The 2013 U.S. Surgeon General’s Report “How Tobacco Smoke Causes Diseases” identifies oxidative stress as one of the key mechanisms underlying all major smoking-related diseases1.
Oxidative stress results from imbalance between the levels of reactive oxygen species (ROS) and antioxidants. ROS and other reactive species act directly on cellular macromolecules damaging lipids, proteins and DNA.
Multiple lines of evidence suggest that ROS are key contributors to molecular signaling pathways underlying the development of atherosclerosis2,3 and play a central role in modifying most of the known main risk factors for CVD including hypertension, hypercholesterolemia, obesity, and diabetes4-7.
Key players of the oxidative stress response include the transcription factors AP-1, NF-KB and Nrf28.
In general, cells respond to oxidative stress by activation of the transcription factor Nrf-2 (encoded by the NFE2L2 gene), a key regulator of detoxification and antioxidant genes9. When expressed, the products of these genes then either act as quenchers to eliminate the oxidative insult or contribute to the regulation of downstream effectors that determine cell fate based on the extent of damage.
However, oxidative damage is also known to elicit a number of other cellular responses triggering various protein kinase signaling cascades, most notably those of the mitogen-activated protein kinase (MAPK) family, and resulting in proliferation, growth arrest, senescence or cell death, typically depending on the type of stressor and the duration and extent of stress10.