PKD3 and Valvular Heart Disease

Valvular Heart Disease (VHD) encompasses a number of common cardiovascular conditions that account for 10% to 20% of all cardiac surgical procedures in the United States. A better understanding of the heart valvular disorders and underlying molecular mechanisms is important to aid in the management and treatment of

patients with VHD. Endothelial mesenchymal transition (EndMT) is a complex biological process in which endothelial cells progressively evolve into cells with a mesenchymal phenotype. EndMT plays an essential role in cardiac valve formation and function, and EndMT is temporally and spatially regulated during organ

development and maintenance. Abnormal EndMT is critically implicated in the pathogenesis of both congenital cardiac valve disease and late-onset cardiac valve dysfunction. Thus, further understanding exact molecular pathways that control EndMT during cardiac valve development and maintenance is likely to be significant in

order to develop therapeutic strategies to ameliorate heart valve disease. It has been well-established that vascular endothelial growth factor (VEGF), one of the most potent regulators of angiogenesis, also plays a key role in control of EndMT during cardiac valve development. A series of our previous studies have demonstrated

that a newly discovered serine/threonine protein kinas family members of protein kinase D (PKD), are key signal molecules in mediating VEGF signaling and function. The nascent data from our recent preliminary studies suggested a key role of protein kinase D3 (PKD3, gene name Prkd3) in regulation of EndMT and VHD.

In current application, we will determine how PKD3 regulates EndMT and heart valve development, physiological function and pathological changes, and how to manipulate the PKD3-dependent signaling pathways to prevent excessive EndMT and cardiac valve enlargement, ultimately, leading to new approaches

to treat VHD. Upon completion of the proposed studies, it will have significant impact on our understanding of EndMT and cardiac valve development and function, and provide valuable information on the underlying molecular mechanisms of cardiac valve development and abnormal factors for VHD, which will help to design

new therapeutic strategies for combating VHD. Recently, as part of the National Heart, Lung, and Blood Institute (NHLBI)’s implementation of the Cardiovascular Advances in Research and Opportunities Legacy (CAROL) Act, NHLBI issued a Notice of Special Interest to seek R01 applications that propose research in

valvular heart disease (NOT-HL-23-079). Thus, our work is extremely important and highly relevant to NHLBI’s mission to elucidate the pathophysiology of VHD and to reduce the burdens of human heart disease.