(883.2) The Role of Sex in the Effects of Cigarette Smoke in Vascular Smooth Muscle Cells

Poster Board Number: E293

Ann Centner (Florida State University)

Cigarette smoke (CS) damages the vasculature and causes atherosclerosis or arterial plaque build-up. While mechanistic differences in males and females likely exist, this area is largely unexplored. In fact, our lab observed that male atherosclerotic mice exposed to CS for 4 months had less severe plaque build-up than their female counterparts. Thus, we hypothesized that male cells had a protective mechanism against the adverse effects of CS.

To test our hypothesis and fill the gap in the literature, we treated male and female vascular smooth muscle cells (VSMCs) with cigarette smoke extract (CSE). Using increasing concentrations of CSE (10-50%), we observed that in female cells mortality increased significantly at 40% and 50% CSE, while in males’ significant mortality only occurred at 50% CSE. Female cells treated with CSE (30%) had higher levels of reactive oxygen species (ROS) and cellular senescence than male cells. Increased resistance of male cells to CSE correlated with a decrease in phosphorylated AKT, which drove an upregulation of endogenous antioxidants (catalase, superoxide dismutase 1 – SOD1) as well as levels of autophagy markers including Sequestosome 1/p62 (SQSTM1) and microtubule-associated protein light chain 3 II (LC3-II). This mechanism was not seen in female cells. Sqstm1-/- VSMCs express lower levels of catalase and SOD1, increased ROS levels and showed a higher mortality to CSE compared with wild type cells, suggesting that the upregulation of SQSTM1 is required for male cell’s protective effects. Differences in cellular and secreted ECM-regulators, metalloproteinases (MMPs), were also observed between sexes, suggesting that plaque stability is different between males and females exposed to CS. Altogether, these data show that intrinsic sex-dependent differences regulate the Akt/SQSTM1 pathway in response to CS and that SQSTM1 is a possible target to reduce the effects of CS in the cardiovascular system.