心肌纤维化程度。结果:与单纯MI对照组相比,MI+preBBR组及MI+postBBR组小鼠生存率提高、心脏收缩功能增强、心脏变小、心脏重量减轻、血浆BNP水平降低、心肌纤维化明显改善。其中,MI+preBBR组上述指标的改善程度优于MI+postBBR组。结论:BBR可抑制MI后心室重构,且BBR预处理效果优于后处理。