The scar neovasculature after myocardial infarction in rats

Wang, Bin; Ansari, Ramin; Sun, Yao; Postlethwaite, Arnold E.; Weber, Karl T.; Kiani, Mohammad F.

doi:10.1152/ajpheart.00001.2005

Cited by 36 publications

(50 citation statements)

References 39 publications

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“…Negative and positive controls for the presence of phosphoSmad2 consisted of lysates of AML12 cells treated with vehicle or TGF-␤1 (21). 3 Samples were resolved by SDS-polyacrylamide gel electrophoresis on 10% gels and transferred to polyvinylidene difluoride membranes in 25 mM Tris, 192 mM glycine, 5% methanol at 85 V for 3 h at 4°C. Filters were blocked overnight with TBS-T (10 mM Tris-HCl, pH 7.4, 150 mM NaCl, 0.05% Tween 20) containing 5% skim milk.…”

Section: Methodsmentioning

confidence: 99%

Mechanisms of Cardiac Fibrosis Induced by Urokinase Plasminogen Activator

Stempien‐Otero

Plawman

Meznarich

et al. 2006

Journal of Biological Chemistry

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Human hearts with end-stage failure and fibrosis have macrophage accumulation and elevated plasminogen activator activity. However, the mechanisms that link macrophage accumulation and plasminogen activator activity with cardiac fibrosis are unclear. We previously reported that mice with macrophage-targeted overexpression of urokinase plasminogen activator (SR-uPA Cardiac fibrosis, the accumulation of excess extracellular matrix in the heart, is a common feature of end-stage heart disease independent of etiology. Cardiac fibrosis may contribute to impaired systolic and diastolic function and is associated with both atrial and ventricular arrhythmias (1, 2). Fibrotic cardiac tissue is relatively avascular (3), and cardiac fibroblasts are unable to propagate cardiac action potentials (for review see Ref. 4). For these reasons, cardiac fibrosis will likely interfere with implementation of cell-based therapies for heart disease (5). Despite the importance of cardiac fibrosis, the mechanisms through which it develops are incompletely understood.Human and animal studies suggest that both macrophage accumulation and increased plasminogen activator (PA) 2 activity contribute to the pathogenesis of cardiac fibrosis. Macrophage accumulation is present in fibrotic, end-stage human hearts (6, 7). Macrophages express urokinase-type plasminogen activator (uPA) (8), and increased PA activity is present, along with macrophages and fibrosis, in failing human hearts (9). Mice with increased macrophage PA activity have early cardiac macrophage accumulation and develop cardiac fibrosis later in life (10). Moreover, mice that lack uPA are resistant to the development of cardiac fibrosis (11, 12).The pathways through which macrophage accumulation and increased cardiac PA activity could lead to cardiac fibrosis in both mice and humans are unknown. These pathways could include PA-mediated conversion of plasminogen to plasmin. Alternatively, cardiac fibrosis could be caused by plasminogen-independent actions of either PAs or macrophages. Definition of the pathways through which increased cardiac macrophage accumulation and PA activity lead to cardiac fibrosis may clarify the basic mechanisms of cardiac fibrosis and suggest new therapeutic approaches.Here we report the use of mice with macrophage-targeted expression of uPA (SR-uPA ϩ/o mice (13)) to investigate the mechanisms through which increased macrophage PA activity causes cardiac macrophage accumulation and fibrosis. SR-uPA ϩ/o mice are an appropriate animal model for these investigations because, in the absence of infarction or any other overt cardiac injury, they develop cardiac macrophage accumulation by 5 weeks of age and cardiac fibrosis by 15 weeks (10). We hypothesized that the uPA receptor (uPAR) (which can facilitate cell migration by focusing uPA and plasmin proteolytic activity to the leading edge of migrating cells (14)) is required for both cardiac macrophage accumulation and the subsequent development of fibrosis in SR-uPA

