# LDHA-lactate signaling in pulmonary arterial hypertension

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $681,551

## Abstract

Pulmonary arterial hypertension (PAH), a progressive fatal disease, manifests by remodeling of pulmonary ar-
teries (PA), leading to increased PA pressure, right heart failure and death. The key component of PA remodeling
is the progressive vessel wall thickening due to hyper-proliferation of PA smooth muscle cells (PASMC), endo-
thelial cells (PAEC), and adventitial fibroblasts (PAAF) the mechanisms of which are not completely understood.
PASMC in PAH switch to unique disease-specific phenotype, characterized by metabolic shift to glycolysis, au-
tonomous proliferation, and apoptosis resistance. PAH pulmonary vascular cells are also highly secretory and
support pro-proliferative microenvironment, further amplifying PA remodeling and PAH. Published and our new
preliminary data strongly suggest that metabolite L-lactate acts as a central regulator of the molecular and met-
abolic processes responsible for pulmonary vascular cell hyper-proliferation, remodeling, and PAH. Our pilot
data show that lactate, over-produced by PAH PASMC due to over-expression of lactate dehydrogenase A
(LDHA), promotes aberrant lactylation of DNA topoisomerase 1 (TOP1) and EMILIN1, leading to TOP1 up-reg-
ulation and EMILIN1 deficiency, consequent up-regulation of pro-proliferative Akt-mTOR, Yap/Taz, TGFβ, in-
creased proliferation and survival. Our data also suggest that lactate over-production in PAH PASMC is self-
supported via glycolysis and EMILIN1-TGFβ1-HIF1α-LDHA circuit, and that lactate is secreted by PAH PASMC
and promotes proliferation of PA endothelial cells (PAEC) and adventitial fibroblasts (PAAF). We further report
that suppression of LDHA-lactate axis reduces proliferation and induces apoptosis in human PAH PASMC, re-
verses pulmonary vascular remodeling and experimental PH in mice. We propose to elucidate the role and
mechanisms of regulation and function of LDHA-lactate signaling in PAH pulmonary vasculature and explore the
benefits of targeting this pathway to correct mechanistic abnormalities and reverse PA remodeling and PH. Spe-
cifically, we will: (1) critically test the role of LDHA-lactate in PAH PASMC proliferation and survival, pulmonary
vascular remodeling and PH using human PAH and non-diseased PASMC and lung tissue samples and SM-
specific Ldhaknock-out mice; determine the relationship among LDHA-lactate, lactylation of TOP1 and EMILIN1,
and Yap/Taz, Akt-mTOR, and TGFβ1 in regulating PASMC proliferation and survival; (2) investigate whether
lactate over-production is supported through up-regulation of glycolysis and EMILIN-TGFβ1-HIF1α-LDHA feed-
forward loop, evaluate the metabolic consequences of lactate over-production, and determine the role of
PASMC-secreted lactate in the proliferation of PAEC and PAAF; and (3) examine whether targeting lactate sig-
naling by LDHA inhibitor oxamate and TOP1 inhibitor indotecan selectively inhibits proliferation and induces
apoptosis in vitro in human PAH PASMC, reverses or attenuates experimental pulmon...

## Key facts

- **NIH application ID:** 10827282
- **Project number:** 1R01HL172488-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Elena Goncharova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $681,551
- **Award type:** 1
- **Project period:** 2023-12-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10827282

## Citation

> US National Institutes of Health, RePORTER application 10827282, LDHA-lactate signaling in pulmonary arterial hypertension (1R01HL172488-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10827282. Licensed CC0.

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