The T-type calcium channel blocker mibefradil reduced interstitial and perivascular fibrosis and improved hemodynamic parameters in myocardial infarction-induced cardiac failure in rats

Fibrillar collagen accumulates within the interstitium and around coronary arteries following cardiac failure and is responsible for abnormal myocardial stiffness and reduced coronary performance associated with impaired cardiac function. The aim of the study was to determine the effects of long-term treatment with the T-type calcium channel antagonist mibefradil on myocardial remodeling and cardiac function after chronic myocardial infarction (MI). MI was induced by permanent ligation of the left coronary artery in male Wistar rats. Animals were assigned to sham-operated, placebo-treated or mibefradil-treated (10 mg/kg per day p.o.) MI groups. Treatment with mibefradil was started either 7 days before, 24 h after, or 7 days after ligation and continued for 6 weeks after MI. At this time point, mean arterial blood pressure (MAP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP) and cardiac contractility (dP/dt_max) were measured in conscious rats. Morphometric parameters were determined in picrosirius red-stained hearts: total heart weight (THW), interstitial and perivascular collagen volume fraction (ICVF, PCVF), myocardial infarct size (IS), vascular perimeter (VP), inner vascular diameter (IVD) and media thickness (MT). Six weeks after MI, MAP and dP/dt_max were decreased, and LVEDP was increased in placebo-treated animals. In mibefradil-treated animals whose treatment started 7 days before or 24 h after MI, MAP and dP/dt_max were higher, and LVEDP was lower than in placebo-treated controls. THW, ICVF, PCVF and MT were higher in placebo-treated animals. Mibefradil treatment resulted in higher ICVF and IS, higher VP and IVD (when started 7 days before MI) and lower PCVF and MT (when started 7 days before or 24 h after MI) than were observed in placebo-treated controls. Chronic treatment with mibefradil reduced interstitial and perivascular fibrosis and improved cardiac function in MI-induced heart failure in rats. Cardiac remodeling was best prevented when treatment was begun before the ischemic event. Received: 16 March 1999 / Accepted: 23 August 1999     

An autologous platelet-rich plasma hydrogel compound restores left ventricular structure,function and ameliorates adverse remodeling in a minimally invasive large animal myocardial restoration model: A translational approach: Vu and Pal “Myocardial Repair: PRP,Hydrogel and Supplements”

AimsCell-based myocardial restoration has not penetrated broad clinical practice yet due to poor cell retention and survival rates.In this study, we attempt a translational, large-scale restorative but minimally invasive approach in the pig, aiming at both structurally stabilizing the left ventricular (LV) wall and enhancing function following ischemic injury.Methods and resultsA myocardial infarction (MI) was created by permanent ligation of left circumflex coronary artery through a small lateral thoracotomy. Thirty-six Yorkshire pigs were randomized to receive transthoracic intramyocardial injection into both infarct and border zone areas with different compounds: 1) Hyaluronic acid-based hydrogel; 2) autologous platelet-rich plasma (PRP); 3) ascorbic acid-enriched hydrogel (50 mg/L), combined with IV ibuprofen (25 mg/kg) and allopurinol (25 mg/kg) (cocktail group); 4) PRP and cocktail (full-compound); or 5) saline (control). The latter two groups received daily oral ibuprofen (25 mg/kg) for 7 days and allopurinol (25 mg/kg) for 30 days, postoperatively. Hemodynamic and echocardiographic studies were carried out at baseline, immediately after infarction and at end-point. Eight weeks after MI, the full-compound group had better LV fractional area change, ejection fraction and smaller LV dimensions than the control group. Also, dp/dt_max was significantly higher in the full-compound group when the heart rate increased from 100 bpm to 160bpm in stress tests. Blood vessel density was higher in the full-compound group, compared to the other treatment groups.ConclusionsA combination of PRP, anti-oxidant and anti-inflammatory factors with intramyocardial injection of hydrogel has the potential to structurally and functionally improve the injured heart muscle while attenuating adverse cardiac remodeling after acute myocardial infarction.     

