scholarly journals Increased syndecan expression following myocardial infarction indicates a role in cardiac remodeling

2004 ◽  
Vol 16 (3) ◽  
pp. 301-308 ◽  
Author(s):  
Alexandra Vanessa Finsen ◽  
Per Reidar Woldbaek ◽  
Jian Li ◽  
Jiaping Wu ◽  
Torstein Lyberg ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Wilms Tumor ◽  
Northern Blotting ◽  
Left Ventricular ◽  
Fgf Receptor ◽  
Protein Levels ◽  
Primary Surgery ◽  
Ventricular Tissue ◽  
And Function

Finsen, Alexandra Vanessa, Per Reidar Woldbaek, Jian Li, Jiaping Wu, Torstein Lyberg, Theis Tonnessen, and Geir Christensen. Increased syndecan expression following myocardial infarction indicates a role in cardiac remodeling. Physiol Genomics 16: 301-308, 2004. First published November 18, 2003; 10.1152/physi-olgenomics. 00144.2002.—The purpose of this study was to identify essential genes involved in myocardial growth and remodeling following myocardial infarction (MI). Left ventricular noninfarcted tissues from six mice subjected to MI under general anesthesia and from six sham-operated mice were obtained 1 wk after primary surgery and analyzed by means of cDNA filter arrays. Out of a total of 1,176 genes, 641 were consistently expressed, twenty-three were upregulated and thirteen downregulated. Five genes were only expressed following MI. Syndecan-3, a transmembranous heparan sulfate proteoglycan, was found to be upregulated together with a transcriptional activator of syndecans, Wilms tumor protein 1 (WT-1). Northern blotting demonstrated a significant upregulation of syndecan-1, -2, -3, and -4, WT-1, fibronectin, and basic fibroblast growth factor (FGF) receptor 1. Furthermore, Western blot analysis showed statistically significant increases in protein levels for syndecan-3 and -4. In conclusion, we have identified a subset of genes with increased expression in noninfarcted left ventricular tissue following MI, including syndecans 1–4, WT-1, fibronectin, collagen 6A, and FGF receptor 1. Since the syndecans link the cytoskeleton to the extracellular matrix and function as required coreceptors for FGF, we suggest a role for the syndecans in cardiac remodeling following MI.

scholarly journals miR155 Deficiency Reduces Myofibroblast Density but Fails to Improve Cardiac Function after Myocardial Infarction in Dyslipidemic Mouse Model

2021 ◽  
Vol 22 (11) ◽  
pp. 5480
Author(s):  
David Schumacher ◽  
Adelina Curaj ◽  
Sakine Simsekyilmaz ◽  
Andreas Schober ◽  
Elisa A. Liehn ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Mouse Model ◽  
Cardiac Remodeling ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Cardiac Inflammation ◽  
Infarction Size ◽  
Adverse Remodeling ◽  
And Function

Myocardial infarction remains the most common cause of heart failure with adverse remodeling. MicroRNA (miR)155 is upregulated following myocardial infarction and represents a relevant regulatory factor for cardiac remodeling by engagement in cardiac inflammation, fibrosis and cardiomyocyte hypertrophy. Here, we investigated the role of miR155 in cardiac remodeling and dysfunction following myocardial infarction in a dyslipidemic mouse model. Myocardial infarction was induced in dyslipidemic apolipoprotein E-deficient (ApoE−/−) mice with and without additional miR155 knockout by ligation of the LAD. Four weeks later, echocardiography was performed to assess left ventricular (LV) dimensions and function, and mice were subsequently sacrificed for histological analysis. Echocardiography revealed no difference in LV ejection fractions, LV mass and LV volumes between ApoE−/− and ApoE−/−/miR155−/− mice. Histology confirmed comparable infarction size and unaltered neoangiogenesis in the myocardial scar. Notably, myofibroblast density was significantly decreased in ApoE−/−/miR155−/− mice compared to the control, but no difference was observed for total collagen deposition. Our findings reveal that genetic depletion of miR155 in a dyslipidemic mouse model of myocardial infarction does not reduce infarction size and consecutive heart failure but does decrease myofibroblast density in the post-ischemic scar.

