Alpha1a-adrenoceptor genetic variant induces cardiomyoblast-to-fibroblast-like cell transition via distinct signaling pathways.

Kleine-Brüggeney, Maren; Gradinaru, Irina; Babaeva, Ekaterina; Schwinn, Debra A; Oganesian, Anush (2014). Alpha1a-adrenoceptor genetic variant induces cardiomyoblast-to-fibroblast-like cell transition via distinct signaling pathways. Cellular signalling, 26(9), pp. 1985-1997. Elsevier 10.1016/j.cellsig.2014.05.007

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The role of naturally occurring human α1a-Adrenergic Receptor (α1aAR) genetic variants associated with cardiovascular disorders is poorly understood. Here, we present the novel findings that expression of human α1aAR-247R (247R) genetic variant in cardiomyoblasts leads to transition of cardiomyoblasts into a fibroblast-like phenotype, evidenced by morphology and distinct de novo expression of characteristic genes. These fibroblast-like cells exhibit constitutive, high proliferative capacity and agonist-induced hypertrophy compared with cells prior to transition. We demonstrate that constitutive, synergistic activation of EGFR, Src and ERK kinases is the potential molecular mechanism of this transition. We also demonstrate that 247R triggers two distinct EGFR transactivation-dependent signaling pathways: 1) constitutive Gq-independent β-arrestin-1/Src/MMP/EGFR/ERK-dependent hyperproliferation and 2) agonist-induced Gq- and EGFR/STAT-dependent hypertrophy. Interestingly, in cardiomyoblasts agonist-independent hyperproliferation is MMP-dependent, but in fibroblast-like cells it is MMP-independent, suggesting that expression of α1aAR genetic variant in cardiomyocytes may trigger extracellular matrix remodeling. Thus, these novel findings demonstrate that EGFR transactivation by α1aAR-247R leads to hyperproliferation, hypertrophy and alterations in cardiomyoblasts, suggesting that these unique genetically-mediated alterations in signaling pathways and cellular function may lead to myocardial fibrosis. Such extracellular matrix remodeling may contribute to the genesis of arrhythmias in certain types of heart failure.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Intensive Care, Emergency Medicine and Anaesthesiology (DINA) > Clinic and Policlinic for Anaesthesiology and Pain Therapy

UniBE Contributor:

Kleine-Brüggeney, Maren

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0898-6568

Publisher:

Elsevier

Language:

English

Submitter:

Jeannie Wurz

Date Deposited:

22 May 2015 14:20

Last Modified:

23 Jan 2018 12:15

Publisher DOI:

10.1016/j.cellsig.2014.05.007

PubMed ID:

24835978

Uncontrolled Keywords:

Adrenergic receptor; Epidermal growth factor receptor (EGFR); G protein coupled receptors (GPCRs); Genetic variant; Matrix metalloproteinases (MMPs); Transactivation

BORIS DOI:

10.7892/boris.69118

URI:

https://boris.unibe.ch/id/eprint/69118

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