Fibroblasts in myocardial infarction: A role in inflammation and repair

Shinde, Arti V.; Frangogiannis, Nikolaos G.

doi:10.1016/j.yjmcc.2013.11.015

Cited by 417 publications

(386 citation statements)

References 99 publications

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“…Thus, activation of stem/progenitor cells by direct/indirect action of Porcn inhibitors may also contribute to improvements in regeneration in some tissues. Finally, although not addressed in this study, changes in the ECM composition because of Porcn inhibition may influence other heart repair processes, such as angiogenesis and inflammation (41).…”

Section: Discussionmentioning

confidence: 94%

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

Moon

Zhou

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The secreted Wnt signaling molecules are essential to the coordination of cell-fate decision making in multicellular organisms. In adult animals, the secreted Wnt proteins are critical for tissue regeneration and frequently contribute to cancer. Small molecules that disable the Wnt acyltransferase Porcupine (Porcn) are candidate anticancer agents in clinical testing. Here we have systematically assessed the effects of the Porcn inhibitor (WNT-974) on the regeneration of several tissue types to identify potentially unwanted chemical effects that could limit the therapeutic utility of such agents. An unanticipated observation from these studies is proregenerative responses in heart muscle induced by systemic chemical suppression of Wnt signaling. Using in vitro cultures of several cell types found in the heart, we delineate the Wnt signaling apparatus supporting an antiregenerative transcriptional program that includes a subunit of the nonfibrillar collagen VI. Similar to observations seen in animals exposed to WNT-974, deletion of the collagen VI subunit, COL6A1, has been shown to decrease aberrant remodeling and fibrosis in infarcted heart tissue. We demonstrate that WNT-974 can improve the recovery of heart function after left anterior descending coronary artery ligation by mitigating adverse remodeling of infarcted tissue. Injured heart tissue exposed to WNT-974 exhibits decreased scarring and reduced Col6 production. Our findings support the development of Porcn inhibitors as antifibrotic agents that could be exploited to promote heart repair following injury.

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Section: Discussionmentioning

confidence: 94%

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

Moon

Zhou

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…During the proliferative phase of infarct healing, abundant myofibroblasts infiltrate the infarct border zone (79,80) and serve as the main source of collagen (81), while participating in extracellular matrix metabolism by secreting matrix metalloproteinases (MMPs). Most infarct myofibroblasts originate from resident fibroblast populations (82,83); TGF-β may play a crucial role in conversion of these highly plastic interstitial cells into myofibroblasts.…”

Section: Tgf-β In Regulation Of Fibroblast Phenotype and Functionmentioning

confidence: 99%

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

Frangogiannis

2017

J. Thorac. Dis.

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113

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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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“…11,12 A potential pitfall of altering fibroblast presence is that in the remote non-infarcted myocardium, local fibroblasts may remain activated in response to volume and pressure overload and promote interstitial fibrosis. 1,13 In light of these considerations, the present study was designed to investigate whether UM206 is capable of limiting adverse LV remodeling after MI in a preclinical setting, that is, when tested in a large translational swine model of reperfused MI. Moreover, we aimed to elucidate the molecular mechanism of a potential beneficial effect of UM206 on remodeling of the infarct area as well as the remote myocardium.…”

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confidence: 99%

UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine

Uitterdijk

Hermans

Wijs-Meijler

et al. 2016

Laboratory Investigation

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Modulation of Wnt/Frizzled signaling with UM206 reduced infarct expansion and prevented heart failure development in mice, an effect that was accompanied by increased myofibroblast presence in the infarct, suggesting that Wnt/Frizzled signaling has a key role in cardiac remodeling following myocardial infarction (MI). This study investigated the effects of modulation of Wnt/Frizzled signaling with UM206 in a swine model of reperfused MI. For this purpose, seven swine with MI were treated with continuous infusion of UM206 for 5 weeks. Six control swine were treated with vehicle. Another eight swine were sham-operated. Cardiac function was determined by echo in awake swine. Infarct mass was estimated at baseline by heart-specific fatty acid-binding protein ELISA and at follow-up using planimetry. Components of Wnt/Frizzled signaling, myofibroblast presence, and extracellular matrix were measured at follow-up with qPCR and/or histology. Results show that UM206 treatment resulted in a significant decrease in infarct mass compared with baseline (−41 ± 10%), whereas infarct mass remained stable in the Control-MI group (+3 ± 17%). Progressive dilation of the left ventricle occurred in the Control-MI group between 3 and 5 weeks after MI, while adverse remodeling was halted in the UM206-treated group. mRNA expression for Frizzled-4 and the Frizzled co-receptor LRP5 was increased in UM206-treated swine as compared with Control-MI swine. Myofibroblast presence was significantly lower in infarcted tissue of the UM206-treated animals (1.53 ± 0.43% vs 3.38 ± 0.61%) at 5 weeks follow-up. This study demonstrates that UM206 treatment attenuates adverse remodeling in a swine model of reperfused MI, indicating that Wnt/Frizzled signaling is a promising target to improve infarct healing and limit post-MI remodeling. Although left ventricular (LV) remodeling after myocardial infarction (MI) is aimed at maintaining cardiac pump function, initial infarct size, and the subsequent progressive expansion and thinning of the infarcted area constitute the main risk factors for the development of post-MI heart failure. 1 Several strategies that influence either the infarct size and/or the ensuing process of LV remodeling have been proposed as potential therapies to halt the development and progression of LV dysfunction. 2,3 Cardiac fibroblasts, which account for up to 70% of the cells present in the myocardium, regulate extracellular matrix (ECM) turnover, and have an essential role in cardiac homeostasis. Fibroblasts are more resistant to ischemia than cardiomyocytes, 4-6 and prolonged myocardial ischemia results in death of particularly the cardiomyocytes, whereas the fibroblasts survive. Fibroblasts have therefore been proposed to be a therapeutic target to influence the healing process of the infarcted myocardium. 1,5,[7][8][9] In addition to these resident fibroblasts, fibroblasts enter the infarcted tissue by migration. When present in the infarcted area, the fibroblasts gradually differentiate into their more contractile and synthetic...

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Fibroblasts in myocardial infarction: A role in inflammation and repair

Cited by 417 publications

References 99 publications

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

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

UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine

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