The Role of Cardiac Fibroblast Talins on Regulating Fibrosis and Hypertrophy Following Pressure Overload of the Heart
Noll, Natalie A.
0000-0002-4066-5598
:
2022-01-13
Abstract
Cardiac fibroblasts are activated during injury, where they become the cells tasked with depositing and compacting collagen leading to interstitial fibrosis. Overactivity of cardiac fibroblasts leads to extensive stiffening of the left ventricular heart wall stimulating increased cardiomyocyte hypertrophy that can eventually lead to heart failure. Talin 1 (Tln1) and talin 2 (Tln2) are focal adhesion proteins that have been shown to be vital links in transmitting signals to and from the extracellular matrix to the fibroblast actin cytoskeleton. Therefore, we hypothesized that Tln1 and Tln2 in cardiac fibroblast would play an important role in mediating interstitial fibrosis during pressure overload injury of the heart. To test this hypothesis, we utilized two novel genetic mouse models to knockdown Tln1 and Tln2 specifically in cardiac fibroblasts in two models of pressure overload injury: transverse aortic constriction (TAC) and angiotensin II (AngII)-infusion. We genetically ablated Tln1 from Postn-lineage myofibroblasts and subjected them to TAC injury. We saw an increase in cardiac hypertrophy, indicated by increase ventricle/body weight ratio and echocardiographic measurements of heart wall thickness, in mice with loss of Tln1 in their myofibroblasts. We also genetically ablated Tln1 from Tcf21-lineage resident cardiac fibroblasts in a Tln2-null mouse in a model of AngII-induced pressure overload injury. Again, we saw similar results of increased cardiomyocyte hypertrophy; however, we saw no change in interstitial fibrosis.
Together, we found that loss of Tln1 and Tln2 in cardiac fibroblasts results in cardiomyocyte hypertrophy without changes in interstitial fibrosis. These findings have important implications for the role of mechanosensitive proteins in cardiac fibroblasts, and their impact on cardiomyocyte function in the pathogenesis of hypertension and cardiac hypertrophy.