# Role of Skeletal Muscle in Pulmonary Vascular Remodeling

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $698,611

## Abstract

PROJECT SUMMARY
Pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF) is the most
common cause of PH worldwide, and at present, it has no proven effective therapies. Previously, we have
found convincing evidence that PH-HFpEF-regulating sirtuin-3 (SIRT3) is predominantly decreased in the
skeletal muscle. During the past grant period, we found a new endocrine signaling axis that links depressed
skeletal muscle SIRT3 to production/secretion of signaling molecules that interact with pulmonary vasculature
in PH-HFpEF. However, underlying mechanisms by which skeletal muscle SIRT3-mediated scretome regulates
pathological changes in pulmonary vasculature are not well-understood at present.
Based on a mass spectrometry-based plasma proteomics approach, our new data show that 2-microglobulin
(B2M) is present at higher levels in patients with PH-HFpEF. Both circulating and skeletal muscle levels of B2M
are markedly increased in mice with skeletal muscle SIRT3 deficiency. Plasma and muscle biopsies from a
validation cohort of PH-HFpEF patients also show higher B2M levels with increased disease severity.
Treatment with B2M recombinant protein reduces expression of WW domain-containing oxidoreductase
(WWOX), which plays a role in repressing cell proliferation, in PASMCs. B2M treatment also increases
expression of canopy fibroblast growth factor signaling regulator 2 (CNPY2), an unfolded protein response
(UPR) initiator known to induce excessive angiogenesis and proliferation, in PAECs. While B2M treatment
increases PAECs migration/proliferation and media conditioned by CNPY2-overexpressed PAECs reduces
WWOX in PASMCs, the role of PAECs CNPY2 in PH-HFpEF remains elusive. Thus, we hypothesize that
skeletal muscle-secreted B2M acts as an endocrine signaling molecule which induces remote pulmonary
vascular remodeling via dysregulating PAECs CNPY2 and PASMCs WWOX.
Specific Aim 1 will determine whether skeletal muscle B2M is an important signaling molecule affecting multiple
pulmonary vascular pathophenotypes. Using wild-type and skeletal muscle-specific B2m KO mice, with or
without high-fat feeding (HFD), which induces a PH-HFpEF phenotype, we will characterize the contribution of
skeletal muscle B2M in PH-HFpEF. In Aim 2, we will determine the role of PAECs CNPY2 in pulmonary vascular
remodeling and PH-HFpEF with EC-specific Cnpy2 KO mice. Specific Aim 3 will use plasma and muscle
biopsies of patients with PH-HFpEF or HFpEF alone collected from biobanks and Phase II clinical trials to
evaluate whether B2M can be a relevant biomarker of PH-HFpEF severity and prognosis. Inducible pluripotent
stem cell (iPSC)-derived ECs of PH-HFpEF patients will also be used to evaluate clinical relevance of CNPY2.
We expect that successful execution of the proposed research plan would provide new mechanistic
understanding of PH-HFpEF pathogenesis and aid in providing important information to guide future research
towards development of t...

## Key facts

- **NIH application ID:** 10876896
- **Project number:** 5R01HL142638-07
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Yen Chun Charly Lai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $698,611
- **Award type:** 5
- **Project period:** 2018-08-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10876896

## Citation

> US National Institutes of Health, RePORTER application 10876896, Role of Skeletal Muscle in Pulmonary Vascular Remodeling (5R01HL142638-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10876896. Licensed CC0.

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