Augmented Cardiac Formation of Oxidatively-Induced Carbonylated Proteins Accompanies the Increased Functional Severity of Post-Myocardial Infarction Heart Failure in the Setting of Type 1 Diabetes Mellitus

SummaryHeart failure (HF) is a dominant cause for the higher mortality of diabetics after myocardial infarction (MI). In the present investigation, we have discovered that higher levels of oxidative stress (OS)-induced carbonylated proteins accompany worsening post-MI HF in the presence of type 1 diabetes. These findings provide a mechanistic link between amplified OS and exacerbation of post-infarction HF in diabetes.BackgroundType 1 diabetes mellitus (DM) patients surviving myocardial infarction (MI) manifest an increased incidence of subsequent heart failure (HF). We have previously shown that after MI, type 1 DM is associated with accentuated myocardial oxidative stress (OS) and concomitant worsening of left ventricular (LV) function. However, the precise mechanisms whereby type 1 DM-enhanced OS adversely affects HF after MI remain obscure. As carbonylation of proteins is an irreversible post-translational modification induced only by OS that often leads to the loss of function, we analyzed protein-bound carbonyls in the surviving LV myocardium of MI and DM+MI rats in relation to residual LV function.MethodsType 1 DM was induced in rats via administration of streptozotocin. Two weeks after induction of type 1 DM, MI was produced in DM and non-DM rats by coronary artery ligation. Residual LV function and remodeling was assessed at 4 weeks post-MI by echocardiography. Myocardial carbonylated proteins were detected through OxyBlot analysis, and identified by mass spectrometry.ResultsCompared with MI rats, DM+MI rats exhibited significantly poorer residual LV systolic function and elevated wet to dry weight ratios of the lungs. Protein carbonyl content in cardiac tissue and isolated heart mitochondria of DM+MI rats was 20% and 48% higher, respectively, versus MI rats. Anti-oxidative enzymes and fatty acid utilization proteins were among the carbonylated protein candidates identified.ConclusionsThese findings implicate myocardial protein carbonylation as part of the molecular pathophysiology of aggravated HF in the type 1 diabetic post-infarction heart.     

八肽胆囊收缩素逆转内毒素休克大鼠心功能降低的实验研究

目的: 观察八肽胆囊收缩素(CCK-8)改善内毒素休克(ES)大鼠心功能的变化,探讨CCK-8抗ES的作用及机制。方法: 实验分对照组、脂多糖(LPS)组、CCK组及CCK+LPS组;监测左室内收缩压(LVP)、左室收缩与舒张期内压变化的最大速率、心率(HR)和平均动脉压(MAP)的动态变化;分别测定2h血清、心肌组织中超氧化物歧化酶(SOD)活性、丙二醛(MDA)和一氧化氮(NO)含量的变化。结果: 静脉注射CCK-8(40μg·kg^-1),引起短时间心率减慢,轻度MAP、LVP和±LVdp/dt_max上升;静脉注时LPS(8mg·kg^-1),引起HR生快后慢双向改变MAP、LVP和±LVdp/dt_max快速持续下降;整体预先注射CCK-8,可明显缓解ES大鼠HR的快速变化,逆转MAP、LVP和±LVdp/dt_max下降,但未恢复至正常水平。CCK-8可提高ES大鼠血清、心肌组织中SOD活性,降低MDA和NO含量。结论: CCK-8可引起短时间心率减慢、轻度MAP上升和心肌收缩力增强;预先应用CCK-8可以减轻ES大鼠心肌氧化损伤,减少NO合成,恢复心肌收缩力,逆转心功能降低及顽固性低血压,是其发挥抗ES的重要机制之一。     

