Changes in Extracellular Matrix and in Transforming Growth Factor Beta Isoforms After Coronary Artery Ligation in Rats

Deten, Alexander; Hölzl, Alexander; Leicht, Monika; Barth, Wilfried; Zimmer, Heinz‐Gerd

doi:10.1006/jmcc.2001.1383

Cited by 190 publications

(118 citation statements)

References 47 publications

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“…Because of this, the level of TGF-β1 is strongly enhanced in infarcted compared to noninfarcted myocardium within 2 days after coronary artery ligation in the rat [30,31]. The measurement of TGF, PDGF, and SPARC secreted from isolated cells in vitro suggests a coordinated sequence of events where, in a first step, integrin α v engagement on cardiac myocytes causes an up-regulation of TGF and PDGF.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast migration after myocardial infarction is regulated by transient SPARC expression

Laser

Han

et al. 2006

J Mol Med

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Secreted protein, acidic, and rich in cysteine (SPARC) is thought to regulate cell matrix interaction during wound repair. We hypothesized that SPARC might promote migration via integrin-dependent mechanisms. The present study was designed to clarify the contribution of SPARC in the wound healing process after myocardial infarction (MI). Adult mice received a specific α v integrin inhibitor or vehicle through osmotic mini pumps. Mice of each group were either sham-operated or MI was induced. SPARC expression was investigated 2 days, 7 days, and 1 month after the surgical procedure. For migration assays, a modified Boyden chamber assay was used. A transient increase of SPARC levels was observed, starting at day 2 (2.55±0.21), day 7 (3.72±0.28), and 1 month (1.9±0.16) after MI. After 2 months, SPARC expression dropped back to normal levels compared to sham-operated hearts. Immunofluorescence analysis showed an increase of SPARC in the infarcted area 2 days after MI, a strong increase in the scar area 7 days after MI, and only low levels in the scar area 2 months after MI. Integrin α v inhibition abolished the upregulation of SPARC. In vitro migration assays demonstrated that fibronectin-stimulated haptotaxis of fibroblasts was modulated by SPARC. This study provides evidence that SPARC is significantly up-regulated in the infarcted region after MI. This up-regulation is dependent on α v integrins. As SPARC is found to regulate fibroblast migration, it appears to play an important role in the injured myocardium with regard to healing and scar formation.

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Section: Discussionmentioning

confidence: 99%

Fibroblast migration after myocardial infarction is regulated by transient SPARC expression

Laser

Han

et al. 2006

J Mol Med

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“…TGF-β isoforms demonstrate distinct patterns of expression in the infarct: TGF-β1 and -β2 are induced early, whereas TGF-β3 shows delayed and prolonged upregulation [305], [11]. TGF-β expression in the infarcted heart is attenuated by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers [306], [307], [308], suggesting that angiotensin II signaling plays an important role in stimulating TGF-β synthesis in the infarct [309].…”

Section: Tgf-β Induction and Activation In Cardiac Injurymentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

572

499

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Myocardial infarction is the most common cause of cardiac injury and results in acute loss of a large number of myocardial cells. Because the heart has negligible regenerative capacity, cardiomyocyte death triggers a reparative response that ultimately results in formation of a scar and is associated with dilative remodeling of the ventricle. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Toll Like Receptor-mediated pathways, the complement cascade and reactive oxygen generation induce Nuclear Factor (NF)-κB activation and upregulate chemokine and cytokine synthesis in the infarcted heart. Chemokines stimulate the chemotactic recruitment of inflammatory leukocytes into the infarct, while cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. Monocyte subsets play distinct roles in phagocytosis of dead cardiomyocytes and in granulation tissue formation through the release of growth factors. Clearance of dead cells and matrix debris may be essential for resolution of inflammation and transition into the reparative phase. Transforming Growth Factor (TGF)-β plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. Myofibroblast proliferation and angiogenesis result in formation of highly vascularized granulation tissue. As the healing infarct matures, fibroblasts become apoptotic and a collagen-based matrix is formed, while many infarct neovessels acquire a muscular coat and uncoated vessels regress. Timely resolution of the inflammatory infiltrate and spatial containment of the inflammatory and reparative response into the infarcted area are essential for optimal infarct healing. Targeting inflammatory pathways following infarction may reduce cardiomyocyte injury and attenuate adverse remodeling. In addition, understanding the role of the immune system in cardiac repair is necessary in order to design optimal strategies for cardiac regeneration.

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“…Induction of TGF-β isoforms has been extensively documented in both mouse and large animal models of myocardial infarction (17,(21)(22)(23)(24)(25)(26). In reperfused mouse infarcts, TGF-β1 and β2 mRNA levels show an early peak after 6-72 h of reperfusion; in contrast, TGF-β3 upregulation exhibits a prolonged time course with persistently elevated expression after 7 days of reperfusion (21).…”

Section: Regulation Of Tgf-β Isoforms In Myocardial Infarctionmentioning

confidence: 99%

The role of transforming growth factor (TGF)-β in the infarcted myocardium

Frangogiannis

2017

J. Thorac. Dis.

119

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The adult mammalian heart has negligible regenerative capacity. Following myocardial infarction, sudden necrosis of cardiomyocytes triggers an intense inflammatory reaction that clears the wound from dead cells and matrix debris, while activating a reparative program. A growing body of evidence suggests that members of the transforming growth factor (TGF)-β family critically regulate the inflammatory and reparative response following infarction. Although all three TGF-β isoforms (TGF-β1, -β2 and -β3) are markedly upregulated in the infarcted myocardium, information on isoform-specific actions is limited.Experimental studies have suggested that TGF-β exerts a wide range of actions on cardiomyocytes, fibroblasts, immune cells, and vascular cells. The findings are often conflicting, reflecting the contextdependence of TGF-β-mediated effects; conclusions are often based exclusively on in vitro studies and on associative evidence. TGF-β has been reported to modulate cardiomyocyte survival responses, promote monocyte recruitment, inhibit macrophage pro-inflammatory gene expression, suppress adhesion molecule synthesis by endothelial cells, promote myofibroblast conversion and extracellular matrix synthesis, and mediate both angiogenic and angiostatic effects. This review manuscript discusses our understanding of the cell biological effects of TGF-β in myocardial infarction. We discuss the relative significance of downstream TGF-β-mediated Smad-dependent and -independent pathways, and the risks and challenges of therapeutic TGF-β targeting. Considering the high significance of TGF-β-mediated actions in vivo, study of cell-specific effects and dissection of downstream signaling pathways are needed in order to design safe and effective therapeutic approaches.

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Changes in Extracellular Matrix and in Transforming Growth Factor Beta Isoforms After Coronary Artery Ligation in Rats

Cited by 190 publications

References 47 publications

Fibroblast migration after myocardial infarction is regulated by transient SPARC expression

Fibroblast migration after myocardial infarction is regulated by transient SPARC expression

The immune system and cardiac repair

The role of transforming growth factor (TGF)-β in the infarcted myocardium

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