Mechanism of nicotine inducing pulmonary arterial remodeling through upregulating connexin 43 to promote inflammatory response in PASMCs in mice

Objective To investigate the mechanism of the gap junction protein connexin 43 (Cx43) mediating the inflammatory response of pulmonary artery smooth muscle cells (PASMCs) in nicotine-induced pulmonary artery remodeling in mice.

Methods Thirty-two 5-week-old male C57BL/6J mice and Tagln-Cre(+); Cx43^flox/WT mice each were randomly divided into control group (sterile water for injection), 0.02 mg/(kg·d) nicotine group, 0.2 mg/(kg·d) nicotine, and 2.0 mg/(kg·d) nicotine group, with 8 mice in each group. The mice were treated through nasal drip according to body weight, once a day at a fixed time for continuous 8 weeks. After exposure, the mice were examined for pulmonary arterial remodeling with hematoxylin-eosin (HE) staining. The primary distal PASMCs of C57BL/6J mice and Tagln-Cre(+); Cx43^flox/WT mice were cultured by magnetic separation. The protein expression levels of Cx43, tumor necrosis factor-alpha, interleukin-1β, and interleukin-6 in mouse PASMCs were measured by Western blot.

Results Compared with C57BL/6J mice in the control group, C57BL/6J mice in the nicotine groups showed a generally increasing trend in body weight, and the body weight growth slowed down with the increase in nicotine concentrations; the distal pulmonary arteries showed typical pathological features of arterial remodeling including wall thickening and lumen narrowing; and the expression of Cx43 was up-regulated in a dose-dependent manner. Tagln-Cre(+); HE staining results of Cx43^flox/WT mice showed milder wall thickening and lumen narrowing of pulmonary arteries and lower expression levels of the inflammatory factors in PASMCs.

Conclusion Downregulating Cx43 can alleviate nicotine-induced inflammatory responses in distal PASMCs, thereby improving pulmonary arterial remodeling in mice.