Interactions between cardiac cells enhance cardiomyocyte hypertrophy and increase fibroblast proliferation

Fredj, Sandra; Bescond, Jocelyn; Louault, Claire; Potreau, Daniel

doi:10.1002/jcp.20197

Cited by 100 publications

(85 citation statements)

References 28 publications

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“…46 Fibroblasts can be transformed into myofibroblasts contributing to extracellular matrix accumulation. Fibrosis, originating from nonmyocytes 47 and enhanced by cardiac myocytes, 48 can lead to increased wall stiffness and diastolic dysfunction. 49 Fibrosis also interrupts electrical signals, 50 rendering the tissue more arrhythmogenic, which is highly prevalent in the CKD population.…”

Section: Discussionmentioning

confidence: 99%

Klotho and Phosphate Are Modulators of Pathologic Uremic Cardiac Remodeling

Hu¹,

Shi²,

Cho³

et al. 2015

Journal of the American Society of Nephrology

234

300

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Cardiac dysfunction in CKD is characterized by aberrant cardiac remodeling with hypertrophy and fibrosis. CKD is a state of severe systemic Klotho deficiency, and restoration of Klotho attenuates vascular calcification associated with CKD. We examined the role of Klotho in cardiac remodeling in models of Klotho deficiencygenetic Klotho hypomorphism, high dietary phosphate intake, aging, and CKD. Klotho-deficient mice exhibited cardiac dysfunction and hypertrophy before 12 weeks of age followed by fibrosis. In wild-type mice, the induction of CKD led to severe cardiovascular changes not observed in control mice. Notably, non-CKD mice fed a high-phosphate diet had lower Klotho levels and greatly accelerated cardiac remodeling associated with normal aging compared with those on a normal diet. Chronic elevation of circulating Klotho because of global overexpression alleviated the cardiac remodeling induced by either high-phosphate diet or CKD. Regardless of the cause of Klotho deficiency, the extent of cardiac hypertrophy and fibrosis correlated tightly with plasma phosphate concentration and inversely with plasma Klotho concentration, even when adjusted for all other covariables. High-fibroblast growth factor-23 concentration positively correlated with cardiac remodeling in a Klotho-deficient state but not a Klotho-replete state. In vitro, Klotho inhibited TGF-b1-, angiotensin II-, or high phosphate-induced fibrosis and abolished TGF-b1-or angiotensin II-induced hypertrophy of cardiomyocytes. In conclusion, Klotho deficiency is a novel intermediate mediator of pathologic cardiac remodeling, and fibroblast growth factor-23 may contribute to cardiac remodeling in concert with Klotho deficiency in CKD, phosphotoxicity, and aging.

show abstract

Section: Discussionmentioning

confidence: 99%

Klotho and Phosphate Are Modulators of Pathologic Uremic Cardiac Remodeling

Hu¹,

Shi²,

Cho³

et al. 2015

Journal of the American Society of Nephrology

234

300

View full text Add to dashboard Cite

show abstract

“…Conditioned supernatant of cardiac fibroblasts is known to induce cellular hypertrophy in cardiomyocytes (7,8).…”

Section: Figurementioning

confidence: 99%

“…These fibroblast-derived mediators may act in an autocrine or paracrine fashion between fibroblasts and cardiomyocytes to stimulate cardiac remodeling (5,6). Further, adult murine cardiomyocytes develop hypertrophy when cocultured with cardiac fibroblasts or treated with conditioned fibroblast media (7,8). However, the underlying mechanisms of fibroblast-cardiomyocyte communication are not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

Cardiac fibroblast–derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy

et al. 2014

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In response to stress, the heart undergoes extensive cardiac remodeling that results in cardiac fibrosis and pathological growth of cardiomyocytes (hypertrophy), which contribute to heart failure. Alterations in microRNA (miRNA) levels are associated with dysfunctional gene expression profiles associated with many cardiovascular disease conditions; however, miRNAs have emerged recently as paracrine signaling mediators. Thus, we investigated a potential paracrine miRNA crosstalk between cardiac fibroblasts and cardiomyocytes and found that cardiac fibroblasts secrete miRNA-enriched exosomes. Surprisingly, evaluation of the miRNA content of cardiac fibroblast-derived exosomes revealed a relatively high abundance of many miRNA passenger strands ("star" miRNAs), which normally undergo intracellular degradation. Using confocal imaging and coculture assays, we identified fibroblast exosomal-derived miR-21_3p (miR-21*) as a potent paracrineacting RNA molecule that induces cardiomyocyte hypertrophy. Proteome profiling identified sorbin and SH3 domain-containing protein 2 (SORBS2) and PDZ and LIM domain 5 (PDLIM5) as miR-21* targets, and silencing SORBS2 or PDLIM5 in cardiomyocytes induced hypertrophy. Pharmacological inhibition of miR-21* in a mouse model of Ang II-induced cardiac hypertrophy attenuated pathology. These findings demonstrate that cardiac fibroblasts secrete star miRNA-enriched exosomes and identify fibroblast-derived miR-21* as a paracrine signaling mediator of cardiomyocyte hypertrophy that has potential as a therapeutic target.

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“…Communication among cardiac cells via secreted factors may contribute to myocardial hypertrophic remodelling 4,5 . The term cardiomyokine has emerged to describe proteins secreted from the heart that have autocrine, paracrine and/or endocrine functions crucial for the maintenance of cardiac function 6 .…”

mentioning

confidence: 99%

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice

et al. 2013

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Fibroblast growth factor 21 is an endocrine factor, secreted mainly by the liver, that exerts metabolic actions that favour glucose metabolism. Its role in the heart is unknown. Here we show that Fgf21 À / À mice exhibit an increased relative heart weight and develop enhanced signs of dilatation and cardiac dysfunction in response to isoproterenol infusion, indicating eccentric hypertrophy development. In addition, Fgf21 À / À mice exhibit enhanced induction of cardiac hypertrophy markers and pro-inflammatory pathways and show greater repression of fatty acid oxidation. Most of these alterations are already present in Fgf21 À / À neonates, and treatment with fibroblast growth factor 21 reverses them in vivo and in cultured cardiomyocytes. Moreover, fibroblast growth factor 21 is expressed in the heart and is released by cardiomyocytes. Fibroblast growth factor 21 released by cardiomyocytes protects cardiac cells against hypertrophic insults. Therefore, the heart appears to be a target of systemic, and possibly locally generated, fibroblast growth factor 21, which exerts a protective action against cardiac hypertrophy.

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Interactions between cardiac cells enhance cardiomyocyte hypertrophy and increase fibroblast proliferation

Cited by 100 publications

References 28 publications

Klotho and Phosphate Are Modulators of Pathologic Uremic Cardiac Remodeling

Klotho and Phosphate Are Modulators of Pathologic Uremic Cardiac Remodeling

Cardiac fibroblast–derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice

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