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Section: Methodsmentioning

confidence: 99%

Mechanisms of Cardiac Fibrosis Induced by Urokinase Plasminogen Activator

Stempien‐Otero

Plawman

Meznarich

et al. 2006

Journal of Biological Chemistry

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“…Also consistent with our findings are the reports of Walther et al (34), who showed that AT 1 inhibits angiogenesis in a mouse alginate implant angiogenesis model, and de Boer et al (5), who showed that post-MI microvessel density is reduced in transgenic rats overexpressing AT 1 in the heart and that the reduction in microvessel density is reversed by the AT 1 blocker losartan. Very recently, Wang et al (35) have shown by a new technique that losartan significantly restored vascular perfusion in a 4-wk-old infarct scar in rat hearts and suggested AT 1 as being antiangiogenic. The difference may partly result from the fact that the effect on angiogenesis is strongly dependent on the model.…”

Section: Effect Of At 1a On Granulation Tissue Cell Dynamics and Its mentioning

confidence: 99%

ANG II type 1A receptor signaling causes unfavorable scar dynamics in the postinfarct heart

Li¹,

Takemura²,

Okada³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Blockade of ANG II type 1A receptor (AT 1A) is known to attenuate postinfarction [postmyocardial infarction (post-MI)] heart failure, accompanying reduction in fibrosis of the noninfarcted area. In the present study, we investigated the influence of AT 1A blockade on the infarcted tissue itself. Consistent with earlier reports, AT1A knockout (AT1AKO) mice showed significantly attenuated left ventricular (LV) remodeling (dilatation) and dysfunction compared with wild-type (WT) mice. Morphometry revealed that the infarcted wall was thicker and had a smaller circumferential length in AT 1AKO than WT hearts. In addition, significantly greater numbers of cells were present within infarcts in AT 1AKO hearts 4 wk post-MI; most notably, there was an abundance of vessels and myofibroblasts. One week post-MI, the incidence of apoptosis among granulation tissue cells was fewer (3.3 Ϯ 0.4 vs. 4.4 Ϯ 0.5% in WT, P Ͻ 0.05), whereas vessel proliferation was higher in AT 1AKO hearts, which likely explains the later abundance of cells within the scar tissue. Insulin-like growth factor receptor-I was upregulated and its downstream signal protein kinase B (Akt) was significantly activated in infarcted AT 1AKO hearts compared with WT hearts. Inactivation of Akt with wortmannin partially but significantly prevented the benefits observed in AT 1AKO. Collectively, in AT1AKO hearts, Akt-mediated granulation tissue cell proliferation and preservation resulting from antiapoptosis likely contributed to an abundant cell population that altered the infarct scar structure, thereby reducing wall stress and attenuating LV dilatation and dysfunction at the chronic stage. In conclusion, altered structural dynamics of infarct scar and increasing myocardial fibrosis may be responsible for the deleterious effects of AT 1A signaling following MI.

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“…Thus, this is the minimal time necessary to reliably exclude contrast enhancement of intravascular agents. The relatively slow transport of intravascular Gd-chelates shown in this and previous studies can be explained by: 1) microvascular obstruction (37,38), 2) high gradient pressure in the interstitium due to edema (9,37), and 3) slow convection process compared with passive diffusion transport (9,12,13,36). In a previous study (8), changes in SI on T 1 -weighted spin echo MRI and histopathology were correlated in acute, subacute, and chronic infarctions.…”

Section: Discussionmentioning

confidence: 50%

“…Because the distribution volume and mechanism of distribution of intravascular and extracellular MR contrast agents differ considerably (9,10), the enhancement pattern in acute myocardial infarctions (AMIs) and chronic infarctions might also be different. This seems likely because vascular integrity is destroyed in acutely infarcted myocardium but is intact in scar tissue (11)(12)(13)(14). The hypothesis of the current study was that intravascular Gd-chelates produce delayed contrast enhancement of acute but not chronic MIs.…”

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confidence: 83%