Recently, a research team led by Researcher Gong Jicheng and Professor Zhu Tong from the College of Environmental Sciences and Engineering at Peking University published groundbreaking findings in the internationally renowned journal Journal of the American College of Cardiology(JACC, 2023 impact factor: 21.7), titled "Associations of short-term ozone exposure with hypoxia and arterial stiffness." This study is the first in the world to reveal that short-term ozone exposure can mediate hypoxia response in the body, leading to a significant increase in arterial stiffness. This discovery provides an important theoretical basis for elucidating the pathogenic mechanisms by which ozone exposure induces cardiovascular damage.

Notably, the study not only established a novel pathway of "ozone exposure-hypoxia stress-arterial stiffness" (Figure 1) but also revealed regulatory mechanisms at the molecular level through multi-dimensional biomarker analysis. The same issue of JACC featured an editorial commentary titled "The Pathogenetic Link Between Ozone Pollution and Cardiovascular Disease."

Dr. Hua Qiaoyi, Dr. Meng Xin, and Dr. Chen Wu from the College of Environmental Sciences and Engineering at Peking University are the co-first authors of the paper. The research was supported by the Ministry of Science and Technology's Scientific Expedition to the Qinghai-Tibet Plateau and projects from the National Natural Science Foundation of China.

Figure 1. The "Ozone Exposure-Hypoxic Stress-Arterial Stiffness" Mechanistic Pathway

Research Background

Currently, the absence of a clearly established causal link between ozone exposure and cardiovascular outcomes leads to systematic biases in related disease burden assessments. This limitation stems primarily from two major academic bottlenecks: the biological effects of ozone exposure on the cardiovascular system, independent of other confounding factors, have not been fully elucidated, and there is a lack of molecular-level empirical support for its pathophysiological mechanisms. Although epidemiological studies have confirmed a dose-response relationship between ozone exposure and an increased risk of major cardiovascular events such as ischemic heart disease, stroke, heart failure, and atherosclerosis, the underlying pathogenic biological pathways have remained unclear. Notably, emerging evidence suggests that a hypoxic microenvironment may serve as a key pathological hub for ozone-related cardiovascular damage, providing a critical breakthrough for this research.

Based on this scientific background, this study innovatively proposes the core hypothesis that "ozone exposure induces cardiovascular damage by mediating hypoxic stress," and constructs a cascade reaction theoretical model of "ozone exposure - hypoxic stress - cardiovascular damage." To overcome the multi-pollutant confounding effects inherent in traditional environmental epidemiological studies, the research team specifically selected the Tibetan Plateau as a natural laboratory to validate this hypothesis. This region offers the unique advantages of combined high-altitude hypoxic conditions and significantly elevated ozone concentrations (average concentration 1.8 times that of plain areas), alongside very low background levels of traditional pollutants like fine particulate matter (annual average PM2.5 concentration < 15 μg/m³), providing an ideal setting for precisely analyzing the independent pathogenic effects of ozone exposure. The study employed a prospective panel design, integrating real-time personal exposure monitoring, dynamic vascular function assessments, and multi-omics methods to systematically reveal the spatiotemporal evolution of vascular endothelial dysfunction induced by ozone exposure.

Research Methods

This study included 210 healthy young residents from Linzhi and Lhasa on the Tibetan Plateau, who completed a total of 772 visits. During each follow-up visit, the participants' oxygen saturation, red blood cell count, hemoglobin concentration, hematocrit, and key gene and protein markers related to the hypoxia-inducible factor-1 (HIF-1) signaling pathway—the core pathway regulating the body's perception and adaptation to hypoxia—were measured. Linear mixed-effects models were used to assess the associations between ozone exposure and these hypoxia biomarkers.

Furthermore, this study used the gold standard for assessing arterial stiffness—carotid-femoral pulse wave velocity—as a surrogate endpoint indicator for cardiovascular damage, to further analyze the impact of ozone exposure on arterial stiffness. Mediation analysis was employed to explore the role of hypoxia biomarkers in the relationship between ozone exposure and arterial stiffness. Stratified analyses (e.g., by altitude difference) and sensitivity analyses (e.g., adjusting for co-pollutants like fine particulate matter and nitrogen dioxide) were conducted to verify the robustness of the findings.

Research Highlights

1. Unique Environment and Efficient Design

This study leveraged the unique environment of the Tibetan Plateau, characterized by high ozone and low particulate matter concentrations, to minimize co-pollutant interference and highlight the independent health effects of ozone exposure. Utilizing a panel study design, it provided a detailed analysis of the cardiovascular effects of short-term ozone exposure in 210 healthy young adults.

2. Revealing the Central Role of Hypoxia

Ozone exposure significantly reduced oxygen saturation (SpO₂) and was accompanied by increases in red blood cell count, hemoglobin concentration, and hematocrit. It also activated the key signaling pathway regulating the body's perception of hypoxia – the Hypoxia-Inducible Factor-1 (HIF-1) pathway. These findings indicate that ozone exposure induces systemic effects through hypoxic pathways.

3. Exacerbation of Arterial Stiffness

Short-term ozone exposure led to a significant increase in carotid-femoral Pulse Wave Velocity (cfPWV), indicating increased arterial stiffness. Further analysis revealed that changes in red blood cell-related indicators played a partial mediating role in ozone-induced arterial stiffness.

Research Implications and Future Directions

This study provides key scientific evidence for establishing a causal link between ozone exposure and cardiovascular health. Furthermore, by monitoring clinically accessible hypoxia biomarkers, such as oxygen saturation and red blood cell indices, early warning of related pathologies can be achieved. Additionally, interventions aimed at improving oxygen delivery, reducing blood viscosity, and modulating the HIF-1 signaling pathway may offer novel strategies for preventing cardiovascular diseases.

Future research should focus on validating the efficacy of these interventions and exploring variations in susceptibility across different populations to support the advancement of precision medicine.

Article Contributors: Qiaoyi Hua, Jicheng Gong, Tong Zhu

Supporting Institutions: College of Environmental Sciences and Engineering, Peking University; Institute of Tibetan Plateau Research

Funding Projects: Ministry of Science and Technology Scientific Expedition to the Tibetan Plateau; National Natural Science Foundation of China

Link to Original Article: https://www.sciencedirect.com/science/article/pii/S0735109724105591

Link to Companion Commentary:

https://www.sciencedirect.com/science/article/pii/S0735109724106584?fr=RR-2&ref=pdf_download&rr=9065a8604831e2ff