Calcific aortic valve disease (CAVD) is a significant cause of morbidity among the aging population and is a strong risk factor for additional cardiovascular events. Currently, there are no therapeutic options for CAVD other than valve replacement or repair due in part to the incomplete understanding of the underlying mechanisms. Interestingly, AV calcification develops in a side-specific manner, occurring preferentially on the fibrosa side exposed to d-flow while the ventricularis side exposed to stable flow is spared. Another mechanical force, elevated stretching commonly observed in bicuspid (BAV) and diseased valves and hypertension, also correlates well with CAVD. These suggest a potential role for d-flow and elevated stretch in the pathogenesis of CAVD, but the mechanism is unclear. Our goal is to define the role and mechanisms of the mechanical forces in CAVD pathogenesis and use the knowledge to develop novel anti-CAVD therapeutics. In the previous funding cycle, we have identified several flow- and side-dependent microRNAs (miRNAs) in human AV endothelial cells (HAVECs) and pig AVs (PAVs) and began determining their roles in CAVD. Recently, we have identified a novel flow- and stretch-sensitive miR-483-3p (miR-483), which has exciting potential as a critical regulator of CAVD pathogenesis. Our preliminary data show that miR-483 expression is decreased 1) by d-flow (OS) compared to stable flow (LS) in HAVECs, 2) in the fibrosa layer compared to the ventricularis in human and pig AVs, and 3) by pathological stretch conditions in PAVs ex vivo. Further data indicate that miR-483 inhibits EC inflammation and endothelial-to-mesenchymal transition (EndoMT), critical pathobiological events in CAVD, and that a key gene target of miR-483 is Ube2c (E2 ubiquitin-conjugating enzyme), which in turn may target the hypoxia- inducible factor (HIF1?) via controlling its upstream regulator pVHL. HIF1?'s role in CAVD is unclear, but its well- known target genes include VEGF (angiogenesis and inflammation), TGF? (fibrosis and calcification), Runx2 (calcification) and Twist1 (EndoMT), key CAVD pathogenic processes. Therefore, our overarching hypothesis is that miR-483 is an anti-CAVD miRNA, which is reduced under OS/pathological stretch conditions, leading to an increase in Ube2c, which in turn ubiquitinates pVHL for its degradation and increases the HIF1? level. HIF?, then, stimulates its target genes leading to inflammation, EndoMT, AV sclerosis and calcification. We will test this in 3 Aims.
Aim 1 will determine the mechanisms by which miR-483 regulates shear-dependent responses of HAVECs and PAVs in a Ube2c- and the HIF1?-dependent manner in vitro and ex vivo.
Aim 2 will determine the role of miR-483 in stretch-dependent calcification of HAVICs and PAVs ex vivo via Ube2c and HIF1?-dependent mechanisms.
Aim 3 is an in vivo study where miR-483, Ube2c, and HIF1? will be modified genetically, molecularly or pharmacologically in a novel mouse model of CAVD that we just developed by treating GATA5-/- BAV mice with AAV-PCSK9 to induce hypercholesterolemia. Here, we will test their roles and their anti-CAVD therapeutic potential.
Calcific aortic valve disease is a significant cause of morbidity among the aging population, but the only treatment options are valve replacement or repair without any drug treatment options available due in large part to lack of detailed disease mechanisms. Studies suggest that bad blood flow conditions and too much stretching of the aortic valve correlate with the disease development, therefore we aim to determine the underlying mechanisms by which these biomechanical forces may cause the disease. By focusing on mechanosensitive genes known as microRNAs and HIF1a gene (a well-known cancer causing gene), we aim to provide the mechanistic insights into the disease and proof of concept whether microRNA mimic or existing cancer drugs that target HIF1a could be used as novel therapy for the calcific aortic valve disease.
|Hoganson, David M; Cooper, Dane A; Rich, Kimberly N et al. (2018) Flow Preservation of Umbilical Vein for Autologous Shunt and Cardiovascular Reconstruction. Ann Thorac Surg 105:1809-1818|
|Schlotter, Florian; Halu, Arda; Goto, Shinji et al. (2018) Spatiotemporal Multi-Omics Mapping Generates a Molecular Atlas of the Aortic Valve and Reveals Networks Driving Disease. Circulation 138:377-393|
|Simmons, Craig A; Jo, Hanjoong (2018) Editorial: Special Issue on Heart Valve Mechanobiology : New Insights into Mechanical Regulation of Valve Disease and Regeneration. Cardiovasc Eng Technol 9:121-125|
|Hu, Shuhong; Liu, Yifei; You, Tao et al. (2018) Vascular Semaphorin 7A Upregulation by Disturbed Flow Promotes Atherosclerosis Through Endothelial ?1 Integrin. Arterioscler Thromb Vasc Biol 38:335-343|
|Heath, Jack M; Fernandez Esmerats, Joan; Khambouneheuang, Lucky et al. (2018) Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3. Cardiovasc Eng Technol 9:141-150|
|Sena, Brena F; Figueiredo, Jose Luiz; Aikawa, Elena (2017) Cathepsin S As an Inhibitor of Cardiovascular Inflammation and Calcification in Chronic Kidney Disease. Front Cardiovasc Med 4:88|
|Kim, Chan Woo; Pokutta-Paskaleva, Anastassia; Kumar, Sandeep et al. (2017) Disturbed Flow Promotes Arterial Stiffening Through Thrombospondin-1. Circulation 136:1217-1232|
|Kumar, Sandeep; Kang, Dong-Won; Rezvan, Amir et al. (2017) Accelerated atherosclerosis development in C57Bl6 mice by overexpressing AAV-mediated PCSK9 and partial carotid ligation. Lab Invest 97:935-945|
|Gogas, Bill D; Kumar, Sandeep; Benham, James et al. (2016) TCT-828 Very Late Vasomotor Responses and Gene Expression Profiles of Porcine Coronary Arteries at 4 Years after Deployment of the Everolimus-eluting Bioresorbable Vascular Scaffold and the Everolimus-eluting Metallic Xience V stent. J Am Coll Cardiol 68:B334-B335|
|Jha, Rajneesh; Wu, Qingling; Singh, Monalisa et al. (2016) Simulated Microgravity and 3D Culture Enhance Induction, Viability, Proliferation and Differentiation of Cardiac Progenitors from Human Pluripotent Stem Cells. Sci Rep 6:30956|
Showing the most recent 10 out of 45 publications