Suppression of NADPH oxidase 4 inhibits PM-induced cardiac fibrosis through ROS-P38 MAPK pathway.

Fine particulate matter (PM) has been consistently linked to cardiovascular diseases, and cardiac fibrosis plays a crucial role in the occurrence and development of heart diseases. It is reported that NOX4-dependent redox signaling are responsible for TGFβ-mediated profibrotic responses. The current study was designed to explore the possible mechanisms of cardiac fibrosis by PM both in vitro and in vivo. Female C57BL/6 mice received PM (3 mg/kg b.w.) exposure with/without NOX4 inhibitor (apocynin, 25 mg/kg b.w.) or ROS scavenger (NALC, 50 mg/kg b.w.), every other day, for 4 weeks. H9C2 cells were incubated with PM (3 μg/mL) with/without 5 mM NALC, TGFβ inhibitor (SB431542, 10 μM), or siRNA-NOX4 for 24 h. The results demonstrated that PM induced evident collagen deposition and elevated expression of fibrosis biomarkers (Col1a1 & Col3a1). Significant systemic inflammatory response and cardiac oxidative stress were triggered by PM. PM increased the protein expression of TGFβ1, NOX4, and P38 MAPK. Notably, the increased effects of PM could be suppressed by SB431542, siRNA-NOX4 in vitro or apocynin in vivo, and NALC. The reverse verification experiments further supported the involvement of the TGFβ/NOX4/ROS/P38 MAPK signaling pathway in the myocardial fibrosis induced by PM. In summary, the current study provided evidence that PM challenge led to cardiac fibrosis through oxidative stress, systemic inflammation, and subsequent TGFβ/NOX4/ROS/P38 MAPK pathway and may offer new therapeutic targets in cardiac fibrosis.