# HIPK2 signaling in Pulmonary Arterial Hypertension

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $388,324

## Abstract

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 succe...

## Key facts

- **NIH application ID:** 10990627
- **Project number:** 7R01HL166932-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Tatiana V Kudryashova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $388,324
- **Award type:** 7
- **Project period:** 2023-02-20 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990627

## Citation

> US National Institutes of Health, RePORTER application 10990627, HIPK2 signaling in Pulmonary Arterial Hypertension (7R01HL166932-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10990627. Licensed CC0.

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