长期TCV116干预对心肌梗死后心室重塑及心功能的影响

目的:研究长期新型血管紧张素Ⅱ1型受体阻断剂TCV116干预对心肌梗死(MI)后心肌重塑及心功能的影响。方法:通过结扎冠状动脉左前降支复制大鼠MI模型,1周后将大鼠随机分为:(1)MI对照组;(2)MITCV116治疗组(2mg.kg^-1·d^-1):另设假手术组及假手术TCV116组。22周后检测:(1)血流动力学参数如平均动脉压(MAP)、左室收缩压(LVSP)、室内压最大上升和下降速率(dp／dt_max)和左室舒张末压(LVEDP)及心脏形态学指标如左室相对重量(LVW／BW)和左室腔相对面积(LVCA／BW);(2)室间隔存活心肌中β肌球蛋白重链(βMHC)、B型钠尿肽(BNP)、转化生长因子β₁(TGF-β₁)、I型和III型胶原(collagenI、III)基因的mRNA表达;(3)存活率。结果:MI对照组与MITCV116治疗组间总体MI范围无显著差异(34%±14％vs33%±13%,P>0.05)。MI对照组LVW／BW和LVCA／BW显著高于假手术组(P<0.01),βMHC、BNP、TGF-β₁、collagenI和III基因的mRAN表达显著大于假手术组(P<0.01);同时MAP、LVSP、dp／dt_max显著低于和LVEDP显著高于假手术组(P<0.01),也伴随着生存时间显著缩短(P<0.05)。TCV116治疗组,LVW／BW和LVCA／BW与MI对照组比无显著差异,βMHC、BNP、TGF-β₁、collagenI和III基因的mRNA表达低于MI对照组(P<0.05或P<0.01);与此同时,MAP、LVSP、dp／dt_max显著高于及LVEDP显著低于MI对照组(P<0.05或P<0.01),并伴随着生存时间的延长(P<0.05)。结论:长期血管紧张素II1型受体阻断剂干预能显著改善心肌梗死后大鼠心室重塑及心功能。     

Mechanical function,glycolysis, and ultrastructure of perfused working mouse hearts following thoracic aortic constriction

BackgroundGlycolytic flux in the mouse heart during the progression of left ventricular hypertrophy (LVH) and mechanical dysfunction has not been described.MethodsThe main objectives of this study were to characterize the effects of thoracic aortic banding, of 3- and 6-week duration, on: (1) left ventricular (LV) systolic and diastolic function of perfused working hearts quantified by analysis of pressure–volume loops; (2) glycolytic flux in working hearts expressed as the rate of conversion of ³H-glucose to ³H₂O, and (3) ultrastructure of LV biopsies assessed by quantitative and qualitative analysis of light and electron micrographs.ResultsResults revealed that (1) indexes of systolic function, including LV end-systolic pressure, cardiac output, and rate of LV pressure development and decline, were depressed to similar degrees at 3 and 6 weeks post-banding; (2) diastolic dysfunction, represented by elevated LV end-diastolic pressure and volume, was more severe at 6 than at 3 weeks, consistent with a transition to failure; (3) a progressive decline in glycolytic flux that was roughly half the control rate by 6 weeks post-banding; and (4) structural derangements, manifested by increases in interstitial collagen content and myocyte Z-band disruption, that were more marked at 3 weeks than at 6 weeks.ConclusionThe results are consistent with the view that myocyte damage, fibrosis, and suppressed glycolytic flux represent maladaptive structural and metabolic remodeling that contribute to the development of failure in high pressure load-induced LVH in the mouse.     

A fibrin patch-based enhanced delivery of human embryonic stem cell-derived vascular cell transplantation in a porcine model of postinfarction left ventricular remodeling

It is unknown how to use human embryonic stem cell (hESC) to effectively treat hearts with postinfarction left ventricular (LV) remodeling. Using a porcine model of postinfarction LV remodeling, this study examined the functional improvement of enhanced delivery of combined transplantation of hESC-derived endothelial cells (ECs) and hESC-derived smooth muscle cells (SMCs) with a fibrin three-dimensional (3D) porous scaffold biomatrix. To facilitate tracking the transplanted cells, the hESCs were genetically modified to stably express green fluorescent protein and luciferase (GFP/Luc). Myocardial infarction (MI) was created by ligating the first diagonal coronary artery for 60 minutes followed by reperfusion. Two million each of GFP/Luc hESC-derived ECs and SMCs were seeded in the 3D porous biomatrix patch and applied to the region of ischemia/reperfusion for cell group (MI+P+C, n = 6), whereas biomatrix without cell (MI+P, n = 5), or saline only (MI, n = 5) were applied to control group hearts with same coronary artery ligation. Functional outcome (1 and 4 weeks follow-up) of stem cell transplantation was assessed by cardiac magnetic resonance imaging. The transplantation of hESC-derived vascular cells resulted in significant LV functional improvement. Significant engraftment of hESC-derived cells was confirmed by both in vivo and ex vivo bioluminescent imaging. The mechanism underlying the functional beneficial effects of cardiac progenitor transplantation is attributed to the increased neovascularization. These findings demonstrate a promising therapeutic potential of using these hESC-derived vascular cell types and the mode of patch delivery.     

