Inhibition of TGF-? signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction

Ikeuchi, Masaki; Tsutsui, Hiroyuki; Shiomi, Tetsuya; Matsusaka, Hidenori; Matsushima, Shouji; Wen, Jing; Kubota, Takeshi; Takeshita, Akira

doi:10.1016/j.cardiores.2004.07.017

Cited by 258 publications

(214 citation statements)

References 25 publications

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“…Two recent studies showed that inhibition of TGF-β signaling by injection of an adenovirus harboring soluble TGF-β type II receptor in the hindlimb muscles resulted in attenuated left ventricular remodeling by modulating cardiac fibrosis [318], [319]. However, early TGF-β inhibition significantly increased mortality and exacerbated left ventricular dilation enhancing cytokine synthesis, suggesting that during the phase of resolution of the inflammatory response, TGF-β signaling plays an important role in suppression of inflammatory mediator synthesis [318].…”

Section: The Role Of Tgf-β In Myocardial Infarctionmentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

568

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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Section: The Role Of Tgf-β In Myocardial Infarctionmentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

568

499

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“…In a model of non-reperfused infarction, TGF-β inhibition through administration of a neutralizing antibody had detrimental effects, accentuating chamber dilation, increasing myocardial MMP expression, and reducing collagen synthesis (84). Two independent investigations inhibiting TGF-β by using gene transfer of the extracellular domain of TβRII suggested that TGF-β may play a key role in fibrosis of the infarcted heart (63,85). TGF-β inhibition after the inflammatory phase of cardiac repair attenuated deposition of fibrous tissue in the infarcted region (85).…”

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.

117

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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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“…However, the timing in TGFβ1 antagonism is a crucial determinant of the postischemic outcome, owing to TGFβ1 antiinflammatory action (43). Consistently, premature TGFβ1 blockade during the immediate postischemic phase accentuates adverse remodeling by preventing timely resolution of the inflammatory reaction (43,44). Our T3 infusion protocol, starting 24 h after I/R, proved to be efficacious, in that the regional reduction of TGFβ1 expression, achieved 3 d post-I/R, resulted in long-term maintenance of contractile mass and reduction of fibrotic tissue deposition.…”

Section: Th Administration Exerts a Modulatory Action On Profibrotic mentioning

confidence: 99%

Early and Short-term Triiodothyronine Supplementation Prevents Adverse Postischemic Cardiac Remodeling: Role of Transforming Growth Factor-β1 and Antifibrotic miRNA Signaling

Nicolini

Forini

Kusmic

et al. 2015

Mol Med

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Activation of transforming growth factor (TGF)-β1 signaling in the ischemia/reperfusion (I/R) injured myocardium leads to dysregulation of miR-29-30-133, favoring the profibrotic process that leads to adverse cardiac remodeling (CR). We have previously shown that timely correction of the postischemic low-T3 syndrome (Low-T3S) exerts antifibrotic effects, but the underlying molecular players are still unknown. Here we hypothesize that a prompt, short-term infusion of T3 in a rat model of post I/R Low-T3S could hamper the early activation of the TGFβ1-dependent profibrotic cascade to confer long-lasting cardioprotection against adverse CR. Twenty-four hours after I/R, rats that developed the Low-T3S were randomly assigned to receive a 48-h infusion of 6 μg/kg/d T3 (I/R-L+T3) or saline (I/R-L) and sacrificed at 3 or 14 d post-I/R. Three days post-I/R, Low-T3S correction favored functional cardiac recovery. This effect was paralleled by a drop in TGFβ1 and increased miR-133a, miR-30c and miR-29c in the infarcted myocardium. Consistently, connective transforming growth factor (CTGF) and matrix metalloproteinase-2 (MMP-2), validated targets of the above miRNAs, were significantly reduced. Fourteen days post-I/R, the I/R-L+T3 rats presented a significant reduction of scar size with a better preservation of cardiac performance and LV chamber geometry. At this time, TGFβ1 and miR-29c levels were in the normal range in both groups, whereas miR-30c-133a, MMP-2 and CTGF remained significantly altered in the I/R group. In conclusion, the antifibrotic effect exerted by T3 in the early phase of postischemic wound healing triggers a persistent cardioprotective response that hampers the progression of heart dysfunction and adverse CR.

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Inhibition of TGF-? signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction

Abstract: The activation of TGF-beta is protective against ischemic myocardial damage during the early phase. However, the beneficial effects might be lost, when its expression is sustained, thereby leading to LV remodeling and failure after MI.

Cited by 258 publications

References 25 publications

The immune system and cardiac repair

The immune system and cardiac repair

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

Early and Short-term Triiodothyronine Supplementation Prevents Adverse Postischemic Cardiac Remodeling: Role of Transforming Growth Factor-β1 and Antifibrotic miRNA Signaling

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