Abstract 17179: Uremic Toxins Contribute to Cardiac Fibrosis after Myocardial Infarction: Role of MicroRNAs

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Indrajeet Rana ◽  
Andrew Kompa ◽  
Joanna Skommer ◽  
Suree Lekawanvijit ◽  
Darren J Kelly ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Cardiac Fibrosis ◽  
Uremic Toxins ◽  
Coronary Artery Ligation ◽  
Uremic Toxin ◽  
Sprague Dawley ◽  
Artery Ligation ◽  
Tgf Β1

Introduction: A decline in renal function is a common consequence of myocardial infarction (MI) resulting in increased cardiovascular events, known as cardiorenal syndrome (CRS). Although molecular mechanisms contributing to CRS are not well understood, a role for elevated plasma levels of the uremic toxin indoxyl sulphate (IS) and increased fibrosis have been described. MicroRNAs are small endogenously transcribed regulatory RNAs that modulate gene expression and regulate many cardiac processes involved in cardiac dysfunction. Aim: Using a rat model we investigated whether MI leads to changes in expression of cardiac microRNA-21 and microRNA-29, both known to contribute to fibrosis. We also investigated the effect of lowering plasma uremic toxins on cardiac expression of these microRNAs. Methods: MI was induced by coronary artery ligation in male Sprague-Dawley rats. At 16 weeks cardiac function was measured prior to sacrifice. Cardiac tissues were assessed for molecular changes using real-time PCR, western blot analysis and histological methods. Results: MI significantly increased cardiac microRNA-21, collagen1A1, fibronectin-1 and TGFβ1 mRNA expression, as well as cardiac fibrosis and collagen 1 protein expression. Conversely, microRNA-29 expression was reduced in the heart (Table). Treatment with the AST-120 significantly reversed all these changes (Table). MicroRNA-21 levels significantly correlated with mRNA for TGF-β1 (P=0.049; r2=0.17) and its target genes collagen1A1 (P=0.004; r2=0.35) and fibronectin-1 (P=0.003; r2=0.52). MicroRNA-29b levels negatively and significantly correlated with TGF-β1 (P=0.017; r2=0.26) and collagen1A1 (P=0.048; r2=0.18) and fibronectin-1 (P=0.013; r2=0.29). Conclusions: We report a link between the beneficial effects of lowering circulating uremic toxins and microRNAs changes in the heart. Targeting microRNA’s may provide a therapeutic target for the treatment of CRS.

Abstract 866: Secreted Frizzled Related Protein 2 Modulates Post Myocardial Infarct Remodeling by Inhibiting Collagen Maturation through the Inhibition of Bone Morphogenetic Protein 1 Activity

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Wei He ◽  
Lunan Zhang ◽  
Richard E Pratt ◽  
Victor J Dzau
Keyword(s):  
Myocardial Infarction ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Myocardial Infarct ◽  
Primary Cultures ◽  
The United States ◽  
Coronary Artery Ligation ◽  
Related Protein ◽  
Artery Ligation

Myocardial infarction and post-infarction remodeling with heart failure are the major cause of mortality and morbidity in the United States. We recently reported that intracardiac implantation of genetically engineered mesenchymal stem cell (MSC) overexpressing the Akt gene dramatically reduced the infarct size and restored cardiac functions in rodent hearts after coronary artery ligation. Further, we identified Secreted Frizzled Related Protein 2 (sfrp2) as a key factor released by Akt-MSC mediating myocardial survival and repair. However, the underlying mechanism remains elusive. Bone Morphogenetic Protein1 (BMP1)/Tolloid (TLD)-like metalloproteinases belong to a subgroup of astacin family and play key roles in the regulation of extracelluar matrix (ECM) formation and cardiac fibrosis. These proteases have procollagen C-proteinase (PCP) activities which are responsible for the cleavage of C-propeptides from procollagen precursors to produce mature collagen fibrils. In this report, we showed that three days following myocardial infarction in rats, both BMP1 protein expression and activity were upregulated in the infarcted left ventricle. Interestingly, we found recombinant sfrp2 could inhibit BMP1 activity in MI tissue samples as measured by an in vitro PCP activity assay. Furthermore, using purified recombinant proteins, we demonstrated that sfrp2, but not sfrp1 or sfrp3, inhibited BMP-1 activity in vitro. Moreover, purified sfrp2 could physically interact with BMP1 protein as shown by the co-immunoprecipitation assay. To provide further evidence that sfrp2 can interfere with collagen processing, we demonstrated that exogenously added sfrp2 interfered with procollagen processing in primary cultures of cardiac fibroblast culture medium. Similar results were obtained when these cells were transiently transfected with sfrp2 expressing plasmids. In summary, our data suggest that one of the molecular mechanisms underlying the cardioprotective and repair effects of sfrp2 protein on myocardial infarction is through the inhibition of BMP-1 activity. Therefore, sfrp2 has the potential clinical application as a novel anti-fibrotic reagent for the modulation of cardiac remodeling after acute myocardial infarction.

