Sustained ATR Stimulation Induces Upregulation of Growth Factors in Human Cardiac Fibroblasts Via G/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-β1), and vascular endothelial growth factor (VEGF) through the ATR subtype. Blockade of G, not G or G, protein signaling inhibited ATR-mediated upregulation of CTGF, TGF-β1, and VEGF. In addition, ATR 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 ATR stimulation contributes to the development of myocardial fibrosis and hypertrophy, and advances understanding of this complex ATR signaling, including fibroblasts-myocytes communication during pathological conditions.