Sustained AT<inf>1</inf>R stimulation induces upregulation of growth factors in human cardiac fibroblasts via G<inf>αq</inf>/TGF-β/ERK signaling that influences myocyte hypertrophy
Issued Date
2022-12-15
Resource Type
ISSN
00142999
eISSN
18790712
Scopus ID
2-s2.0-85141977525
Pubmed ID
36372276
Journal Title
European Journal of Pharmacology
Volume
937
Rights Holder(s)
SCOPUS
Bibliographic Citation
European Journal of Pharmacology Vol.937 (2022)
Suggested Citation
Duangrat R., Parichatikanond W., Morales N.P., Pinthong D., Mangmool S. Sustained AT<inf>1</inf>R stimulation induces upregulation of growth factors in human cardiac fibroblasts via G<inf>αq</inf>/TGF-β/ERK signaling that influences myocyte hypertrophy. European Journal of Pharmacology Vol.937 (2022). doi:10.1016/j.ejphar.2022.175384 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/86819
Title
Sustained AT<inf>1</inf>R stimulation induces upregulation of growth factors in human cardiac fibroblasts via G<inf>αq</inf>/TGF-β/ERK signaling that influences myocyte hypertrophy
Author's Affiliation
Other Contributor(s)
Abstract
Stimulation of angiotensin II receptor (ATR) with angiotensin II (Ang II) accelerates cardiac fibroblast activation, resulting in upregulation of cytokines and growth factors. Growth factors were strongly upregulated in animal models of myocardial fibrosis and hypertrophy as well as patients with heart failure. Nevertheless, the signal transduction of ATR for upregulation of growth factors in human cardiac fibroblasts contributing to myocyte hypertrophy have not fully understood. Long-term Ang II treatment of human cardiac fibroblasts provokes the synthesis and secretion of connective tissue growth factor (CTGF), transforming growth factor beta1 (TGF-β1), and vascular endothelial growth factor (VEGF) through the AT1R subtype. Blockade of Gαq, not Gαi or Gα12/13, protein signaling inhibited AT1R-mediated upregulation of CTGF, TGF-β1, and VEGF. In addition, AT1R overstimulation induced upregulation of growth factors via the TGF-β-dependent and ERK1/2-dependent pathways. Growth factors secreted from cardiac fibroblasts are necessary for the induction of hypertrophic markers, atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC), resulting in myocyte hypertrophy. Candesartan, irbesartan, and valsartan had greater effects than losartan for blockade of fibrotic and hypertrophic effects of Ang II. Our data support the concept whereby sustained AT1R stimulation contributes to the development of myocardial fibrosis and hypertrophy, and advances understanding of this complex AT1R signaling, including fibroblasts-myocytes communication during pathological conditions.