Effects of carbon nanotube-mediated Caspase3 gene silencing on cardiomyocyte apoptosis and cardiac function during early acute myocardial infarction

Nanoscale ◽  
2020 ◽  
Vol 12 (42) ◽  
pp. 21599-21604
Author(s):  
Yi Li ◽  
Hong Yu ◽  
Liang Zhao ◽  
Yuting Zhu ◽  
Rui Bai ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Gene Silencing ◽  
Ventricular Remodeling ◽  
Myocardial Cell ◽  
Coronary Artery Ligation ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Artery Ligation ◽  
Sd Rats

Caspase3 gene silencing based on the gene transfer carrier F-CNT-siCas3 had obvious protective effects on myocardial cell apoptosis, ventricular remodeling, and cardiac function in Sprague-Dawley (SD) rats after coronary artery ligation.

scholarly journals Effect of Wenxin Granules on Gap Junction and MiR-1 in Rats with Myocardial Infarction

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Aiming Wu ◽  
Mingjing Zhao ◽  
Lixia Lou ◽  
Jianying Zhai ◽  
Dongmei Zhang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Gap Junctions ◽  
Gap Junction ◽  
High Dose ◽  
Coronary Artery Ligation ◽  
Sprague Dawley ◽  
Artery Ligation ◽  
Ventricular Fibrillation Threshold ◽  
Transmission Electron ◽  
Lethal Arrhythmia

Myocardial infarction (MI) patients are at high risk of potential lethal arrhythmia. Gap junction and microRNA-1 (miR-1) are both arrhythmia generating conditions. The present study investigated whether Wenxin Granules (Wenxin-Keli, WXKL) could prevent potential lethal arrhythmia by improving gap junctions and miR-1 following MI. Male Sprague-Dawley rats were divided randomly into control, model, metoprolol, low dose WXKL, and high dose WXKL groups. The MI rat model was created by coronary artery ligation. Treatments were administrated intragastrically to the rats for 4 weeks. Conventional transmission electron microscopy was performed to observe the ultrastructure of gap junctions. Quantitative real-time PCR and western blotting were used to detect the expression of miR-1, protein kinase C (PKC), and related proteins. Additionally, a programmatic electrophysiological stimulation test was performed to detect the ventricular fibrillation threshold (VFT). WXKL protected the ultrastructure of the gap junctions and their constituent Cx43 by regulating miR-1 and PKC mediated signal transduction and increased the VFT significantly in the rat MI model. The results suggested that WXKL is an effective alternative medicine to prevent potentially lethal arrhythmia following MI.

Abstract 430: Immature Cardiac Fibroblasts With Upregulated P53 Contributed to Fibrosis in Ikke Deficient Mouse Myocardial Infarction Model

