Abstract
In response to stretch, cardiac tissue produces natriuretic peptides, which have been suggested to have beneficial effects in heart failure patients. In the present study, we explored the mechanism of stretch-induced brain natriuretic peptide (Nppb) expression in cardiac fibroblasts. Primary adult rat cardiac fibroblasts subjected to 4 h or 24 h of cyclic stretch (10% 1 Hz) showed a 6.6-fold or 3.2-fold (p < 0.05) increased mRNA expression of Nppb, as well as induction of genes related to myofibroblast differentiation. Moreover, BNP protein secretion was upregulated 5.3-fold in stretched cardiac fibroblasts. Recombinant BNP inhibited TGFβ1-induced Acta2 expression. Nppb expression was >20-fold higher in cardiomyocytes than in cardiac fibroblasts, indicating that cardiac fibroblasts were not the main source of Nppb in the healthy heart. Yoda1, an agonist of the Piezo1 mechanosensitive ion channel, increased Nppb expression 2.1-fold (p < 0.05) and significantly induced other extracellular matrix (ECM) remodeling genes. Silencing of Piezo1 reduced the stretch-induced Nppb and Tgfb1 expression in cardiac fibroblasts. In conclusion, our study identifies Piezo1 as mediator of stretch-induced Nppb expression, as well as other remodeling genes, in cardiac fibroblasts.
Highlights
Mechanical factors influence the form and function of cells [1,2,3,4]
Cardiac fibroblasts exposed to cyclic stretch (10%, 1 Hz) for 4 h showed a significant increase in mRNA expression of Tgfb1, Tenascin C (Tnc), Connective tissue growth factor (Ctgf) and Acta2 compared to non-stretched controls (Figure 1a)
After 24 h of cyclic stretch the effect remained for Tgfb1, Ctgf and
Summary
Mechanical factors influence the form and function of cells [1,2,3,4]. in the heart, mechanical signals include the forces of cyclic contraction and relaxation of the myocardial walls and the hemodynamic load leading to stretch of the cardiac chambers during the filling phase, and increased wall stress during the contraction phase [5].These factors are known to regulate myocardial function, gene expression and structural appearance [6,7].Cardiovascular tissue is composed of cardiomyocytes, fibroblasts, vascular and immune cells which reside within the myocardial extracellular matrix (ECM) [8]. Mechanical factors influence the form and function of cells [1,2,3,4]. In the heart, mechanical signals include the forces of cyclic contraction and relaxation of the myocardial walls and the hemodynamic load leading to stretch of the cardiac chambers during the filling phase, and increased wall stress during the contraction phase [5]. These factors are known to regulate myocardial function, gene expression and structural appearance [6,7]. Cardiac fibroblasts play an important role in the regulation of the ECM, by synthesizing structural
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