Stem cell-loaded nanofibrous patch promotes the regeneration of infarcted myocardium with functional improvement in rat model

Myocardial infarction (MI) leads to the loss of cardiomyocytes, followed by left ventricular (LV) remodeling and cardiac dysfunction. The authors hypothesize that an elastic, biodegradable nanofibrous cardiac patch loaded with mesenchymal stem cells (MSC) could restrain LV remodeling and improve cardiac function after MI. Poly(ε-caprolactone)/gelatin (PG) nanofibers were fabricated by electrospinning, and the nanofibers displayed a porous and uniform nanofibrous structure with a diameter of 244 ± 51 nm. An MI model was established by ligation of the left anterior descending coronary artery of female Sprague–Dawley rats. The PG nanofibrous patch seeded with MSC, isolated from rat bone marrow, was implanted on the epicardium of the infarcted region of the LV wall of the heart. After transplantation, the PG–cell patch restricted the expansion of the LV wall effectively and reduced the scar size, and the density of the microvessels increased. Cells within the patch were able to migrate towards the scar tissue, and promoted new blood vessel formation at the infarct site. Angiogenesis and the cardiac functions improved significantly after 4 weeks of implantation. The MSC-seeded PG nanofibrous patches are demonstrated to provide sufficient mechanical support, to induce angiogenesis and to accelerate cardiac repair in a rat model of MI. The study highlights the positive impact of implantation of an MSC-seeded PG nanofibrous patch as a novel constituent for MI repair.     

不同程度冠状动脉粥样硬化病变下心肌组织中melusin的表达研究

目的:观察不同程度冠状动脉粥样硬化病变下心肌组织的病理改变,检测心肌组织内melusin蛋白的水平,探讨melusin在冠心病的发生发展过程中所发挥的作用。方法:筛选尸检取材的冠心病案例,分3组:动脉粥样硬化斑块稳定者(B组);粥样硬化斑块不稳定但无血栓形成、斑块破裂、斑块内出血等任一种继发病变者(C组);斑块不稳定且伴有上述任一种继发病变者(D组)。以无心脏疾病死亡者为对照组(A组)。分别收集冠状动脉和心肌组织,常规HE染色观察各组心肌的结构变化,免疫组织化学染色、Western blot及real-time PCR法检测心肌组织内melusin的表达分布,利用logistic回归分析melusin的表达改变与冠心病发生发展的关系。结果:(1)与A组比较,其余3组心肌呈现肥大、萎缩、坏死及脂肪浸润等病理改变;(2) B组心肌组织中的melusin表达较A组增高,C组和D组中melusin表达较A组显著降低(P<0.05);(3) melusin在心肌细胞中的表达与冠心病发生发展呈负相关(OR=0.3; 95%CI:0.2～0.4;P<0.01)。结论:人心肌组织中melu...     

Medroxyprogesterone acetate aggravates oxidative stress and left ventricular dysfunction in rats with chronic myocardial infarction

The role of estrogens during myocardial ischemia has been extensively studied. However, effects of a standard hormone replacement therapy including 17β-estradiol (E2) combined with medroxyprogesterone acetate (MPA) have not been assessed, and this combination could have contributed to the negative outcomes of the clinical studies on hormone replacement. We hypothesized that adding MPA to an E2 treatment would aggravate chronic heart failure after experimental myocardial infarction (MI). To address this issue, we evaluated clinical signs of heart failure as well as left ventricular (LV) dysfunction and remodeling in ovariectomized rats subjected to chronic MI receiving E2 or E2 plus MPA. After eight weeks MI E2 showed no effects. Adding MPA to E2 aggravated LV remodeling and dysfunction as judged by increased heart weight, elevated myocyte cross-sectional areas, increased elevated left ventricle end diastolic pressure, and decreased LV fractional shortening. Impaired LV function in rats receiving MPA plus E2 was associated with increased cardiac reactive oxygen species generation and myocardial expression levels of NADPH oxidase subunits. These results support the interpretation that adding MPA to an E2 treatment complicates cardiovascular injury damage post-MI and therefore contributes to explain the adverse outcome of prospective clinical studies.     

