Interactions between cardiac cells enhance cardiomyocyte hypertrophy and increase fibroblast proliferation

Abstract

In cardiac hypertrophy, both excessive enlargement of cardiac myocytes (CMs) and progressive fibrosis are known to occur simultaneously. To investigate the nature of interactions between ventricular CMs and cardiac fibroblasts (CFs) in these conditions, we have established a "dedifferentiated model" of adult murine CMs in coculture with CFs. In such a model, which is recognized to study cardiac cell hypertrophy in vitro, dedifferentiated CMs in culture and in coculture were characterized by immunopositive staining to ANP (atrial natriuretic peptide) and beta-myosin heavy chain (beta-MHC). The results confirm that ANP secretion by CMs was significantly increased during the cultures. The increase size of cultured CMs was significantly higher in CM/CF cocultures than in CM cultures which was also observed when CMs were cultured with fibroblast conditioned medium (FCM). In addition, fibroblast proliferation studies showed that CMs favored fibroblast adhesion and/or growth at the beginning of the coculture and fibroblast proliferation throughout the time course of the coculture. Furthermore, a significant level of interleukin-6 (IL-6) production was detected by ELISA in CM/CF cocultures. A similar higher increase was observed when CMs were cultured in the presence of FCM. These results demonstrate that CFs enhance myocyte hypertrophy and that CMs regulate fibroblast adhesion and/or proliferation, suggesting a paracrine interaction between CMs and CFs which could involve IL-6.

Klotho and Phosphate Are Modulators of Pathologic Uremic Cardiac Remodeling

“…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.…”

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

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

“…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.…”

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice

“…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 .…”