Alpha1a-adrenoceptor genetic variant induces cardiomyoblast-to-fibroblast-like cell transition via distinct signaling pathways.
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.
Department of Anesthesiology & Pain Medicine, University of Washington, 850 Republican Street, Box 358050, Seattle, WA 98109, USA.
Maren
M
Kleine-Brueggeney
Department of Anesthesiology & Pain Medicine, University of Washington, 850 Republican Street, Box 358050, Seattle, WA 98109, USA.
Irina
I
Gradinaru
Department of Anesthesiology & Pain Medicine, University of Washington, 850 Republican Street, Box 358050, Seattle, WA 98109, USA.
Ekaterina
E
Babaeva
Department of Anesthesiology & Pain Medicine, University of Washington, 850 Republican Street, Box 358050, Seattle, WA 98109, USA; Department of Pharmacology, University of Washington, 850 Republican Street, Box 358050, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington, 850 Republican Street, Box 358050, Seattle, WA 98109, USA.
Debra A
DA
Schwinn
Department of Anesthesiology & Pain Medicine, University of Washington, 850 Republican Street, Box 358050, Seattle, WA 98109, USA. Electronic address: anush@u.washington.edu.
Anush
A
Oganesian
D000818:Animals; D019390:Arrestins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D032386:Myoblasts, Cardiac / Q000166:cytology*; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D020032:Tyrphostins / Q000494:pharmacology; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D019061:src-Family Kinases / Q000378:metabolism
C000605253:ARRB1 protein, human; C000605256:Arrb1 protein, rat; D019390:Arrestins; D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011799:Quinazolines; D018340:Receptors, Adrenergic, alpha-1; D020032:Tyrphostins; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; C101044:RTKI cpd; D010656:Phenylephrine; D066246:ErbB Receptors; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020782:Matrix Metalloproteinases
Adrenergic receptor; Epidermal growth factor receptor (EGFR); G protein coupled receptors (GPCRs); Genetic variant; Matrix metalloproteinases (MMPs); Transactivation