Regulatory role of Uncoupling Protein 2 (UCP2) in a rat model of chronic tobacco smoke-induced cardiopulmonary comorbidity

Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a progressive inflammatory condition characterized by airway obstruction and emphysema. In Hungary, the disease affects ~400,000–500,000 people, while in Europe, it affects 36 million, with a 24% five-year mortality rate often driven by cardiovascular complications. This study evaluated the role of Uncoupling Protein 2 (UCP2) in a translationally relevant rat model of chronic tobacco smoke-induced cardiopulmonary comorbidity. UCP2, in the inner mitochondrial membrane, regulates reactive oxygen species (ROS) and provides cardioprotective effects.

Methods

Wild-type and UCP2 gene-deficient (KO) rats (n=3–8/group) were used. Smoke-exposed groups were subjected to tobacco smoke 4x30 minutes daily, 5 days/week, over 6 months. Monitoring included longitudinal in vivo echocardiography, plethysmography for respiratory function, and high-resolution micro-CT. Statistical analysis focused on effect size using Hedges’ g, where values > 0.8 were considered significant.

Results

UCP2 absence significantly altered cardiac and pulmonary pathology progression. Regarding body weight, KO animals showed a persistent growth lag under smoke exposure. Cardiological assessments revealed that UCP2 deficiency leads to spontaneous right heart dysfunction even in intact animals. Following smoke exposure, KO rats exhibited more severe ventricular impairments compared to wild-type controls. Ejection fraction (EF%) and tricuspid annular plane systolic excursion (TAPSE) both showed a marked decline in the smoke-exposed KO group (Hedges’ g > 0.8) at 6 months. Specifically, posterior wall (PW) thickness was significantly reduced in smoke-exposed KO animals, indicating advanced structural remodeling.

Respiratory function analysis showed a transient but significant impairment at the 4-month peak (Hedges’ g > 0.8), potentially signaling the height of the inflammatory response. Micro-CT imaging revealed a significantly decreased volume of aerated lung area following smoke exposure in KO animals. Interestingly, while this deficiency exacerbated cardiac dysfunction, it appeared to inhibit classical emphysema development, suggesting a shift toward a more fibrotic pulmonary phenotype requiring further quantification.

Conclusion

UCP2 plays a complex regulatory role in cardiopulmonary comorbidities. Its absence predisposes the heart to spontaneous dysfunction and increases vulnerability to chronic tobacco smoke-induced damage. These findings suggest that mitochondrial UCP2 pathways are critical for cardiovascular preservation in chronic respiratory diseases and may serve as future therapeutic targets.EF_TAPSE_ECHOPW_LVEDv_ECHO