HDAC6 Activates ERK in Airway and Pulmonary Vascular Remodeling of COPD.

Chronic obstructive pulmonary disease (COPD) is a multisystemic respiratory disease which is associated with progressive airway and pulmonary vascular remodeling due to the increased proliferation of bronchial and pulmonary arterial smooth muscle cells (BSMCs and PASMCs) and overproduction of extracellular matrix (ECM), e.g., collagen. Cigarette smoke (CS) and several mediators such as PDGF and IL-6 play critical role in the COPD pathogenesis. Histone deacetylase 6 (HDAC6) has been shown to be implicated in vascular remodeling. However, the HDAC6 signaling in airway and pulmonary vascular remodeling of COPD and the underlying mechanisms remain undetermined. Here we show that HDAC6 expression is upregulated in lungs of COPD patients and animal model. We also found that cigarette smoke extract (CSE), PDGF and IL-6 increase the protein levels and activation of HDAC6 in BSMCs and PASMCs. Furthermore, CSE and these stimulants induced deacetylation and phosphorylation of ERK1/2 and increased collagen synthesis and proliferation of BSMCs and PASMCs which were prevented by HDAC6 inhibition. Inhibition of ERK1/2 also diminished the CSE, PDGF and IL-6-caused elevation in collagen levels and cell proliferation. Pharmacological HDAC6 inhibition by tubastatin A prevented the CS-stimulated increases in the thickness of the bronchial and pulmonary arterial wall, airway resistance, emphysema as well as right ventricular (RV) systolic pressure (RVSP) and RV hypertrophy in rat model of COPD. These data demonstrate that the upregulated HDAC6 governs the collagen synthesis and proliferation of BSMCs and PASMCs leading to airway and vascular remodeling in COPD.