# The Therapeutic Role for LOLX2 in Pulmonary Hypertension

> **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2021 · $171,720

## Abstract

PROJECT SUMMARY
In patients with pulmonary hypertension (PH) and especially with pulmonary arterial hypertension
(PAH), pulmonary artery (PA) stiffness increases right ventricular strain and ultimately leads to death
from heart failure. However, despite pulmonary vasculature stiffening with increased impedance being a
paramount mechano-biological regulator of PAH, no therapies currently target this mechanism. Therapy
for PAH continues to focus on symptomatic treatment, vasodilatory therapy, or treatment of the
underlying disease (if known). None of these addresses the fundamental changes in vascular
remodeling.
My long-term career goal is to become an expert in understanding the mechanisms underlying PAH,
thus facilitating the identification of more effective therapies and improving outcomes. This goal directly
builds on my prior research and extends my interests from the systemic to the pulmonary circulation.
Our preliminary data has clearly demonstrated that Lysyl oxidase like-2 (LOXL2) is an attractive gene in
pulmonary arterial stiffness and cardiac fibrosis. LOXL2, is an amine oxidase that catalyzes collagen
crosslinking and contributes to matrix remodeling and stiffening. Our core hypothesis is that increased
LOXL2 expression, secretion, and function contributes to the development of PA stiffening. Our
objective here is to study LOXL2 biology, mechanism, and pathobiology in a hierarchical manner from
cells to rodent models. We will determine how LOXL2 influences cell behavior, tissue mechanics,
function, and matric generation during hypoxia. We will utilize lentiviral shRNA and CRISPR/Cas9 in rat
PA smooth muscle cells. We will use magnetic torsion cytometry, cell substrate impedance sensing, and
tensile testing; test collagen assembly, vasoreactivity, and compliance; and evaluate adhesion, motility,
and proliferation. Furthermore, we will study the relationships between LOXL2 and the TGF-β1 pathway,
as well as its role in rat models of PH and PAH, using multiple models to induce pulmonary vascular
stiffening in the presence an absence of a LOXL2 inhibitor. Measurements will include PA stiffness using
pressure myography and stress strain relationships in isolated vessels, right ventricular function using
high-resolution echocardiography, and right ventricular function using pressure-volume loops. We will
establish the therapeutic potential of LOXL2 inhibition in PAH and test its effects in models of PH and
PAH. This could entail not only a new drug within an existing paradigm but a whole new approach to the
treatment of these patients - altering the structural composition of the extracellular matrix.
With the support of my mentors, my goal during the K08 award period is to acquire the expertise and
training in a nurturing academic setting that will enable me to attain the proficiency necessary to
conduct these experiments, and the independence to continue beyond the award period.

## Key facts

- **NIH application ID:** 10076853
- **Project number:** 5K08HL145132-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Jochen Steppan
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $171,720
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10076853

## Citation

> US National Institutes of Health, RePORTER application 10076853, The Therapeutic Role for LOLX2 in Pulmonary Hypertension (5K08HL145132-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10076853. Licensed CC0.

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