HIPK2 signaling in Pulmonary Arterial Hypertension

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PROJECT SUMMARY/ABSTRACT Pulmonary arterial hypertension (PAH) is a progressive deadly disease with no cure. Despite recent therapeutic advances, the prognosis of patients with PAH remains poor. The key pathological feature of PAH is an inward remodeling of small pulmonary arteries (PA) due to, at least in part, increased proliferation and decreased cell death (apoptosis) of pulmonary arterial vascular smooth muscle cells (PAVSMC). This leads to obliteration of the PA lumen, elevated PA pressure, and death due to right heart failure. The mechanisms driving PAVSMC hyper-proliferation/survival and PA remodeling in PAH are not fully understood, and new potential anti- proliferative molecular targets are urgently needed to develop effective remodeling-focused therapies to reverse this deadly disease. Homeodomain-interacting protein kinase 2 (HIPK2) is an important regulator of cell proliferation and survival, dysregulation of which is linked with various proliferative disorders, including cancer. However, the status, role, mechanisms of regulation and function, and potential therapeutic attractiveness of HIPK2 to modulate PAVSMC proliferation, remodeling and PAH had never been studied. Our preliminary data show that HIPK2 is over-expressed in medial layer of small remodeled PAs and in hyper-proliferative, apoptosis- resistant PAVSMC from human PAH lungs and its overexpression is required for abnormal cell proliferation and survival. We found that HIPK2 acts through the up-regulation of pro-proliferative/pro-survival transcriptional co- activators YAP/TAZ and regulator of cytokinesis centrosomal protein 55 (CEP55), which, in turn, up-regulates Akt. Importantly, pharmacological targeting of HIPK2 reduced proliferation and induced apoptosis in human PAH PAVSMC, and attenuated experimental PH in mice, strongly suggesting the important role of HIPK2 as a driver of PAVSMC hyper-proliferation and survival in PAH and the potential attractiveness of HIPK2 as a remodeling- focused target for therapeutic intervention. In this proposal, we will test the hypothesis that HIPK2 is up-regulated in PAH PAVSMC, leading to pulmonary vascular remodeling and PH, and that pharmacological targeting of HIPK2 suppresses PAVSMC proliferation, induces apoptosis, re-remodels PAs and reverses or attenuates existing PH. Specifically, we will (1) determine the status and role of HIPK2 in PAVSMC proliferation, survival, remodeling and PH using de-identified lung tissues and PAVSMC fromPAH and non-diseased subjects (in vitro) and transgenic mice with conditional SM-specific Hipk2 knockout (in vivo); (2) evaluate the mechanisms of HIPK2 (up)regulation in PAH PAVSMC and dissect the interrelations within the HIPK2-YAP/TAZ-CEP55-Akt axis; (3) test whether pharmacological inhibition of HIPK2 selectively suppresses proliferation and induces apoptosis in vitro in human PAH PAVSMC, and reverses or attenuates experimental pulmonary vascular remodeling and overall PH in rats in vivo. If successful, the proposedstudy will define the function of HIPK2 in growth, proliferation and survival of PAH PAVSMC, identify main signaling pathways regulated by HIPK2, and evaluate attractiveness of HIPK2 as a new potential molecular target for development of novel anti-proliferative therapies for PAH.