# The effect of Myristolated alanine-rich C Kinase Substrate (MARCKS) on kinase interacting with stathmin (KIS) in differential proliferation of vascular smooth muscle and endothelial cells

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $386,250

## Abstract

Summary
Over 80 million people in the United States have cardiovascular disease resulting in over 7 million
revascularization procedures each year. Revascularization procedures are endovascular, angioplasty or
stenting, or open surgical procedures, endarterectomy or bypass. All of these procedures cause trauma to the
blood vessel and damage the endothelium. This trauma causes a series of biological changes that result in
the medial vascular smooth muscle cells (VSMCs) migrating to the intmal where they proliferate causing a
cellular lesion in the lumen of the vessel, reducing the inner diameter and ultimately causing the vessel to
restenose. Currently, drug-eluting stents (DES) and drug-coated balloons (DCB) are used to prevent
restenosis. The agents on these devices are frequently calcineurin inhibitors (such as sirolimus) or
chemotherapeutics (such as paclitaxel). What all these agents have in common is that they all inhibit both
VSMC proliferation and endothelial cell (EC) proliferation. The endothelium provides an antithrombotic, anti-
adhesive surface for blood vessels. When endothelium regeneration is prevented by the antiproliferative
agents, the patient needs to remain on a potent antiplatelet agent (clopidogrel) indefinitely. Failure of the
antiplatelet regiment can result in life-threatening in situ thrombosis of the vessel. We have previously reported
that knockdown of the myristolated alanine-rich C kinase Substrate (MARCKS) results in arrest of VSMC
proliferation and a modest potentiation of EC proliferation, making it an ideal target for the prevention of
restenosis. We further demonstrated that the effect of MARCKS on proliferation is p27kip1-dependent. In
VSMCs, p27kip1 is expressed at greater levels and is trapped in the nucleus whereas in ECs, p27kip1 expression
is decreased. The expression of p27kip1 is regulated by degradation by the 26s proteasome. Degradation of
p27kip1 is a multi-step process beginning with phosphorylation by the kinase interaction with stathmin (KIS),
which allows p27kip1 to transit from the nucleus. In VSMCs, MARCKS knockdown decreases KIS protein
expression. In stark contrast, MARCKS knockdown in increased KIS expression in ECs. The goal of this
proposal is to define the mechanism through which MARCKS differentially regulates KIS expression in these
two cell types. The overall hypothesis is that MARCKS binds to KIS in VSMCs, but not ECs preventing,
degradation of KIS. This hypothesis will be tested in three Specific Aims: 1) To determine the point of
regulation of KIS expression in VSMCs and ECs 2) To determine the domains of MARCKS and KIS that
mediate MARCKS protection of KIS from degradation in VSMCs but not ECs and 3) To determine the in vivo
effect of tissue-specific MARCKS knockdown and KIS deletion. The rationale for the proposed work is to
further delineate the downstream effects of MARCKS signaling to identify other potentially better or synergistic
targets for translational therapy targeting in...

## Key facts

- **NIH application ID:** 10198997
- **Project number:** 5R01HL134938-05
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** RAJABRATA SARKAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $386,250
- **Award type:** 5
- **Project period:** 2017-07-10 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198997

## Citation

> US National Institutes of Health, RePORTER application 10198997, The effect of Myristolated alanine-rich C Kinase Substrate (MARCKS) on kinase interacting with stathmin (KIS) in differential proliferation of vascular smooth muscle and endothelial cells (5R01HL134938-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10198997. Licensed CC0.

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