HDAC6 regulates calpain activation in airway and pulmonary vascular remodeling in COPD

Airway and pulmonary vascular remodeling are important pathological features of chronic obstructive pulmonary disease (COPD), which leads to airflow obstruction and development of pulmonary hypertension. Exposure to cigarette smoke and common mediators in COPD including platelet-derived growth factor (PDGF) and inflammatory cytokines (e.g., interleukin-6, IL-6) contribute to the remodeling of airways and pulmonary vessel walls. We found that cigarette smoke extract (CSE) and mediators of COPD (PDGF and IL6) activate histone deacetylase 6 (HDAC6) and calpain in bronchial and pulmonary artery smooth muscle cells (BSMCs and PASMCs). We have reported that calpain mediates collagen synthesis, cell proliferation, and migration of PASMCs and plays an important role in hypoxia- and monocrotaline (MCT)-induced pulmonary vascular remodeling in PAH. However, no prior studies have investigated the role of HDAC6/calpain signaling in the pathogenesis of COPD. We will test the hypothesis that calpain is activated via HDAC6-mediated deacetylation in airway and pulmonary vascular remodeling of COPD. First, we will determine whether CSE and COPD mediators induce calpain activation and deacetylation via HDAC6 signaling pathway. We will study whether inhibition of HDAC6 prevents the CSE and COPD mediator-induced calpain activation and deacetylation. The lysine residue/s which is/are deacetylated by HDAC6 will be identified by using MALDI-TOF-TOF mass spectrometry and site-directed mutagenesis. Second, we will determine whether inhibition of HDAC6 activity prevents or attenuates airway and pulmonary vascular remodeling in animal models of CS-induced COPD. The proposed research is to answer the question whether CSE and COPD mediators (PDGF and IL-6) activate calpain through HDAC6-dependent deacetylation of calpain in BSMCs and PASMCs. This proposal for the first time identifies the HDAC6-deacetylated residues of calpain and demonstrates that HDAC6/calpain axis is critical common signal pathway for CSE and COPD mediators. The fundamental finding that HDAC6-mediated calpain deacetylation/activation lead to the development of airway and pulmonary vascular remodeling in COPD will provide a framework from which novel therapeutic strategies can be developed for intervention and treatment of CS-induced COPD. (AHA Program: Career Development Award)