Abstract
PM2.5 is a well-known air pollutant threatening public health, and long-term exposure to PM2.5 increases the risk of cardiovascular diseases. Nrf2 plays a pivotal role in the amelioration of PM2.5-induced lung injury. However, if Nrf2 is involved in PM2.5-induced heart injury, and the underlying molecular mechanisms have not been explored. In this study, wild type (Nrf2+/+) and Nrf2 knockout (Nrf2-/-) mice were exposed to PM2.5 for 6 months. After PM2.5 exposure, Nrf2-/- mice developed severe physiological changes, lung injury and cardiac dysfunction. In the PM2.5-exposed hearts, Nrf2 deficiency caused significant collagen accumulation through promoting the expression of fibrosis-associated signals. Additionally, Nrf2-/- mice exhibited greater oxidative stress in cardiac tissues after PM2.5 exposure. Furthermore, PM2.5-induced inflammation in heart samples were accelerated in Nrf2-/- mice through promoting inhibitor of α/nuclear factor κB (IκBα/NF-κB) signaling pathways. We also found that Nrf2-/- aggravated autophagy initiation and glucose metabolism disorder in hearts of mice with PM2.5 challenge. Cardiac receptor-interacting protein kinase 3 (RIPK3) expression triggered by PM2.5 was further enhanced in mice with the loss of Nrf2. Collectively, these results suggested that strategies for enhancing Nrf2 could be used to treat PM2.5-induced cardiovascular diseases.
Highlights
Fine particulate matter 2.5 (PM2.5) is a collective term referring to atmospheric fine particles, which is regarded as one of the most essential air pollutants in many cities of China [1, 2]
Significant enhancements of blood glucose were observed in Nuclear factor erythroid 2-related factor 2 (Nrf2)+/+/PM2.5 mice compared to Nrf2+/+/filtered air (FA) group
Long term exposure of PM2.5 led to significant increases in the mean blood pressure (MBP) of Nrf2+/+ mice compared with Nrf2+/+/FA mice, which was further accelerated in PM2.5-exposed mice with Nrf2-/- (Figure 1C)
Summary
Fine particulate matter 2.5 (PM2.5) is a collective term referring to atmospheric fine particles, which is regarded as one of the most essential air pollutants in many cities of China [1, 2]. Upon exposure to stressors or inducers, the release of Nrf from Keap translocates into the nuclear to promote the expression of multiple cytoprotective genes, such as HO1, NAD(P)H: quinone oxidoreductase 1 (NQO1) and glutamate-cysteine ligase modifier (GCLM) [12, 13]. Nrf could modulate the expression of numerous anti-inflammatory and pro-fibrotic genes by antioxidant response elements in their promoters to neutralize free radicals and enhance removal of environmental toxins [14]. Our previous studies indicated that PM2.5-induced hypothalamus inflammation and renal injury were associated with the deregulation of Nrf signaling, which subsequently influenced inflammatory response both in vivo and in vitro [15, 16]. Prolonged PM2.5 exposure elevates risk of oxidative stress-driven nonalcoholic fatty liver disease partly through the irregular modulation of Nrf2 [17]. Considering the critical role of Nrf in regulating cardiovascular disease and PM2.5-induced tissue injuries, we hypothesized that Nrf might be involved in PM2.5-induced heart dysfunction and injury
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