Sustained AT1R stimulation induces upregulation of growth factors in human cardiac fibroblasts via Gαq/TGF-β/ERK signaling that influences myocyte hypertrophy

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-beta 1), and vascular endothelial growth factor (VEGF) through the AT1R subtype. Blockade of G alpha q, not G alpha i or G alpha 12/13, protein signaling inhibited AT1R-mediated upregulation of CTGF, TGF-beta 1, and VEGF. In addition, AT1R over-stimulation induced upregulation of growth factors via the TGF-beta-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 beta-myosin heavy chain (beta-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.

Automated summary

Stimulation of angiotensin II receptor (ATR) with angiotensin II (Ang II) leads to the activation of cardiac fibroblasts and upregulation of growth factors. Long-term Ang II treatment of human cardiac fibroblasts results in the synthesis and secretion of connective tissue growth factor (CTGF), transforming growth factor beta1 (TGF-beta 1), and vascular endothelial growth factor (VEGF) through the AT1R subtype. Blockade of G alpha q signaling inhibits the upregulation of these growth factors. AT1R over-stimulation induces upregulation of growth factors via the TGF-beta-dependent and ERK1/2-dependent pathways. The growth factors secreted by cardiac fibroblasts are necessary for the induction of myocyte hypertrophy.