Abstract 302: Cathepsin D Haploinsufficiency Exacerbates Post Myocardial Infarction Cardiac Remodeling and Malfunction by Impairing Autophagosome Removal

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Penglong Wu ◽  
Wei Zhu ◽  
Jingbo Li ◽  
Xuejun “XJ” Wang
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Cathepsin D ◽  
Left Ventricular ◽  
Post Myocardial Infarction ◽  
Control Group ◽  
Autophagic Flux ◽  
Protein Levels ◽  
Lysosomal Protease ◽  
The Impact

Background: A marked decrease in the protein level and activity of cathepsin D (Ctsd), a major lysosomal protease, has been observed in failing human hearts; however, the pathophysiological significance of Ctsd downregulation in the heart remains undefined. Given the increasingly recognized role of the autophagic-lysosomal pathway in cardiac pathobiology, we sought to determine the impact of Ctsd haploinsufficiency on post myocardial infarction (MI) cardiac remodeling and explore the underlying mechanism. Methods and Results: MI was induced in 2-3 months old mixed-sex wild type (WT) or heterozygous Ctsd knockout (Ctsd +/- ) mice via permanent ligation of the left anterior descending (LAD) coronary artery. Myocardial Ctsd protein levels are reduced by ~50% in Ctsd +/- mice, compared with WT mice. Echocardiography (Echo) did not detect discernible difference between Ctsd +/- and WT mice immediately before and 1 week (wk) after MI; however, compared with the WT MI group, significantly greater left ventricular (LV) internal diameters at end systole and at end diastole and significantly smaller ejection fraction and fractional shortening were detected in the Ctsd +/- MI group at 2, 3, and 4 wks post-MI (p<0.05 ~ 0.001). LV pressure-volume relationship analyses at 4 wks post-MI also revealed that LV maximum and minimum dP/dt values were significantly reduced in the WT MI group, compared with the WT sham control group (p<0.05, 0.01); these post-MI reductions were more pronounced in the Ctsd +/- MI group (P<0.05, 0.01). The infarct size at 4 wks post-MI measured with trichrome staining was significantly enlarged by Ctsd +/- (p<0.002). These results indicate that Ctsd haploinsufficiency exacerbates post-MI cardiac remodeling and malfunction. Post-MI myocardial Ctsd protein levels were increased in WT mice but this increase was not detectable in Ctsd +/- mice. However, the myocardial protein levels of LC3-II, beclin1, and Atg5 were further elevated in Ctsd +/- MI mice, compared with the WT MI mice, indicative of impairment of autophagic flux in Ctsd +/- MI mice. Conclusion: Ctsd haploinsufficiency exacerbates maladaptive post-MI cardiac remodeling and malfunction likely through impairing autophagosome removal.

Abstract 14664: Reduced Activin Like Kinase 1 Activity Promotes Cardiac Fibrosis in Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Kevin Morine ◽  
Vikram Paruchuri ◽  
Xiaoying Qiao ◽  
Emily Mackey ◽  
Mark Aronovitz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Left Ventricular ◽  
Lv Function ◽  
Type I ◽  
Mrna Levels ◽  
Protein Levels