大鼠肥厚心脏卸负荷后心室逆重塑相关的信号通路改变

目的： 研究肥厚心脏心室重塑及逆重塑过程中Akt/GSK3β、MAPKs和NF-κB信号通路的变化。方法：以Lewis大鼠行腹主动脉缩窄术,建立压力超负荷性心肌肥厚模型。将肥厚心脏移植到同源Lewis大鼠腹部,建立压力卸负荷模型。对各组心肌取材进行病理学评价。Western blotting法检测心肌组织中相关信号通路蛋白的表达。结果：在心肌肥厚大鼠心脏中Akt/GSK3β、MAPKs和NF-κB磷酸化水平均显著升高,移植卸负荷后除p38 MAPK和JNK外,其它蛋白磷酸化水平均显著降低。结论：肥厚心脏经异位移植卸负荷后产生逆重塑现象,Akt/GSK3β、ERK1/2和NF-κB信号通路的改变参与其中,该结果为临床心室逆重塑的研究提供了实验依据。     

Qiliqiangxin improves cardiac function and attenuates cardiac remodeling in rats with experimental myocardial infarction

Objective: It has been reported that Qiliqiangxin (QL), a traditional Chinese medicine compound, could inhibit cardiac hypertrophy and remodeling, and improve cardiac function. However, whether and how it reverses cardiac remodeling in rats post myocardial infarction (MI) remains unknown. This study aims to explore related mechanisms linked with cardiac function improvement and attenuation of cardiac remodeling by QL in rats with experimental MI. Methods: MI was induced by ligation of left anterior descending coronary artery (LAD) in male Sprague-Dawley rats. Rats with LVEF < 50% at four weeks after procedure were treated for another 6 weeks with placebo, QL and captopril. Echocardiography and plasma NT-proBNP were measured at the end of study, and histological studies were performed. Protein expressions of Neuregulin-1 (NRG-1), total-Akt, phospho-Akt (Ser473), hydroxy-HIF-1α (Pro564), VEGF, Bax, Bcl-2 and Caspase 3 were examined by Western blot. mRNA expression of NRG-1 and p53 was detected by real-time PCR. Results: Compared with the placebo group, QL improved cardiac function, reduced left ventricular dimension, inhibited interstitial inflammation and fibrosis, increased neovascularization, and attenuated cardiomyocyte apoptosis. Meanwhile QL significantly upregulated the expression of HIF-1α, VEGF, enhanced phosphorylation of Akt, decreased the ratio of Bax/Bcl-2 and Caspase 3 expression. Furthermore, we observed upregulation of NRG-1 and downregulation of p53 after QL treatment. Conclusion: Our data suggest that the beneficial effects of QL on improving cardiac function and attenuating cardiac remodeling post MI are associated with angiogenesis enhancement and apoptosis inhibition, which may be mediated via activation of NRG-1/Akt signaling and suppression of p53 pathway.     

Multiparametric CMR imaging of infarct remodeling in a percutaneous reperfused Yucatan mini‐pig model

To further understanding of the temporal evolution and pathophysiology of adverse ventricular remodeling over the first 60 days following a myocardial infarction (MI) in both the infarcted and remote myocardium, we performed multi‐parametric cardiac magnetic resonance (CMR) imaging in a closed‐chest chronic Yucatan mini‐pig model of reperfused MI. Ten animals underwent 90 min left anterior descending artery occlusion and reperfusion. Three animals served as controls. Multiparametric CMR (1.5T) was performed at baseline, Day 2, Day 30 and in four animals on Day 60 after MI. Left ventricular (LV) volumes and infarct size were measured. T₁ and T₂ mapping sequences were performed to measure values in the infarct and remote regions. Remote region collagen fractions were compared between infarcted animals and controls. Procedure success was 80%. The model created large infarcts (28 ± 5% of LV mass on Day 2), which led to significant adverse myocardial remodeling that stabilized beyond 30 days. Native T₁ values did not reliably differentiate remote and infarct regions acutely. There was no evidence of remote fibrosis as indicated by partition coefficient and collagen fraction analyses. The infarct T₂ values remained elevated up to 60 days after MI. Multiparametric CMR in this model showed significant adverse ventricular remodeling 30 days after MI similar to that seen in humans. In addition, this study demonstrated that remote fibrosis is absent and that infarct T₂ signal remains chronically elevated in this model. These findings need to be considered when designing preclinical trials using CMR endpoints.     