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Yong Sook Kim ◽  
Hyang Hee Cho ◽  
Ju Hee Jun ◽  
Dong Im Cho ◽  
Meeyoung Cho ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Cardiac Fibroblasts ◽  
Smooth Muscle Actin ◽  
Healing Process ◽  
Wound Healing Process ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Background: Inhibitor of NF-κB kinase (IKK), an upstream of nuclear factor-kappa B (NF-κB), is a critical modulator for pathophysiological inflammation. IKKε is a non-classical IKK and has been studied in infectious diseases and cancers. However, the role of IKKε in a myocardial infarction (MI) has not been addressed. Methods and Results: In this study, we used IKKε knockout (KO) mice to induce MI by coronary artery ligation. The IKKε KO group showed poor early survival rate, large cardiac fibrosis (14.7±4.8% in KO vs. 31.1±10.2% in WT, p <0.05), and low fractional shortening (13.47±1.21% in KO vs. 16.36±4.46% in WT, p <0.05) compared with WT group. Next, we investigated the inflammatory responses and found that inflammatory markers such as inducible nitric oxide synthase (iNOS) and CD80 were much higher in both cardiac macrophages and bone marrow-derived macrophages (BMDM) in the IKKε KO group than in the wild type (WT) group. To explore the responsible mediator, we performed phosphorylated protein array and found phosphorylated p38 was significantly downregulated in the IKKε knockout BMDM. Conversely, both knockdown of p38 by siRNA and inhibition of p38 by SB203580 treatment in RAW264.7 cells upregulated iNOS. More interestingly, IKKε deficient cardiac fibroblasts showed highly accumulated nuclear p53 and exhibited immature differentiation. The levels of myofibroblast markers containing α-smooth muscle actin, periostin, and transforming growth factor-β1 were lower, and functional contractility was substantially impaired in the cardiac fibroblasts isolated from IKKε KO mice. Conclusion: Our data showed excessive inflammation was associated with p38 inactivation in macrophages and pathological fibrosis was resulted from immature myofibroblast phenotype with p53 upregulation. Collectively, IKKε is involved in the control of inflammation resolution and wound healing process in the infarcted myocardium.

scholarly journals Preservation of Functional Microvascular Bed Is Vital for Long-Term Survival of Cardiac Myocytes Within Large Transmural Post-Myocardial Infarction Scar

2017 ◽  
Vol 66 (2) ◽  
pp. 99-120 ◽  
Author(s):  
Colleen Nofi ◽  
Yevgen Bogatyryov ◽  
Eduard I. Dedkov
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Myocyte ◽  
Coronary Artery Ligation ◽  
Sprague Dawley ◽  
Artery Ligation ◽  
Term Survival ◽  
Long Term Survival ◽  
Thebesian Veins ◽  
Transverse Area

This study was aimed to understand the mechanism of persistent cardiac myocyte (CM) survival in myocardial infarction (MI) scars. A transmural MI was induced in 12-month-old Sprague–Dawley rats by permanent coronary artery ligation. The hearts were collected 3 days, 1, 2, 4, 8, and 12 weeks after MI and evaluated with histology, immunohistochemistry, and quantitative morphometry. Vasculature patency was assessed in 4-, 8-, and 12-week-old scars by infusion of 15-micron microspheres into the left ventricle before euthanasia. The infarcted/scarred area has a small continually retained population of surviving CMs in subendocardial and subepicardial regions. Surprisingly, whereas the transverse area of subepicardial CMs remained relatively preserved or even enlarged over 12 post-MI weeks, subendocardial CMs underwent progressive atrophy. Nevertheless, the fractional volume of viable CMs remained comparable in mature scars 4, 8, and 12 weeks after MI (3.6 ± 0.4%, 3.4 ± 0.5%, and 2.5 ± 0.3%, respectively). Despite the opposite dynamics of changes in size, CMs of both regions displayed sarcomeres and gap junctions. Most importantly, surviving CMs were always accompanied by patent microvessels linked to a venous network composed of Thebesian veins, intramural sinusoids, and subepicardial veins. Our findings reveal that long-term survival of CMs in transmural post-MI scars is sustained by a local microcirculatory bed.

scholarly journals The pericardium promotes cardiac repair and remodelling post-myocardial infarction

2019 ◽  
Author(s):  
Katie J. Mylonas ◽  
Lucy H. Jackson-Jones ◽  
Jack P. M. Andrews ◽  
Marlene S. Magalhaes ◽  
Marco Meloni ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Cardiac Fibrosis ◽  
Stable Coronary Artery Disease ◽  
Coronary Artery Ligation ◽  
Immune Functions ◽  
Tissue Remodelling ◽  
Artery Ligation ◽  
Macrophage Polarisation ◽  
Artery Disease