Introduction: Activin receptor like kinase 1 (ALK1) mediates signaling via transforming growth factor beta-1 (TGFb1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure. Methods and Results: ALK1 mRNA expression was quantified by RT-PCR in left ventricular (LV) tissue from patients with end-stage heart failure and compared to control LV tissue obtained from the National Disease Research Interchange (n=8/group). Compared to controls, LV ALK1 mRNA levels were reduced by 85% in patients with heart failure. Next, using an siRNA approach, we tested whether reduced ALK1 levels promote TGFb1-mediated collagen production in human cardiac fibroblasts. Treatment with an ALK1 siRNA reduced ALK1 mRNA levels by 75%. Compared to control, TGFb1-mediated Type I collagen and pSmad-3 protein levels were 2.5-fold and 1.7-fold higher, respectively, after ALK1 depletion. To explore a role for ALK1 in heart failure, ALK1 haploinsufficient (ALK1) and wild-type mice (WT; n=8/group) were studied 2 weeks after thoracic aortic constriction (TAC). Compared to WT, baseline LV ALK1 mRNA levels were 50% lower in ALK1 mice. Both LV and lung weights were higher in ALK1 mice after TAC. Cardiomyocyte area and LV mRNA levels of BNP, RCAN, and b-MHC were increased similarly, while SERCa levels were reduced in both ALK1 and WT mice after TAC. Compared to WT, LV fibrosis (Figure) and Type 1 Collagen mRNA and protein levels were higher among ALK1 mice. Compared to WT, LV fractional shortening (48±12 vs 26±10%, p=0.01) and survival (Figure) were lower in ALK1 mice after TAC. Conclusions: Reduced LV expression of ALK1 is associated with advanced heart failure in humans and promotes early mortality, impaired LV function, and cardiac fibrosis in a murine model of heart failure. Further studies examining the role of ALK1 and ALK1 inhibitors on cardiac remodeling are required.

scholarly journals Comparative and Combinatorial Effects of Resveratrol and Sacubitril/Valsartan alongside Valsartan on Cardiac Remodeling and Dysfunction in MI-Induced Rats

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 5006
Author(s):  
Pema Raj ◽  
Karen Sayfee ◽  
Mihir Parikh ◽  
Liping Yu ◽  
Jeffrey Wigle ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Remodeling ◽  
Left Ventricular ◽  
Myocardial Tissue ◽  
Additive Effects ◽  
Sprague Dawley ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Sprague Dawley Rats ◽  
And Function ◽  
Neutrophil Gelatinase

The development and progression of heart failure (HF) due to myocardial infarction (MI) is a major concern even with current optimal therapy. Resveratrol is a plant polyphenol with cardioprotective properties. Sacubitril/valsartan is known to be beneficial in chronic HF patients. In this study, we investigated the comparative and combinatorial benefits of resveratrol with sacubitril/valsartan alongside an active comparator valsartan in MI-induced male Sprague Dawley rats. MI-induced and sham-operated animals received vehicle, resveratrol, sacubitril/valsartan, valsartan alone or sacubitril/valsartan + resveratrol for 8 weeks. Echocardiography was performed at the endpoint to assess cardiac structure and function. Cardiac oxidative stress, inflammation, fibrosis, brain natriuretic peptide (BNP), creatinine and neutrophil gelatinase associated lipocalin were measured. Treatment with resveratrol, sacubitril/valsartan, valsartan and sacubitril/valsartan + resveratrol significantly prevented left ventricular (LV) dilatation and improved LV ejection fraction in MI-induced rats. All treatments also significantly reduced myocardial tissue oxidative stress, inflammation and fibrosis, as well as BNP. Treatment with the combination of sacubitril/valsartan and resveratrol did not show additive effects. In conclusion, resveratrol, sacubitril/valsartan, and valsartan significantly prevented cardiac remodeling and dysfunction in MI-induced rats. The reduction in cardiac remodeling and dysfunction in MI-induced rats was mediated by a reduction in cardiac oxidative stress, inflammation and fibrosis.

Abstract 999: Gated Micro Computed Tomography Scanning: An Emerging Tool for Longitudinal Assessment of Murine Cardiac Remodeling.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Ahmad Y Sheikh ◽  
Timothy C Doyle ◽  
Maryam K Sheikh ◽  
Feng Cao ◽  
Katherine J Ransohoff ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Cardiac Remodeling ◽  
High Energy ◽  
Left Ventricular ◽  
Structure And Function ◽  
Coronary Artery Ligation ◽  
Micro Ct ◽  
Ventricular Ejection Fraction ◽  
Computed Tomography Scanning ◽  
And Function