p38 Mitogen-Activated Protein Kinase Inhibition Decreases TNFalpha Secretion and Protects Against Left Ventricular Remodeling in Rats with Myocardial Ischemia

The purpose of this study was to test our hypothesis that p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580 may favorably affect tumor necrosis factor alpha (TNFα) secretion and left ventricular (LV) remodeling after myocardial ischemia (MI). The left anterior descending coronary artery (LAD) was ligated to produce anterior MI in 40 rats that were randomly divided into two groups: p38i group (n = 24) and MIR group (MI rat models, n = 24). A sham operation group without LAD ligation (Sham, n = 16) was also studied. SB203580 (2 mg/kg) and saline was injected i.p. once every 3 days in the first two groups, respectively. One and six weeks after MI, cardiac function, myocardial fibrosis, the cardiac expressions of phosphorylated p38 MAPK (p-p38 MAPK), TNFα, alpha smooth muscle actin (αSMA) and collagen I, the ultramicrostructure of the myocardium were examined by echocardiography, histological staining, western blot, immunohistochemical staining, transmission electron microscope (TEM), respectively. Treatments with SB203580 suppressed myocardial fibrosis and LV remodeling, as well as attenuated the expressions of p-p38-MAPK, TNFα, αSMA and collagen I as compared with the MIR. In conclusion, SB203850 has an effect of inhibiting inflammation-induced fibrosis, which leads to attenuation of LV remodeling.     

Cardioprotective role of growth/differentiation factor 1 in post‐infarction left ventricular remodelling and dysfunction

Growth/differentiation factor 1 (GDF1) is a secreted glycoprotein of the transforming growth factor‐β (TGF‐β) superfamily that mediates cell differentiation events during embryonic development. GDF1 is expressed in several tissues, including the heart. However, the functional role of GDF1 in myocardial infarction (MI)‐induced cardiac remodelling and dysfunction is not known. Here, we performed gain‐of‐function and loss‐of‐function studies using cardiac‐specific GDF1 transgenic (TG) and knockout (KO) mice to determine the role of GDF1 in the pathogenesis of functional and architectural cardiac remodelling after MI, which was induced by surgical left anterior descending coronary artery ligation. Our results demonstrate that overexpression of GDF1 in the heart causes a significant decrease in MI‐derived mortality post‐MI and leads to attenuated infarct size expansion, left ventricular (LV) dilatation, and cardiac dysfunction at 1 week and 4 weeks after MI injury. Compared with control animals, cardiomyocyte apoptosis, inflammation, hypertrophy, and interstitial fibrosis were all remarkably reduced in the GDF1‐TG mice following MI. In contrast, GDF1 deficiency greatly exacerbated the pathological cardiac remodelling response after infarction. Further analysis of the in vitro and in vivo signalling events indicated that the beneficial role of GDF1 in MI‐induced cardiac dysfunction and LV remodelling was associated with the inhibition of non‐canonical (MEK–ERK1/2) and canonical (Smad) signalling cascades. Overall, our data reveal that GDF1 in the heart is a novel mediator that protects against the development of post‐infarction cardiac remodelling via negative regulation of the MEK–ERK1/2 and Smad signalling pathways. Thus, GDF1 may serve as a valuable therapeutic target for the treatment of MI. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Early, selective growth hormone administration may ameliorate left ventricular remodeling after myocardial infarction

Left ventricular (LV) remodeling after myocardial infarction (MI) may lead to congestive heart failure, disability and death. It consists of expansion of the infarct zone and dilatation of the non-infarcted myocardium, causing shape distortion and ventricular enlargement. Experimental studies have shown that treatment with growth hormone (GH) stimulates cardiac repair, resulting in increased infarct zone collagen scar formation and possibly enhanced proteinosynthesis. These actions may ameliorate the process of LV remodeling. We hypothesize that these beneficial effects may be more prominent, if GH is delivered selectively in the infarct area, during the early phase of acute MI. Experimental and clinical studies are necessary to validate this hypothesis.     

