# Role of Protein Phosphatase 2A in Aortic Aneurysm

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $547,449

## Abstract

Project Summary
Disruption of aortic homeostasis arising from genetic defects or exposure to environmental risk factors leads to
localized abnormal widening of the aorta, a degenerative disease state termed aortic aneurysm (AA).
Experimental studies reveal that AA is associated with compromised smooth muscle contractility, extracellular
matrix (ECM) deterioration, and increased vascular inflammation associated with leukocyte infiltration. This
pathologic state culminates with weakening of the vessel wall and progressive dilatation that, if left untreated,
results in an often fatal dissection and/or rupture. Despite the high degree of morbidity and mortality associated
with aortic aneurysm, medical treatments remain inadequate and urgent surgery is unfortunately the top
therapeutic option. Therefore, it is imperative to address this important unmet clinical need, potentially by the
development of novel pharmacologic therapies as well as more effective management strategies to combat
this dreadful disease. However, a critical roadblock lies in the incomplete understanding of the molecular
mechanisms governing AA formation and progression. To that end, this project seeks to develop a promising
group of therapeutic agents termed small molecule activators of Protein Phosphatase 2A (SMAPs) for the
treatment of aortic aneurysm and gain mechanistic insights into the role of PP2A in the pathogenesis of this
disease.
Reversible protein phosphorylation plays a ubiquitous cellular regulatory role in biological functions. The
regulation of protein phosphorylation involves a balance between the activities of both protein kinases and
protein phosphatases. Although there is a significant understanding of how aberrant kinase activity contributes
to human cardiovascular disease, the regulation and therapeutic potential of phosphatases in this area remains
under-explored. Protein phosphatase 2A (PP2A) is a holoenzyme with notable serine/threonine phosphatase
activity in mammalian cells. Restoration of PP2A activity has been shown to be of significant therapeutic value,
however pharmaceutically tractable approaches to directly activate PP2A remain elusive. Recent observations
from our laboratory revealed that a profound loss of PP2A activity in both human and mouse aortic aneurysmal
tissues. Furthermore, administration of the orally bioavailable small molecule activator of PP2A (SMAPs),
markedly suppressed AA progression in both Marfan's syndrome (MFS) and angiotensin II- (Ang II) induced
abdominal aortic aneurysm (AAA) in animal models. These observations provide the basis for the two main
hypotheses for this application: (1) PP2A inactivation is involved in aortic aneurysm (AA) etiology and (2)
activation of PP2A may serve as a novel strategy to limit AA progression. In this proposal, we will leverage
both pharmacologic and genetic approaches to dissect the molecular basis and functional consequences of
PP2A activation/inactivation on aortic aneurysm.

## Key facts

- **NIH application ID:** 9850993
- **Project number:** 5R01HL144741-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Zhiyong Lin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $547,449
- **Award type:** 5
- **Project period:** 2019-01-16 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850993

## Citation

> US National Institutes of Health, RePORTER application 9850993, Role of Protein Phosphatase 2A in Aortic Aneurysm (5R01HL144741-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9850993. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*