Insulin‐like growth factors and their potential role in cardiac epigenetics

Husted, Cristiana Iosef; Valencik, Maria L.

doi:10.1111/jcmm.12845

Cited by 8 publications

(11 citation statements)

References 161 publications

(230 reference statements)

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“…IGF2 is another major paracrine growth signal released from epicardial cells and converges to the same downstream AKT and ERK signaling axis. 3,15 Conditional knockout of either IGF2 in the epicardium or its major receptor IGFR1 (IGF1 receptor) in cardiac progenitors (Nkx2-5+) resulted in reduced cardiomyocyte proliferation and ventricular wall hypoplasia. [16][17][18] In contrast, conditional deletion of IGF2 in the endocardium or myocardium did not give rise to any apparent cardiac phenotypes.…”

Section: What New Information Does This Articlementioning

confidence: 99%

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Epicardial HDAC3 Promotes Myocardial Growth Through a Novel MicroRNA Pathway

Jang

Song

Pettit

et al. 2022

Circulation Research

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BACKGROUND: Establishment of the myocardial wall requires proper growth cues from nonmyocardial tissues. During heart development, the epicardium and epicardium-derived cells instruct myocardial growth by secreting essential factors including FGF (fibroblast growth factor) 9 and IGF (insulin-like growth factor) 2. However, it is poorly understood how the epicardial secreted factors are regulated, in particular by chromatin modifications for myocardial formation. The current study is to investigate whether and how HDAC (histone deacetylase) 3 in the developing epicardium regulates myocardial growth. METHODS AND RESULTS: We deleted Hdac3 in the developing murine epicardium, and mutant hearts showed ventricular myocardial wall hypoplasia with reduction of epicardium-derived cells. The cultured embryonic cardiomyocytes with supernatants from Hdac3 knockout (KO) mouse epicardial cells also showed decreased proliferation. Genome-wide transcriptomic analysis revealed that Fgf9 and Igf2 were significantly downregulated in Hdac3 KO mouse epicardial cells. We further found that Fgf9 and Igf2 expression is dependent on HDAC3 deacetylase activity. The supplementation of FGF9 or IGF2 can rescue the myocardial proliferation defects treated by Hdac3 KO supernatant. Mechanistically, we identified that microRNA (miR)-322 and miR-503 were upregulated in Hdac3 KO mouse epicardial cells and Hdac3 epicardial KO hearts. Overexpression of miR-322 or miR-503 repressed FGF9 and IGF2 expression, while knockdown of miR-322 or miR-503 restored FGF9 and IGF2 expression in Hdac3 KO mouse epicardial cells. CONCLUSIONS: Our findings reveal a critical signaling pathway in which epicardial HDAC3 promotes compact myocardial growth by stimulating FGF9 and IGF2 through repressing miR-322 or miR-503, providing novel insights in elucidating the etiology of congenital heart defects and conceptual strategies to promote myocardial regeneration.

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Section: What New Information Does This Articlementioning

confidence: 99%

“…3,19 Most previous research has focused on understanding the function or the downstream signaling of these growth factors. 12,15 How the expression of these growth factors in the developing epicardium is regulated is still poorly understood.…”

Section: What New Information Does This Articlementioning

confidence: 99%

Epicardial HDAC3 Promotes Myocardial Growth Through a Novel MicroRNA Pathway

Jang

Song

Pettit

et al. 2022

Circulation Research

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“…Insulin-like growth factor (IGF) and IGF-II receptor (IGF-IIR) signaling is crucial for cardiac development and remodelling [1–3]. IGF-IIR is parentally imprinted and knocking down its expression had severe fetal cardiac abnormalities [4,5].…”

Section: Introductionmentioning

confidence: 99%

Synergistic cardiac pathological hypertrophy induced by high-salt diet in IGF-IIRα cardiac-specific transgenic rats

