Duong, TB; Ravisankar, P; Song, YC; Gafranek, JT; Rydeen, AB; Dohn, TE; Barske, LA; Crump, JG; Waxman, JS. Nr2f1a balances atrial chamber and atrioventricular canal size via BMP signaling-independent and -dependent mechanisms. Developmental Biology. 2018; 434(1):7-14.
Mutations in highly conserved proteins, called Nr2fs, associate with congenital heart defects affecting the atria and valves in humans. Our work using zebrafish embryos is the first to demonstrate that Nr2f proteins simultaneously determine the sizes of both the atrial chamber and atrioventricular valve during development. Specifically, we find that Nr2f proteins promote atrial chamber development while restricting valve development. Therefore, our results provide novel insight into the molecular mechanisms that may underlying atrial and valve malformations found in humans.
Khalil, H; Kanisicak, O; Prasad, V; Correll, RN; Fu, X; Schips, T; Vagnozzi, RJ; Liu, R; Huynh, T; Lee, SJ; Karch, J; Molkentin, JD. Fibroblast-specific TGF-beta-Smad2/3 signaling underlies cardiac fibrosis. Journal of Clinical Investigation. 2017; 127(10):3770-3783.
Excessive deposition of extracellular matrix and collagen in the diseased heart exacerbates declining ventricular function by reducing wall compliance; it also reduces diffusion efficiency, promotes arrhythmia, and possibly limits regenerative efforts of cardiomyocytes. This progressive cardiac fibrosis in the diseased heart is predominantly mediated by the tissue resident cardiac fibroblast, which becomes activated and then differentiated into a cell-type referred to as the myofibroblast. Here we showed that fibroblast to myofibroblast conversion requires a TGFβ-responsive signaling pathway, and more specifically, the transcriptional effectors of this pathway; SMAD2 and SMAD3. Mice lacking the two genes encoding the TGFβ receptors, or the genes encoding SMAD2 and SMAD3, have protection against fibrosis and heart failure when challenged with various models of surgically-induced injury. Thus, TGFβ-SMAD2/3 signaling are fundamental regulators of myofibroblast formation and cardiac fibrosis during disease.
McLendon, PM; Davis, G; Gulick, J; Singh, SR; Xu, N; Salomonis, N; Molkentin, JD; Robbins, J. An Unbiased High-Throughput Screen to Identify Novel Effectors That Impact on Cardiomyocyte Aggregate Levels. Circulation Research. 2017; 121(6):604-616.
We found that protein aggregation is an important contributing factor in cardiovascular disease. This paper described a functional search for new proteins that impact on cardiac aggregation and validates some of the unexpected proteins identified. It opens up potential new therapeutic targets for decreasing the pathologies often seen during the development of heart failure.
Xiang, FL; Fang, M; Yutzey, KE. Loss of beta-catenin in resident cardiac fibroblasts attenuates fibrosis induced by pressure overload in mice. Nature Communications. 2017; 8(1).
In this study, researchers determined the role of Wnt/β-catenin signaling in cardiac fibrosis in mice with cardiac pressure overload. Wnt/β-catenin signaling induces in resident cardiac fibroblasts during the fibrotic response, and loss of β-catenin specifically in cardiac fibroblasts leads to improved cardiac function, blunted cardiac hypertrophy, reduced interstitial fibrosis, and decreased expression of fibrotic extracellular matrix (ECM) protein genes. Together, these results provide new insights into the molecular mechanisms of cardiac fibrosis with potential applications in the development of new therapeutic approaches. The observation that specific loss of β-catenin in resident fibroblasts results, not only in reduced fibrotic ECM, but also in reduced cardiomyocyte hypertrophy and improved cardiac function, underscores the importance of anti-fibrotic therapies in treatment of cardiovascular disease.