# Pharmacologic PTEN upregulation: A novel therapeutic approach to prevent pathological vascular remodeling and fibrosis > **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2020 · $21,132 ## Abstract Project Summary/Abstract Cardiovascular disease is the leading cause of death in the United States and is marked by the development of pathological vascular remodeling which contributes to disease progression. In response to injury or pathological stimuli, resident vascular smooth muscle cells (SMCs) contribute to these remodeling processes by de- differentiating from a quiescent, contractile phenotype towards a proliferative, pro-inflammatory, pro-fibrotic phenotype capable of recruiting immune cells like macrophages and T-cells. The preliminary data supporting this proposal indicates genetic, systemic upregulation of the potent tumor suppressor PTEN maintains SMC differentiation, reduces perivascular immune cell recruitment and blunts remodeling in multiple pre-clinical animal models of cardiovascular disease. This suggests that pharmacologic PTEN upregulation could hold significant therapeutic potential in treating cardiovascular disease by inhibiting vascular remodeling. Currently, the therapeutic potential of PTEN is not fully exploited as there are few compounds known to increase PTEN expression. To fill this knowledge gap, a recently completed high-throughput compound screen (HTS) of over 2,500 compounds using a fluorescence-based PTEN promoter-reporter system was used to identify 11 hit compounds with dose-responsive ability to induce PTEN promoter activity. Recently, JQ1, an inhibitor of the epigenetic reader protein Brd4 that is known to have anti-remodeling effects, was shown to upregulate PTEN. However, preliminary data presented in this proposal suggest that the anti-remodeling effects of JQ1 are blunted in PTEN depleted SMCs both in vitro and in vivo, suggesting that the protective effects of JQ1 are mediated through PTEN upregulation. Little is known about the role of Brd4, the target of JQ1, in regulating PTEN levels in SMCs. However, Brd4 has been shown to interact directly with the histone acetyltransferase p300 and the p65 subunit of the pro-inflammatory transcription factor NFkB, both of which are known to affect PTEN expression. This application presents a novel model of PTEN regulation where competition for limited amounts of p300 drives either PTEN expression through promoter acetylation, or inflammatory gene expression through p300-NFkB interaction mediated by Brd4. Specific Aim 1 will expand upon the preliminary data and will use in vitro and in vivo PTEN depletion to determine whether the vasculoprotective effects of JQ1 are due to increased PTEN expression mediated by increased p300 activity at the PTEN promoter and inhibition of Brd4-p300-NFkB complex formation. Specific Aim 2 will extend the results of the completed HTS to test hit compounds in vitro and in vivo for their ability to induce PTEN expression and reduce vascular remodeling, focusing specifically on how PTEN upregulation affects crosstalk between SMCs and recruited macrophages/T-cells. To summarize, these studies will explore a potentially novel mechanism ... ## Key facts - **NIH application ID:** 9960312 - **Project number:** 5F31HL147393-02 - **Recipient organization:** UNIVERSITY OF COLORADO DENVER - **Principal Investigator:** Keith Strand - **Activity code:** F31 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $21,132 - **Award type:** 5 - **Project period:** 2019-05-10 → 2020-12-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9960312 ## Citation > US National Institutes of Health, RePORTER application 9960312, Pharmacologic PTEN upregulation: A novel therapeutic approach to prevent pathological vascular remodeling and fibrosis (5F31HL147393-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9960312. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*