Cardiac oxidative stress and remodeling following infarction: role of NADPH oxidase

BackgroundThere is growing recognition that oxidative stress plays a role in the pathogeneses of myocardial repair/remodeling following myocardial infarction (MI). Nicotinamide adenine denucleotide phosphate (NADPH) oxidase is a major source for cardiac reactive oxygen species production. Herein, we studied the importance of NADPH oxidase in development of cardiac oxidative stress and its induced molecular and cellular changes related to myocardial repair/remodeling.MethodsMI was created by coronary artery ligation in C57/BL (wild type) and NADPH oxidase (gp91^phox) knockout mice. Cardiac oxidative stress, inflammatory/fibrogenic responses, apoptosis, and hypertrophy were detected by in situ hybridization, immunohistochemistry, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL), picrosirius red staining, and image analysis, respectively, at different stages post MI.ResultsIn wild-type mice with MI, and compared to sham-operated animals, we observed significantly increased gp91^phox and 3-nitrotyrosine, a marker of oxidative stress, in the infarcted myocardium; accumulated macrophages and myofibroblasts at the infarct site; abundant apoptotic myocytes primarily at border zones on Day 3; and numerous apoptotic inflammatory/myofibroblasts in the later stages. In addition, we detected significantly increased transforming growth factor β1, tissue inhibitor of metalloprotease 2, and type 1 collagen gene expression; continuously increasing collagen volume in the infarcted myocardium; and hypertrophy in noninfarcted myocardium. Compared to wild-type mice with MI, we did not observe significant difference in infarct size/thickness, cardiac hypertrophy, myocyte apoptosis, inflammatory/fibrogenic responses, as well as cardiac oxidative stress in gp91^phox knockout mice.ConclusionOur findings indicate that during NADPH oxidase deficiency, superoxide production can be compensated by other sources, which leads to cardiac oxidative stress and its related molecular/cellular events in the infarcted heart.     

Anti-Inflammation Role for Mesenchymal Stem Cells Transplantation in Myocardial Infarction

The aim of the present study was to investigate the role of anti-inflammation for MSCs transplantation in rat models of myocardial infarction. Rats with AMI induced by occlusion of the left coronary artery were randomized to MSCs transplantation group, MI group and sham operated group. The effects of MSCs transplantation on cardiac inflammation and left ventricular remodeling in non-infarcted zone were observed after 4 weeks of MI. We found that MSC transplantation (1) decreased protein production and gene expression of inflammation cytokines TNF-α, IL-1β and IL-6, (2) inhibited deposition of type I and III collagen, as well as gene and protein expression of MMP-1 and TIMP-1, (3) attenuated LV cavitary dilation and transmural infarct thinning, thus prevent myocardial remodeling after myocardial infarction, and (4) increased EF, FS, LVESP and dp/dtmax (P < 0.01), decreased LVDd, LVEDV, LVEDP (P < 0.05). Anti-inflammation role for MSCs transplantation might partly account for the cardiac protective effect in ischemic heart disease.     

The role of the sca-1+/CD31- cardiac progenitor cell population in postinfarction left ventricular remodeling

Cardiac stem cell-like populations exist in adult hearts, and their roles in cardiac repair remain to be defined. Sca-1 is an important surface marker for cardiac and other somatic stem cells. We hypothesized that heart-derived Sca-1(+)/CD31(-) cells may play a role in myocardial infarction-induced cardiac repair/remodeling. Mouse heart-derived Sca-1(+)/CD31(-) cells cultured in vitro could be induced to express both endothelial cell and cardiomyocyte markers. Immunofluorescence staining and fluorescence-activated cell sorting analysis indicated that endogenous Sca-1(+)/CD31(-) cells were significantly increased in the mouse heart 7 days after myocardial infarction (MI). Western blotting confirmed elevated Sca-1 protein expression in myocardium 7 days after MI. Transplantation of Sca-1(+)/CD31(-) cells into the acutely infarcted mouse heart attenuated the functional decline and adverse structural remodeling initiated by MI as evidenced by an increased left ventricular (LV) ejection fraction, a decreased LV end-diastolic dimension, a decreased LV end-systolic dimension, a significant increase of myocardial neovascularization, and modest cardiomyocyte regeneration. Attenuation of LV remodeling was accompanied by remarkably improved myocardial bioenergetic characteristics. The beneficial effects of cell transplantation appear to primarily depend on paracrine effects of the transplanted cells on new vessel formation and native cardiomyocyte function. Sca-1(+)/CD31(-) cells may hold therapeutic possibilities with regard to the treatment of ischemic heart disease.