Abstract 352: Unhealthy Diet and Air Pollution Induce Cardiovascular Dysfunction

Abstract

Cardiovascular diseases remain the dominant cause of deaths worldwide. Unhealthy diet and air pollution have each been described as risk factors for cardiovascular diseases. The molecular mechanisms involved in translating unhealthy diet and/or exposure to air pollution into cardiovascular dysfunctions remain yet to be identified. First, we investigated the impact of an unhealthy diet on disease-related signaling pathways in human primary cardiovascular cells. Based on nutrition health reports on diet composition in industrialized countries, we supplemented cell culture media of human primary endothelial cells (EC), smooth muscle cells (SMC) and cardiomyocytes (CM) with 100 mg/dl LDL and replaced 1/3 of the glucose with fructose. This treatment did not induce cell death in any of the cell types. However, we observed hypertrophy in CM, enhanced proliferation in SMC and increased senescence, loss of endothelial nitric oxide synthase (eNOS) and increased nuclear localization FoxO3A in EC. Based on several studies, which demonstrated that ultrafine particles can enter the circulation and thus directly interact with EC, we investigated the impact of ultrafine carbon black particles (ufCB), one of the major constituents of industrial and exhaust emissions, on human primary EC. Treatment with ufCB in non-toxic concentrations increased reactive oxygen species and dramatically reduced the S-NO content, a marker for NO-bioavailability. NO has been shown to increase the activation of Telomerase Reverse Transcriptase (TERT), which is required for proper endothelial cell function and is inactivated by the Src kinase under conditions of oxidative stress. ufCB significantly reduced Telomerase activity while increasing Src kinase activity. Subsequently, ufCB dramatically increased senescence of EC. To investigate whether ufCB effects also occur in vivo, we instilled ufCB in non-inflammatory concentrations into mice. Indeed, eNOS expression was reduced in the abdominal aorta of animals treated with ufCB. Taken together, common unhealthy diet as well as low-level air pollution, which we are exposed to permanently, seem to accelerate cardiovascular diseases.