Up-Regulation of mRNA Ventricular PRNP Prion Protein Gene Expression in Air Pollution Highly Exposed Young Urbanites: Endoplasmic Reticulum Stress, Glucose Regulated Protein 78, and Nanosized Particles

Abstract

Mexico City Metropolitan Area children and young adults exposed to high concentrations of air pollutants including fine and ultrafine particulate matter (PM) vs. clean air controls, exhibit myocardial inflammation and inflammasome activation with a differential right and left ventricular expression of key inflammatory genes and inflammasomes. We investigated the mRNA expression levels of the prion protein gene PRNP, which plays an important role in the protection against oxidative stress and metal toxicity, and the glucose regulated protein 78, a key protein in endoplasmic reticulum (ER) stress signaling, in ventricular autopsy samples from 30 children and young adults age 19.97 ± 6.8 years with a lifetime of low (n:4) vs. high (n:26) air pollution exposures. Light microscopy and transmission electron microscopy studies were carried out in human ventricles, and electron microscopy studies were also done in 5 young, highly exposed Mexico City dogs. There was significant left ventricular PRNP and bi-ventricular GRP78 mRNA up-regulation in Mexico City young urbanites vs. controls. PRNP up-regulation in the left ventricle was significantly different from the right, p < 0.0001, and there was a strong left ventricular PRNP and GRP78 correlation (p = 0.0005). Marked abnormalities in capillary endothelial cells, numerous nanosized particles in myocardial ER and in abnormal mitochondria characterized the highly exposed ventricles. Early and sustained cardiac ER stress could result in detrimental irreversible consequences in urban children, and while highly complex systems maintain myocardial homeostasis, failure to compensate for chronic myocardial inflammation, oxidative and ER stress, and particles damaging myocardial organelles may prime the development of pathophysiological cardiovascular states in young urbanites. Nanosized PM could play a key cardiac myocyte toxicity role.

Combustion- and friction-derived magnetic air pollution nanoparticles in human hearts

“…To determine the mRNA expression of PrP C and GRP78, total RNA was extracted from the 72 heart samples using Trizol Reagent (InVitrogen Corp) (Villarreal-Calderon et al, 2013).…”

“…The roadside Fe-rich NPs exhibit primary particle sizes ranging from < 10 to > 100 nm (Sanderson et al, 2016). These Fe-rich, traffic-derived CFDNPs display a range of undesirable characteristics including surface charge, high redox activity, association with transition metals and carcinogenic organic compounds, and strongly magnetic behavior, all likely to activate critical pathways for cellular and organ damage, including the heart and brain (Maher et al, 2016;Villarreal-Calderon et al, 2012a,2013 Calderón- Garcidueñas et al, 2018). Our previous studies have identified magnetic CFDNPs in the brains of Metropolitan Mexico City (MMC) residents of all ages (Maher et al, 2016) concomitant with Alzheimer's pathology starting at age 11 months (Calderón- Garcidueñas et al, 2018).…”

“…PrP C has a key role in the protective adaptive response against oxidative stress, as suggested by the increased PrP C expression post-ischemic reperfusion (Zanetti et al, 2014). We investigated PrP C in the myocardium of young residents, given its role in countering oxidative stress and hence in 'cardioprotection' (Villarreal-Calderon et al, 2013;Zanetti et al, 2014).…”

Iron-rich air pollution nanoparticles: An unrecognised environmental risk factor for myocardial mitochondrial dysfunction and cardiac oxidative stress

“…Indeed, chronic and acute increases in myocardial mitochondrial ROS production can lead to a catastrophic cycle of mitochondrial DNA damage, functional decline, and further oxygen radical generation (Manickam et al, 2017;Nemmar et al, 2016;Tsutsui et al, 2006). Resultant cellular injury can include myocyte hypertrophy, endothelial dysfunction, apoptosis, and thrombosis (Tsutsui et al, 2006), and progressive modification of myocardial gene responses to oxidative and endoplasmic reticulum stress (Manickam et al, 2017;Villarreal-Calderon et al, 2013). Thus, irondriven myocardial mitochondrial dysfunction and uncontrolled ROS production can play a major role in initiation and progression of cardiovascular disease.…”

Diesel Exhaust Particles Induce Impairment of Vascular and Cardiac Homeostasis in Mice: Ameliorative Effect of Emodin

“…Epidemiological studies reported that particulate air pollution not only has impact on the respiratory tract, but it has systemic and cardiovascular effects as well [1][2][3]. Acute exposure to particulate air pollution has been linked to a range of adverse cardiovascular events including hospital admissions with angina, myocardial infarction, and heart failure [4,5].…”