AbstractThe pericardium is widely recognised for its lubricating and bio-mechanical properties. It also contains fat-associated lymphoid clusters (FALCs) and its immune functions have been widely overlooked. Here we aimed to assess the inflammatory activity of the pericardium in patients who suffered a recent myocardial infarction (MI) and to determine its importance for repair and remodelling in a murine MI model induced by coronary artery ligation (CAL). By comparing 18F-fluorodeoxyglucose (FDG) activity in the pericardium of patients with stable coronary artery disease and patients who had a recent MI, we demonstrate that MI is associated with increased pericardial inflammation. We confirm in mice, that pericardial FALCs undergo a major expansion following CAL. We show that despite similar initial injury, removal of the pericardium prior to MI disrupted subsequent repair, resulting in 50% mortality due to cardiac rupture, while all mice with intact pericardia survived. Removal of the pericardium also led to decreased staining for Ym1, a marker of reparative macrophages and adverse cardiac fibrosis within the infarct area. Together, this work indicates a crucial role for the pericardium in regulating inflammation, macrophage polarisation and tissue remodelling in the heart following MI.

Abstract 372: Regulation of Ski and Scleraxis in the Infarcted Rat Heart

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Krista L Filomeno ◽  
Sunil G Rattan ◽  
Sheri Bage ◽  
Matthew Zeglinski ◽  
Michael P Czubryt ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Wound Healing ◽  
Mrna Expression ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Scar Tissue ◽  
Sprague Dawley ◽  
Scar Area ◽  
Tgf Β1

Introduction: Coronary heart disease is causal to myocardial infarction (MI) and cardiac fibrosis. Upon ischemic myocardial injury, resident cardiac fibroblasts phenoconvert to myofibroblasts and synthesize large amounts of fibrillar collagens to produce scar tissue. Although the myofibroblast numbers are reduced in the infarct scar following the completion of wound healing, a sub-population of cells persist in the wounded area, leading to maladaptive chronic remodeling of the scar area and eventually the non-infarcted myocardium. Ski has been identified as a repressor of the TGF-β1 signaling pathway, attenuating the myofibroblast phenotype and its functional properties. Scleraxis has been implicated in canonical TGF-β1 signaling to promote collagen1α2 expression. We investigated how Ski and Scleraxis contribute to physiological and pathological wound healing in vivo. Methods: The study was carried out using 64 male Sprague-Dawley rats. The left anterior descending (LAD) coronary artery was ligated to induce a myocardial infarction. Control (sham) operated animals underwent surgery without ligation of the LAD artery. Animals were sacrificed at 2, 4, and 8 weeks post-MI and tissue collected for Western blot and qPCR studies. Results: Scleraxis mRNA expression remained at baseline at 2 and 8 weeks post-MI, but was significantly increased 4 weeks post-MI. Scleraxis protein expression was down-regulated within the scar area of infarcted hearts when compared to control samples 2 and 4 weeks post-MI. Ski mRNA expression was up-regulated within the scar area of infarcted hearts 2, 4 and 8 weeks after infarction. Conclusions: Scleraxis protein is down-regulated in myofibroblasts of the infarct scar in the chronic stages of myocardial infarction, corresponding to the maturation of the scar. At these stages of wound healing, we have previously published that Ski is up-regulated in the cytosol of these same cells. We suggest reciprocal feedback in the expression of these two proteins exists in myofibroblasts in the infarct scar. We hope to learn more about the Ski/Scleraxis feedback loop in pathological wound healing to identify novel therapeutic targets.

