Right ventricular (RV) remodeling and dysfunction are serious cardiovascular consequences due to prolonged hypoxic exposure, commonly seen in conditions such as chronic lung disease and high-altitude environments. The associated pathological changes include structural changes in the RV, impaired cardiac function, and increased inflammation in cardiac tissues. Although previous studies have indicated that intense light exerts cardioprotective effects against ischemic injury by enhancing circadian pathways, its impact on hypoxia-induced RV injury and the underlying cellular mechanisms remain largely unexplored.

A recent Genes & Diseases study by researchers from the Army Medical University, Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Diseases, and Key Laboratory of Extreme Environmental Medicine utilized mouse models of chronic hypoxia to demonstrate that targeted intense light exposure not only significantly alleviates RV hypertrophy and fibrosis but also restores impaired cardiac function.

The authors divided the mice into groups exposed to either physiological normoxia or hypoxia, with or without intense light intervention. Functional assessments—including echocardiography, hemodynamic measurements, and the Fulton index (a measure of RV hypertrophy)—demonstrated that hypoxia caused marked RV dysfunction and structural remodeling. Conversely, intense light significantly attenuated these detrimental effects. Specifically, intense light improved RV systolic function, reduced ventricular hypertrophy, lowered pulmonary artery pressures, and decreased collagen deposition compared to hypoxic mice under normal light. These findings suggest a comprehensive mitigation of adverse remodeling processes.

To unravel the mechanisms underlying the beneficial effects, the authors examined cardiac inflammation at the single-cell level, revealing that hypoxia increased the number of macrophages in the right ventricle, shifted the immune environment toward a pro-inflammatory state, and accelerated the release of damaging cytokines such as TNF-α and IL-6. However, light exposure reprogrammed the macrophage landscape toward an anti-inflammatory, cardioprotective phenotype. These findings identify macrophage-mediated inflammation as a key contributor to remodeling and suggest that the therapeutic benefits of light stem from its capacity to "reprogram" the immune response within the cardiac tissue.

The authors identified that the expression of platelet factor 4 (PF4), a chemokine expressed by macrophages, was elevated during hypoxia but suppressed by intense light. PF4+ macrophages accumulated in the RV during hypoxia; statistical analysis confirmed a direct correlation between the abundance of these cells and the severity of heart dysfunction. Intense light intervention specifically suppressed PF4 gene expression and reduced the accumulation of resident macrophages (Res_Macro). Gene ontology analyses further showed that PF4+ resident macrophages are enriched in inflammatory processes that contribute to RV dysfunction. Together, these findings indicate that modulating PF4 and its macrophage subtypes is crucial for alleviating inflammation.

Advanced pseudo-temporal analysis demonstrated that macrophages underwent a dynamic transition toward a pro-inflammatory "fate" during hypoxia, and specific genes, including PF4, H2-Aa, and Cmss1, coordinated this cellular shift. This trajectory was reversed with intense light therapy, which guided resident macrophages away from inflammatory states and toward a more protective profile.

In conclusion, this study reveals intense light therapy as a novel, noninvasive approach that mitigates hypoxia-induced RV remodeling and dysfunction by suppressing macrophage-associated inflammation. The findings demonstrate that targeting PF4+ resident macrophages and their inflammatory pathways offers new avenues for treating hypoxia-related cardiac pathology.

Reference

Title of the original paper: Intense light mitigates hypoxia-induced right ventricular remodeling and dysfunction through reducing inflammation associated with PF4+ resident macrophages

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101867

Funding Information:

Chongqing Natural Science Foundation (China) (No. CSTB2024NSCQ-MSX0645)
Army Medical University Science and Technology Innovation Ability Promotion Special Program (China) (No. 2022XQN24)
Key Laboratory Project of Ministry of Education of China (No. PR-KL2022GY009, PR-KL2022GY008)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus CiteScore: 8.4 | Impact Factor: 9.4

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