Molecular Mechanisms of Heart Valve and Skeletal Muscle Development and Disease

Margaret E. Benny Klimek, University of Miami


Heart valves function to provide unidirectional blood flow during each cardiac cycle. The development of the heart valves from embryonic stages is a highly regulated process involving many signaling pathways in order to provide the proper extracellular matrix components in the trilaminar structure. When these processes are dysregulated, disease can persist in the valves. Here we examined additional levels of regulation in the heart valves at the level of miRNAs and phosphate homeostasis. There are many studies examining miRNA regulation in the heart, however, there is little knowledge about which miRNAs are expressed in the heart valves during development, maturation, homeostasis and disease. To address this gap and determine miRNA regulators of valve development and disease, RNA was extracted from mouse atrioventricular (AV) heart valves at mE11.5 (endocardial cushion), mE15.5 (remodeling), postnatal (maturing), and 4 months (4m) of age (maintained). Here we found several groups of miRNAs that cluster between timepoints that are also conserved between species (murine and avian systems). Additionally, we demonstrate miR-101 binds to the 3’UTR of Sox9, a SRY transcription factor required for proper valve development, which suggests Sox9 may be regulated in the valves by miR-101 during development. In addition to the miRNA valve studies, although elevated FGF23 and phosphate serum levels have been demonstrated to be associated with vascular calcification in patients with chronic kidney disease (CKD), the direct effect on the heart valves remains unknown. Here we show evidence for phosphate, but not FGF23 promoting calcification in heart valve explants, valve interstitial cells and in mouse aortic smooth muscle cells. Sodium phosphate (NaPh) Co-transporters are required for this calcification and their expression is altered by phosphate and FGF23. Lastly, the data presented here also shows a mechanism by which skeletal muscle wasting or cachexia can be prevented in mouse models of cancer cachexia. These studies specifically look at inhibiting myostatin-family ligands in order to protect skeletal muscles from cancer induced wasting. Taken together, these studies provide evidence as to examine both heart valve and skeletal muscle signaling pathways further in order to understand the developmental processes that have gone awry in diseases associated with these tissues.