New insights into IGF-1 signaling in the heart

Troncoso, Rodrigo; Ibarra, Carmen; Vicencio, José M.; Jaimovich, Enrique; Lavandero, Sergio

doi:10.1016/j.tem.2013.12.002

Cited by 197 publications

(161 citation statements)

References 111 publications

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“…However, when subjected to high-pressure overload, knockout hearts developed severe heart failure, suggesting that the cardiac fibroblast is also cardioprotective. The same group further demonstrated that Klf5 drives expression of Igf1, which has been shown by many groups to positively impact on myocardial growth and survival (Santini et al, 2007;Troncoso et al, 2014). Our group has noted a beneficial effect of impaired cardiac fibroblast activity on myocardial regeneration through the deletion of the cardiogenic transcription factor Tbx20 (Furtado et al, 2014a).…”

Section: Demystifying Cardiac Progenitor Cellssupporting

confidence: 61%

View from the heart: cardiac fibroblasts in development, scarring and regeneration

et al. 2016

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In the adult, tissue repair after injury is generally compromised by fibrosis, which maintains tissue integrity with scar formation but does not restore normal architecture and function. The process of regeneration is necessary to replace the scar and rebuild normal functioning tissue. Here, we address this problem in the context of heart disease, and discuss the origins and characteristics of cardiac fibroblasts, as well as the crucial role that they play in cardiac development and disease. We discuss the dual nature of cardiac fibroblasts, which can lead to scarring, pathological remodelling and functional deficit, but can also promote heart function in some contexts. Finally, we review current and proposed approaches whereby regeneration could be fostered by interventions that limit scar formation.

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Section: Demystifying Cardiac Progenitor Cellssupporting

confidence: 61%

View from the heart: cardiac fibroblasts in development, scarring and regeneration

et al. 2016

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“…8). IGF1R in the heart is recognized to activate multiple pathways involving classic second messengers, phosphorylation cascades, lipid signalling, Ca 2 þ transients and gene expression 39 . Furthermore, signalling via IGF1R can occur in multiple subcellular locations, including the plasma membrane, perinuclear T tubules and internalized vesicles.…”

Section: Discussionmentioning

confidence: 99%

The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice

et al. 2014

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Heart failure (HF) and atrial fibrillation (AF) share common risk factors, frequently coexist and are associated with high mortality. Treatment of HF with AF represents a major unmet need. Here we show that a small molecule, BGP-15, improves cardiac function and reduces arrhythmic episodes in two independent mouse models, which progressively develop HF and AF. In these models, BGP-15 treatment is associated with increased phosphorylation of the insulin-like growth factor 1 receptor (IGF1R), which is depressed in atrial tissue samples from patients with AF. Cardiac-specific IGF1R transgenic overexpression in mice with HF and AF recapitulates the protection observed with BGP-15. We further demonstrate that BGP-15 and IGF1R can provide protection independent of phosphoinositide 3-kinase-Akt and heat-shock protein 70; signalling mediators often defective in the aged and diseased heart. As BGP-15 is safe and well tolerated in humans, this study uncovers a potential therapeutic approach for HF and AF.

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“…IGF-1 controls cell survival by activating the insulin receptor substrate (IRS)-1/phosphoinositide 3 kinase/Akt and IRS-2/MEK/ERK effector pathways (21). Despite a lack of change in IGF-1R mRNA expression (relative expression: 1 ± 0.19 versus 1.19 ± 0.14 in 72-h post-I/R WT and Mcpt4 −/− hearts, respectively; n = 4 per group; P = 0.39), Mcpt4 deletion increased the abundance of phosphorylated Akt-S473 and phosphorylated ERK-1/2 in 72-h post-I/R hearts (Fig.…”

Section: Mmcp-4 Regulates Cardiac Igf-1 and Igf-1/igf-1r Signaling Pomentioning

confidence: 99%

IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction

Tejada

Tan

Torres

et al. 2016

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

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Heart disease is a leading cause of death in adults. Here, we show that a few days after coronary artery ligation and reperfusion, the ischemia-injured heart elaborates the cardioprotective polypeptide, insulin-like growth factor-1 (IGF-1), which activates IGF-1 receptor prosurvival signaling and improves cardiac left ventricular systolic function. However, this signaling is antagonized by the chymase, mouse mast cell protease 4 (MMCP-4), which degrades IGF-1. We found that deletion of the gene encoding MMCP-4 (Mcpt4), markedly reduced late, but not early, infarct size by suppressing IGF-1 degradation and, consequently, diminished cardiac dysfunction and adverse structural remodeling. Our findings represent the first demonstration to our knowledge of tissue IGF-1 regulation through proteolytic degradation and suggest that chymase inhibition may be a viable therapeutic approach to enhance late cardioprotection in postischemic heart disease.insulin-like growth factor-1 | chymase | mouse mast cell protease 4 | ischemia-reperfusion injury | cardioprotection

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New insights into IGF-1 signaling in the heart

Cited by 197 publications

References 111 publications

View from the heart: cardiac fibroblasts in development, scarring and regeneration

View from the heart: cardiac fibroblasts in development, scarring and regeneration

The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice

IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction

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