Background: Recent advances in high energy X-ray source computed tomography (CT) technology have made it possible to accurately image murine cardiac structure and function. We describe the use of a gated Micro CT system to assess cardiac remodeling in a murine model of myocardial infarction (MI). Methods: Adult FVB mice (n = 10) were randomized to surgically induced MI by left coronary artery ligation or sham procedure. Dual gated cardiac and respiratory Micro CT scans were performed pre-operatively and at weeks 4, 8 and 12 post-procedure. End-diastolic and end-systolic images were acquired by gating on the ECG P-and S’-waves, respectively. Post-acquisition analysis was performed using image analysis software and the following parameters were quantified: left ventricular (LV) volume and mass, right ventricular volume and mass, right and left atrial volumes, and ventricular ejection fraction (EF). Results: Images were successfully acquired with a resolution of 100 microns allowing for identification and quantification of key cardiac structures (Fig 1A ). Following MI, animals exhibited left ventricular failure with significantly increased* end systolic and diastolic volumes by week 4. Ventricular dilation continued through week 8, plateauing by week 12. Left ventricular mass increased steadily over 12 weeks*, with a significantly decreased* LVEF of 28.0 ± .05% by week 12 (pre-MI: 66.7 ± .06%,*p < 0.01). Post-MI left ventricular change is detailed in Fig 1B . Conclusions: MicroCT scanning can be successfully used to characterize murine myocardial structure and function, making it a useful tool to assess cardiac phenotypes and models of cardiovascular disease.

scholarly journals Loss of Endogenously Cycling Adult Cardiomyocytes Worsens Myocardial Function

2020 ◽  
Author(s):  
Leigh A Bradley ◽  
Alexander Young ◽  
Hongbin Li ◽  
Helen O Billcheck ◽  
Matthew J Wolf
Keyword(s):  
Myocardial Infarction ◽  
Cell Cycle ◽  
Myocardial Function ◽  
Cultured Cells ◽  
Left Ventricular ◽  
Left Ventricular Chamber ◽  
Adult Cardiomyocytes ◽  
Border Zones ◽  
And Function ◽  
Chamber Size

Rationale: Endogenously cycling adult cardiomyocytes (CMs) increase after myocardial infarction (MI) but remain scare, and are generally thought not to contribute to myocardial function. However, this broadly held assumption has not been tested, mainly because of the lack of transgenic reporters that restrict Cre expression to adult CMs that reenter the cell cycle. Objective: We created and validated a new transgenic mouse, αMHC-MerDreMer-Ki67p-RoxedCre::Rox-Lox-tdTomato-eGFP (denoted αDKRC) that restricts Cre expression to cycling adult CMs and uniquely integrates spatial and temporal adult CM cycling events based on the DNA specificities of orthologous Dre- and Cre recombinases. We then created mice that expressed an inducible Diphtheria toxin (DTA), αDKRC::DTA mice, in adult cycling CMs and examined the effects of ablating these endogenously cycling CMs on myocardial function after Ischemic-Reperfusion (I/R) MI. Methods and Results: A tandem αDKRC transgene was designed, validated in cultured cells, and used to make transgenic mice. The αDKRC transgene integrated between MYH6 and MYH7 and did not disrupt expression of the surrounding genes. Compared to controls, αDKRC::RLTG mice treated with Tamoxifen expressed tdTomato+ in CMs with rare Bromodeoxyuridine (BrdU)+, eGFP+ CMs, consistent with reentry of the cell cycle. We then pre-treated αDKRC::RLTG mice with Tamoxifen to activate the reporter before sham or reperfusion (I/R) myocardial infarction (MI) surgeries. Compared to Sham surgery, the I/R MI group had increased single and paired eGFP+ CMs predominantly in the border zones (5.8 {plus minus} 0.5 vs. 3.3 {plus minus} 0.3 CMs per ten-micron section, N = 8-9 mice per group, n = 16-24 sections per mouse), indicative of cycled CMs. The single to paired eGFP+ CM ratio was ~9 to 1 (5.2 {plus minus} 0.4 single vs. 0.6 {plus minus} 0.2 paired CMs) in the I/R MI group after MI, suggesting that cycling CMs were more likely to undergo polyploidy than replication. The ablation of endogenously cycling adult CMs in αDKRC::DTA mice caused progressive worsening left ventricular chamber size and function after I/R MI, compared to controls. Conclusions: Although scarce, endogenously cycling adult CMs contribute to myocardial function after injury, suggesting that these cells may be physiologically relevant.

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