| Popis: |
The ability of cardiac fibroblasts to sense and control the mechanical properties of the extracellular matrix is essential to adapt the heart tissue to mechanical load, such as in conditions of hypertension and to repair injuries after myocardial infarct. Aberrant mechanosensing and/or persistent stress results in the chronic activation of cardiac fibroblasts and other progenitors into myofibroblasts. Myofibroblasts drive the development of fibrosis by excessive collagen secretion and contraction of the neo-matrix into scar tissue. Stiff fibrotic tissue impairs heart distensibility, pumping and valve function, contributes to diastolic and systolic dysfunction, and affects myocardial electrical transmission, leading to arrhythmia and ultimately heart failure. To explore novel therapeutic strategies that specifically target the myofibroblasts in heart fibrosis, we here elaborate on the common factors that control myofibroblast activation from different precursor cells in the heart. At least two factors are pivotal for myofibroblast activation and function: mechanical stress, manifested in disease as a stiff extracellular matrix, and active TGF-β1. Because of uncontrollable side effects, global TGF-β1 inhibition has failed in clinical trials to treat fibrosis but preventing TGF-β1 activation in a myofibroblast-specific manner has promising perspectives. |
