Epigenetic Drivers of Pulmonary Hypertension: Environment Meets Genome

Our plain-English summary of Epigenetic Drivers of Pulmonary Hypertension: Environment Meets Genome, by W.N. Whitley, R.M. Millis (Curēus, 2026).

The study

• Authors: W.N. Whitley, R.M. Millis
• Journal: Curēus
• Published: 2026;18(2):e104241
• Type of article: Review
• Read it: PubMed · Publisher · Free full text

Abstract

Pulmonary hypertension (PH) is a progressive disease in which the pulmonary arteries thicken and narrow, raising pulmonary vascular resistance (PVR) and eventually straining the right ventricle. Known gene mutations explain only a minority of cases and often do not account for why the disease starts, worsens, or varies so widely between patients. Growing evidence suggests that epigenetic changes, chemical marks on DNA and its packaging that alter how genes are used without changing the DNA sequence, help explain this gap. These changes, including DNA methylation, histone modification, and non-coding RNAs, can be triggered by common exposures and disease states, and they can produce lasting shifts in vascular, immune, and metabolic pathways. This narrative review synthesizes current data showing how intrinsic stresses (mitochondrial dysfunction, oxidative stress, and cancer-like metabolic reprogramming) interact with extrinsic and often modifiable factors. Obesity, cigarette smoke, asbestos exposure, chronic hypoxia, and systemic inflammation drive PH through epigenetic reprogramming. We highlight major molecular hubs implicated across studies, including bone morphogenetic factor receptor 2 (BMPR2), NOTCH3, endothelin-1 (ET-1), transforming growth factor‑β (TGF-β), interleukin‑6 (IL-6), and CCL5, and we summarize emerging therapeutic approaches aimed at epigenetic regulators and microRNA networks. This narrative review was not conducted under Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and does not constitute a formal systematic review. The information in this review provides a practical framework for clinicians and researchers to improve risk assessments, to employ biomarkers, and to develop therapies that go beyond vasodilation to address upstream drivers of pulmonary arterial remodeling. This framework may also serve as a model for other difficult-to-treat diseases in which incomplete genetic explanations and limited attention to environmental exposures have slowed progress in prevention, early detection, and personalized treatment.

Copyright © 2026, Whitley et al.

In plain English

This was a narrative review, not a systematic review, of research on how epigenetic changes may link genes and environment in pulmonary hypertension. Epigenetic changes are chemical marks that alter how genes are used without changing the DNA sequence. Pulmonary hypertension is a disease in which the lung arteries thicken and narrow. The authors searched PubMed/MEDLINE, Scopus and Google Scholar through December 2025, expanding the search to January 2026 for clarifications. They discussed obesity, cigarette smoke, asbestos, high-altitude low oxygen and chronic inflammation. The authors stated that asbestos is a risk factor for pulmonary hypertension. They described inhaled fibers persisting in the lung and causing chronic inflammation, citing a study of NLRP3 inflammasome activation in immune cells. This inflammation can lead to lung fibrosis, low oxygen and blood vessel remodeling. They noted that asbestos remains in UK buildings despite a 1999 ban. The asbestos section named no fiber type and gave no patient numbers. The authors concluded that genetic susceptibility and environmental stressors converge through epigenetic changes. They noted that most of the evidence came from pulmonary arterial hypertension.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published literature (not a systematic review or meta-analysis)
• Who was studied: Published studies found by searches of PubMed/MEDLINE, Scopus and Google Scholar through December 2025, expanded to January 2026 for clarifications; no new patients or animals were studied
• Exposure: Extrinsic factors reviewed: obesity, cigarette smoke, asbestos, chronic high-altitude hypoxia and chronic inflammation. For asbestos the article discussed inhaled asbestos fibers generally, mentioning construction work, asbestos removal or maintenance, and older housing. No fiber type was named in the text.
• Main results:
  • The authors stated that asbestos exposure is a risk factor for pulmonary hypertension and suggested that people working in construction or living in older housing could be identified as higher-risk groups.
  • The authors noted that asbestos still exists in a significant proportion of UK infrastructure despite the 1999 UK ban.
  • Citing another study, the authors described asbestos activating the NLRP3 inflammasome in macrophages, leading to the pro-inflammatory cytokines IL-1β and IL-18 and sustained lung inflammation.
  • The authors described asbestos-induced chronic inflammation leading to pulmonary fibrosis and low blood oxygen. They wrote that prolonged low oxygen in areas of the lung can lead to cardiac and vascular remodeling that induces pulmonary hypertension.
  • In the review's summary table, the asbestos row listed chronic inflammation from inhaled asbestos fibers as the mechanism, with NLRP3 inflammasome activation and DNA methylation as key epigenetic changes.
  • For cigarette smoke, the review described a study in which smoke exposure increased levels of the DNA-methylating protein DNMT1, and linked smoke to hypermethylation and reduced expression of RASEF.
  • For high-altitude hypoxia, the review described a cited study reporting that the microRNAs miR-17, miR-21 and miR-190 were upregulated.
  • Citing another source, the review stated that downregulation of the BMPR2 gene is implicated in approximately 75% of hereditary pulmonary hypertension cases and 26% of idiopathic or immune-related cases.
• The authors' conclusion: The authors concluded that pulmonary hypertension is increasingly understood as a multi-hit disorder in which genetic susceptibility and environmental or metabolic stressors converge through epigenetic reprogramming. They suggested that future efforts may be guided by therapies aimed at epigenetic regulators combined with management of exposures, including mitigation of occupational toxins.
• Limitations the authors state:
  • The review was narrative and did not follow PRISMA guidelines for systematic reviews.
  • Although the review addressed pulmonary hypertension broadly, most of the mechanistic and epigenetic evidence came from pulmonary arterial hypertension (Group 1).

Topics

Medical terms in this study, explained in our Lexicon: Pulmonary Hypertension, Oxidative Stress, Asbestos Exposure, Hypoxia, Inflammation, Systematic Review, Biomarker, Environmental Exposure.

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