et al. 2019

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Stress-induced cardiac hypertrophy leads to heart failure. Our previous studies demonstrate that insulin-like growth factor—II receptor (IGF-IIR) signaling is pivotal to hypertrophy regulation. In this study, we show a novel IGF-IIR alternative spliced transcript, IGF-IIRα (150 kDa) play a key role in high-salt induced hypertrophy mechanisms. Cardiac overexpression of IGF-IIRα and high-salt diet influenced cardiac dysfunction by increasing pathophysiological changes with up-regulation of hypertrophy markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). We found that, cardiac hypertrophy under high-salt conditions were amplified in the presence of IGF-IIRα overexpression. Importantly, high-salt induced angiotensin II type I receptor (AT1R) up regulation mediated IGF-IIR expressions via upstream mitogen activated protein kinase (MAPK)/silent mating type information regulation 2 homolog 1 (SIRT1)/heat shock factor 1 (HSF1) pathway. Further, G-coupled receptors (Gαq) activated calcineurin/nuclear factor of activated T-cells, cytoplasmic 3 (NFATc3)/protein kinase C (PKC) signaling was significantly up regulated under high-salt conditions. All these effects were observed to be dramatically over-regulated in IGF-IIRα transgenic rats fed with a high-salt diet. Altogether, from the findings, we demonstrate that IGF-IIRα plays a crucial role during high-salt conditions leading to synergistic cardiac hypertrophy.

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“…Either global deletion of FGF9 or conditional knockout of FGFR1/2 in the myocardium leads to ventricular hypoplasia 23 , suggesting that FGF9 and its downstream signaling is important for myocardial growth. IGF2 is another major paracrine growth signal released from epicardial cells and converges to the same downstream AKT and ERK signaling axis 5, 29 . Conditional knockout of either IGF2 in the epicardium or its major receptor, IGFR1 in cardiac progenitors (Nkx2-5+) resulted in reduced cardiomyocyte proliferation and ventricular wall hypoplasia 24-26 .…”

Section: Introductionmentioning

confidence: 99%

“…In the developing heart, FGF9 and IGF2 are mainly secreted by the epicardium and its EPDCs, with minor contributions from cardiac endothelial cells 5, 20 . Most previous research has focused on understanding the function and/or the downstream signaling of these growth factors 27, 29 . How the expression of these growth factors in the developing epicardium is regulated is still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Epicardial HDAC3 promotes myocardial growth through a novel microRNA pathway

Jang

Song

et al. 2021

Preprint

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Rational: Establishment of the myocardial wall requires proper growth cues from nonmyocardial tissues. During heart development, the epicardium and epicardium-derived cells (EPDCs) instruct myocardial growth by secreting essential factors including fibroblast growth factor 9 (FGF9) and insulin-like growth factor 2 (IGF2). However, it is poorly understood how the epicardial secreted factors are regulated, in particular by chromatin modifications for myocardial formation. Objective: To understand whether and how histone deacetylase 3 (HDAC3) in the developing epicardium regulates myocardial growth. Methods and Results: We deleted Hdac3 in the developing murine epicardium and mutant hearts showed ventricular myocardial wall hypoplasia with reduction of EPDCs. The cultured embryonic cardiomyocytes with supernatants from Hdac3 knockout (KO) mouse epicardial cells (MECs) also showed decreased proliferation. Genome-wide transcriptomic analysis revealed that Fgf9 and Igf2 were significantly down-regulated in Hdac3 KO MECs. We further found that Fgf9 and Igf2 expression is dependent on HDAC3 deacetylase activity. The supplementation of FGF9 or IGF2 can rescue the myocardial proliferation defects treated by Hdac3 KO supernatant. Mechanistically, we identified that microRNA (miR)-322 and miR-503 were upregulated in Hdac3 KO MECs and Hdac3 epicardial KO hearts. Overexpression of miR-322 or miR-503 repressed FGF9 and IGF2 expression, while knockdown of miR-322 or miR-503 restored FGF9 and IGF2 expression in Hdac3 KO MECs. Conclusions: Our findings reveal a critical signaling pathway in which epicardial HDAC3 promotes compact myocardial growth by stimulating FGF9 and IGF2 through repressing miR-322/miR-503, providing novel insights in elucidating etiology of congenital heart defects, and conceptual strategies to promote myocardial regeneration.

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Insulin‐like growth factors and their potential role in cardiac epigenetics

Cited by 8 publications

References 161 publications

Epicardial HDAC3 Promotes Myocardial Growth Through a Novel MicroRNA Pathway

Epicardial HDAC3 Promotes Myocardial Growth Through a Novel MicroRNA Pathway

Synergistic cardiac pathological hypertrophy induced by high-salt diet in IGF-IIRα cardiac-specific transgenic rats

Epicardial HDAC3 promotes myocardial growth through a novel microRNA pathway

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