# MKP1, VSMC, and Vascular Remodeling

> **NIH NIH R01** · GEORGIA STATE UNIVERSITY · 2020 · $687,739

## Abstract

Abstract
Overwhelming evidence from previous studies suggests that vascular smooth muscle cells
(VSMCs) plays a critical role in development of neointima hyperplasia and atherosclerosis but
exact molecular mechanisms are poorly understood. We have obtained exciting preliminary data
suggesting that down-regulation of mitogen-activated protein kinase phosphatase-1 (MKP-1)
protein levels is associated with increased cell proliferation and stenosis in patients with
atherosclerosis. Similarly, MKP-1 protein levels and neointimal hyperplasia are decreased in a
mouse model of wire-mediated carotid artery injury. MKP-1 is known to suppress activation of
signal transducer and activator of transcription (STAT1) signaling, a critical step leading to
VSMC proliferation and neointimal hyperplasia. More importantly, MKP-1 overexpression is
associated with decreased human aortic smooth muscle cell (HASMC) proliferation, STAT1
phosphorylation, and neointimal hyperplasia formation in response to vascular injury. With a
concomitant reduction in MKP-1 expression, both liver kinase (LKB)1 activity and LKB1
phosphorylation at Ser428 is decreased in the carotid artery after wire-mediated injury. Further,
LKB1 directly phosphorylates MKP-1 in a cell-free system, and overexpression of constitutively
active LKB1 in LKB1-deficient A549 cells inhibits MKP-1 degradation. Finally, VSMC-specific
LKB1 deletion mice exhibit lower levels of MKP-1 in mouse aortas and exacerbated neointimal
hyperplasia and atherosclerosis. Thus we hypothesize that LKB1-regulated MKP-1
suppresses VSMC proliferation, migration, neointimal formation, and atherosclerosis
through the inhibition of STAT1 signaling. The goals of the present application are to
characterize the mechanism by which LKB1 via MKP-1 suppresses VSMC proliferation, intimal
hyperplasia, atherosclerosis, and determine whether the effect of MKP-1 is mediated through
the inhibition of STAT1 signaling, which has been shown to promote VSMC proliferation and
intimal hyperplasia (1) and impair thrombus resolution (2) and wound healing (3). Defining the
roles of LKB1 in the regulation of VSMC proliferation, intimal hyperplasia, and atherosclerosis
may identify potential targets for the treatment of atherothrombotic vascular diseases.

## Key facts

- **NIH application ID:** 9842978
- **Project number:** 5R01HL140954-03
- **Recipient organization:** GEORGIA STATE UNIVERSITY
- **Principal Investigator:** Ping Song
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $687,739
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842978

## Citation

> US National Institutes of Health, RePORTER application 9842978, MKP1, VSMC, and Vascular Remodeling (5R01HL140954-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9842978. Licensed CC0.

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