Cardiac adaptations to endurance training in rats with a chronic myocardial infarction

1989 ◽  
Vol 66 (2) ◽  
pp. 712-719 ◽  
Author(s):  
T. I. Musch ◽  
R. L. Moore ◽  
P. G. Smaldone ◽  
M. Riedy ◽  
R. Zelis
Keyword(s):  
Myocardial Infarction ◽  
Endurance Training ◽  
Left Ventricular ◽  
Treadmill Running ◽  
Coronary Artery Ligation ◽  
Maximal Heart Rate ◽  
Chronic Myocardial Infarction ◽  
Artery Ligation ◽  
Training Paradigm ◽  
Myosin Isozyme

The hemodynamic response to maximal exercise was determined in sedentary and trained rats with a chronic myocardial infarction (MI) produced by coronary artery ligation and in rats that underwent sham operations (SHAM). Infarct size in the MI groups of rats comprised 28–29% of the total left ventricle and resulted in both metabolic and hemodynamic changes that suggested that these animals had moderate compensated heart failure. The training regimen used in the present study produced significant increases in maximal O2 uptake (VO2max) when expressed in absolute terms (ml/min) or when normalized for body weight (ml.min-1.kg-1) and consisted of treadmill running at work loads that were equivalent to 70–80% of the animal's VO2max for a period of 60 min/day, 5 days/wk over an 8- to 10-wk interval. This training paradigm produced two major cardiocirculatory adaptations in the MI rat that had not been elicited previously when using a training paradigm of a lower intensity. First, the decrement in the maximal heart rate response to exercise (known as “chronotropic incompetence”) found in the sedentary MI rat was completely reversed by endurance training. Second, the downregulation of cardiac myosin isozyme composition from the fast ATPase V1 isoform toward the slower ATPase (V2 and V3) isoforms in the MI rat was partially reversed by endurance training. These cardiac adaptations occurred without a significant increase in left ventricular pump function as an increase in maximal cardiac output (Qmax) and maximal stroke volume (SVmax) did not occur in the trained MI rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of Myocardial Infarction with Sequential Ligation of the Left Anterior Descending Artery and Its Diagonal Branch in Dogs and Sheep

2003 ◽  
Vol 26 (4) ◽  
pp. 351-357 ◽  
Author(s):  
W.G. Kim ◽  
Y.C. Shin ◽  
S.W. Hwang ◽  
C. Lee ◽  
C.Y. Na
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Pulmonary Artery ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Suitable Model ◽  
Artery Ligation ◽  
Diagonal Branch ◽  
Left Anterior Descending Artery ◽  
Arterial Blood

We report a comparison of the effects of myocardial infarction in dogs and sheep using sequential ligation of the left anterior descending artery (LAD) and its diagonal branch (DA), with hemodynamic, ultrasonographic and pathological evaluations. Five animals were used in each group. After surgical preparation, the LAD was ligated at a point approximately 40% of the distance from the apex to the base of the heart, and after one hour, the DA was ligated at the same level. Hemodynamic and ultrasonographic measurements were performed preligation, 30 minutes after LAD ligation, and 1 hour after DA ligation. As a control, two animals in each group were used for the simultaneous ligation of the LAD and the DA. Two months after the coronary ligation, the animals were evaluated as previously, and killed for postmortem examination of their hearts. All seven animals in the dog group survived the experimental procedures, while in the sheep group only animals with sequential ligation of the LAD and DA survived. Statistically significant decreases in systemic arterial blood pressure and cardiac output, and an increase in the pulmonary artery capillary wedge pressure (PACWP) were observed one hour after sequential ligation of the LAD and its DA in the sheep, while only systemic arterial pressures decreased in the dog. Ultrasonographic analyses demonstrated variable degrees of anteroseptal dyskinesia and akinesia in all sheep, but in no dogs. Data two months after coronary artery ligation showed significant increases in central venous pressure, pulmonary artery pressure, and PACWP in the sheep, but not in the dog. Left ventricular end-diastolic dimension and left ventricular end-systolic dimension in ultrasonographic studies were also increased only in the sheep. Pathologically, the well-demarcated thin-walled transmural anteroseptal infarcts with chamber enlargement were clearly seen in all specimens of sheep, and only-mild-to-moderate chamber enlargements with endocardial fibrosis were observed in the dog hearts. In conclusion, this study confirms that the dog is not a suitable model for myocardial infarction with failure by coronary artery ligation despite negligent operative mortality, when compared directly with an ovine model.

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