Abstract
Hypercapnia, elevated carbon dioxide (CO2), is common in advanced chronic obstructive pulmonary disease (COPD) and predicts poor clinical outcomes. Traditionally considered a consequence of disease severity, hypercapnia may drive disease progression by promoting airway dysfunction. Here, we show that hypercapnia acts as an active stressor, driving airway smooth muscle (ASM) constriction through a stromal interaction molecule 1 (STIM1)-dependent pathway. Hypercapnia rapidly activates ERK, triggering sarcoplasmic reticulum calcium (Ca2+) release via phosphorylation of the inositol 1,4,5-trisphosphate receptor. ERK also induces nuclear translocation of the transcription factor c-Fos, enhancing STIM1 transcription. These responses were observed under both supraphysiological (~120 mmHg) and clinically relevant (50-60 mmHg) hypercapnia. Increased STIM1 abundance sustains store-operated Ca2+ entry (SOCE), amplifying ASM signaling. In mice, hypercapnia increased ASM and airway contractility in a STIM1-dependent manner. Human genetic analyses revealed noncoding STIM1 variants associated with reduced lung expression that were enriched in COPD patients. These variants correlated with lower airway resistance under normocapnia; however, this benefit was lost during hypercapnia, indicating a potential gene–environment interaction. Together, our findings position STIM1 as a key mechanistic node linking hypercapnia to Ca2+ dysregulation and airway obstruction, defining a CO2–ERK–STIM1–SOCE axis with translational relevance to chronic lung disease.
Authors
Masahiko Shigemura, Vitalii Kryvenko, Jennifer A. Pacheco, Megan J. Puckelwartz, Milos Aleksic, Natalia D. Magnani, Emma E. Thompson, Francisco Javier Martin-Romero, Eoin P. Cummins, Werner Seeger, Andreas Bräuninger, Lynn C. Welch, G.R. Scott Budinger, Emilia Lecuona, Laura A. Dada, Ankit Bharat, István Vadász, Murali Prakriya, Jacob I. Sznajder
