p63RhoGEF regulates auto- and paracrine signaling in cardiac fibroblasts

• Verfasst von: Ongherth, Anita [VerfasserIn]
• Verfasst von: Weis, Cleo-Aron Thias [VerfasserIn]
• Verfasst von: Vettel, Christiane [VerfasserIn]
• Verfasst von: Wieland, Thomas [VerfasserIn]
• Titel: p63RhoGEF regulates auto- and paracrine signaling in cardiac fibroblasts
• Verf.angabe: Anita Ongherth, Sebastian Pasch, Christina M. Wuertz, Karolin Nowak, Naim Kittana, Cleo A. Weis, Aline Jatho, Christiane Vettel, Malte Tiburcy, Karl Toischer, Gerd Hasenfuss, Wolfram-Hubertus Zimmermann, Thomas Wieland, Susanne Lutz
• E-Jahr: 2015
• Jahr: November 2015
• Umfang: 16 S.
• Fussnoten: Gesehen am 04.01.2018
• Titel Quelle: Enthalten in: Journal of molecular and cellular cardiology
• Ort Quelle: New York, NY [u.a.] : Elsevier, 1970
• Jahr Quelle: 2015
• Band/Heft Quelle: 88(2015), C, Suppl., Seite 39-54
• ISSN Quelle: 1095-8584
• DOI: doi:10.1016/j.yjmcc.2015.09.009
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Cardiac remodeling
• Sach-SW: Connective tissue growth factor
• Sach-SW: p63RhoGEF
• Sach-SW: RhoA
• K10plus-PPN: 1566866049

Abstract

Cardiac remodeling, a hallmark of heart disease, is associated with intense auto- and paracrine signaling leading to cardiac fibrosis. We hypothesized that the specific mediator of Gq/11-dependent RhoA activation p63RhoGEF, which is expressed in cardiac fibroblasts, plays a role in the underlying processes. We could show that p63RhoGEF is up-regulated in mouse hearts subjected to transverse aortic constriction (TAC). In an engineered heart muscle model (EHM), p63RhoGEF expression in cardiac fibroblasts increased resting and twitch tensions, and the dominant negative p63ΔN decreased both. In an engineered connective tissue model (ECT), p63RhoGEF increased tissue stiffness and its knockdown as well as p63ΔN reduced stiffness. In 2D cultures of neonatal rat cardiac fibroblasts, p63RhoGEF regulated the angiotensin II (Ang II)-dependent RhoA activation, the activation of the serum response factor, and the expression and secretion of the connective tissue growth factor (CTGF). All these processes were inhibited by the knockdown of p63RhoGEF or by p63ΔN likely based on their negative influence on the actin cytoskeleton. Moreover, we show that p63RhoGEF also regulates CTGF in engineered tissues and correlates with it in the TAC model. Finally, confocal studies revealed a closely related localization of p63RhoGEF and CTGF in the trans-Golgi network.