Abstract 5559: Lack of Sequestosome1 Accelerates Neointimal Hyperplasia and Carotid Artery Remodeling

Abstract

The cytoplasmic signal adaptor protein designated sequestosome1 (SQSTM1) (A170 in mouse, ZIP in rat or p62 in human) plays a key role in modulating signal transduction via membrane receptors. SQSTM1 has a UBA ubiquitin-binding domain in the C-terminus and participates in the assembly of ubiquitinated protein aggregates termed sequestosome and modulation of ubiquitination pathways involved in NF- κ B activity and receptor trafficking. We have found that deficiency of SQSTM1 in mice exhibits mature-onset obesity accompanied by insulin and leptin resistance. We previously established that redox sensitive transcription factor Nrf2 upregulates SQSTM1 expression in response to atherogenic stimuli or laminar shear stress in vascular cells, and here examine role of SQSTM1 in neointimal hyperplasia and vascular remodeling in vivo following carotid artery ligation. Neointimal hyperplasia was markedly enhanced at proximal sites of ligation after 3 weeks in SQSTM1−/− (n=10) compared with wild type mice (n=10). The intimal area and stenotic ratio were 2.1- and 1.7-fold higher in SQSTM1−/− mice, respectively, indicating enhanced proliferation of vascular smooth muscle cells (SMCs). When aortic SMCs were isolated from wild type and SQSTM1−/− mice and cultured in vitro, we found that SQSTM1−/− SMCs proliferated more rapidly in response to fetal calf serum (FCS) and attained 2–3-fold higher cell densities compared to wild type SMCs. Moreover, FCS caused a rapid transient down regulation of SQSTM1 in wild type SMCs. Early and late phases of p38MAPK activation in response to FCS stimulation were more enhanced in SQSTM1−/− SMCs, and inhibitors of p38 and ERK1/2 signaling pathways significantly attenuated SMCs proliferation. In summary, SQSTM1−/− mice exhibit enhanced neointimal hyperplasia and vascular remodeling following arterial ligation in vivo. The enhanced proliferation of SQSTM1−/− aortic SMCs in vitro highlights a novel role for SQSTM1 in suppressing smooth muscle proliferation following vascular injury.