Cellular shortening and calcium dynamics are improved by noisy stimulus in a model of cardiomyopathy.

Noise is present in cell biology. The capability of cells to respond to noisy environment have become essential. This study aimed to investigate whether noise can enhance the contractile response and Ca2+ handling in cardiomyocytes from a cardiomyopathy model. Experiments were conducted in an experimental setup with Gaussian white noise, frequency, and amplitude control to stimulate myocytes. Cell shortening, maximal shortening velocity, time to peak shortening, and time to half relaxation variables were recorded to cell shortening. Ca2+ transient amplitude and raise rate variables were registered to measure Ca2+ transients. Our results for cell shortening, Ca2+ transient amplitude, and raise rate suggest that cell response improve when myocytes are noise stimulated. Also, cell shortening, maximal shortening velocity, Ca2+ transient amplitude, and raise improves in control cells. Altogether, these findings suggest novel characteristics in how cells improve their response in a noisy environment.

Subchronic co-exposure to particulate matter and fructose-rich-diet induces insulin resistance in male Sprague Dawley rats.

Insulin resistance (IR) and metabolic disorders are non-pulmonary adverse effects induced by fine particulate matter (PM2.5) exposure. The worldwide pandemic of high fructose sweeteners and fat rich modern diets, also contribute to IR development. We investigated some of the underlying effects of IR, altered biochemical insulin action and Insulin/AKT pathway biomarkers. Male Sprague Dawley rats were subchronically exposed to filtered air, PM2.5, a fructose rich diet (FRD), or PM2.5 + FRD. Exposure to PM2.5 or FRD alone did not induce metabolic changes. However, PM2.5 + FRD induced leptin release, systemic hyperinsulinemia, and Insulin/AKT dysregulation in insulin-sensitive tissues preceded by altered AT1R levels. Histological damage and increased HOMA-IR were also observed from PM2.5 + FRD co-exposure. Our results indicate that the concomitant exposure to a ubiquitous environmental pollutant, such as PM2.5, and a metabolic disease risk factor, a FRD, can contribute to the metabolic disorder pandemic occurring in highly polluted locations.

PM2.5 induces airway hyperresponsiveness and inflammation via the AhR pathway in a sensitized Guinea pig asthma-like model.

Exposure to fine particulate matter (PM2.5) induces airway inflammation and hyperreactivity that lead to asthma. The mechanisms involved are still under investigation. We investigated the effect of resveratrol (3,4',5-trihydroxystilbene) (RES) on airway hyperresponsiveness, inflammation and CYP1A1 protein expression (an aryl hydrocarbon receptor (AhR) target) induced by PM2.5 exposure in an allergic asthma experimental guinea pig model. The polyphenolic compound RES was used due to its antioxidant and anti-inflammatory properties and as an antagonist of the AhR; thus, providing mechanistic insights. Animals were sensitized with aluminum hydroxide and ovalbumin and exposed to filtered air or PM2.5. Exposure to PM2.5 was conducted using a whole-body chamber particle concentrator (5 h/day) for 15 days. Animals received saline solution or RES (10 mg/kg per day) orally for 21 days simultaneously to the OVA challenge or PM2.5 exposure. PM2.5 exposure (mean 433 ± 111 µg/m3 in the exposure chamber) in OVA challenged animals induced an asthma-like phenotype characterized by increased baseline lung resistance (Rrs) and central airway resistance (Rn) in response to acetylcholine (ACh) evaluated using a flexiVent system®. A parallel increase of pro-inflammatory cytokines (IL-6, IL-17, TNF-α and IFN-γ), inflammatory cells (eosinophils and neutrophils) in bronchoalveolar lavage fluid (BALF) and lung CYP1A1 increase also occurred. RES significantly inhibited airway hyperresponsiveness, inflammation, and CYP1A1 protein expression in the OVA-challenged PM2.5 exposed animals. In summary, with the use of RES we demonstrate that PM-induced airway hyperreactivity is modulated by the inflammatory response via the AhR pathway in an allergic asthma guinea pig model.

In vitro exposure to ambient fine and ultrafine particles alters dopamine uptake and release, and D2 receptor affinity and signaling.

The exposure to environmental pollutants, such as fine and ultrafine particles (FP and UFP), has been associated with increased risk for Parkinson's disease, depression and schizophrenia, disorders related to altered dopaminergic transmission. The striatum, a neuronal nucleus with extensive dopaminergic afferents, is a target site for particle toxicity, which results in oxidative stress, inflammation, astrocyte activation and modifications in dopamine content and D2 receptor (D2R) density. In this study we assessed the in vitro effect of the exposure to FP and UFP on dopaminergic transmission, by evaluating [3H]-dopamine uptake and release by rat striatal isolated nerve terminals (synaptosomes), as well as modifications in the affinity and signaling of native and cloned D2Rs. FP and UFP collected from the air of Mexico City inhibited [3H]-dopamine uptake and increased depolarization-evoked [3H]-dopamine release in striatal synaptosomes. FP and UFP also enhanced D2R affinity for dopamine in membranes from either rat striatum or CHO-K1 cells transfected with the long isoform of the human D2R (hD2LR)2LR). In CHO-K1-hD2L In CHO-K1-hD2LR cells or striatal slices, FP and UFP increased the potency of dopamine or the D2R agonist quinpirole, respectively, to inhibit forskolin-induced cAMP formation. The effects were concentration-dependent, with UFP being more potent than FP. These results indicate that FP and UFP directly affect dopaminergic transmission.

In utero exposure to ultrafine particles promotes placental stress-induced programming of renin-angiotensin system-related elements in the offspring results in altered blood pressure in adult mice.

BACKGROUND: Exposure to particulate matter (PM) is associated with an adverse intrauterine environment, which can promote adult cardiovascular disease (CVD) risk. Ultrafine particles (UFP) (small size and large surface area/mass ratio) are systemically distributed, induce inflammation and oxidative stress, and have been associated with vascular endothelial dysfunction and arterial vasoconstriction, increasing hypertension risk. Placental stress and alterations in methylation of promoter regions of renin-angiotensin system (RAS)-related elements could be involved in UFP exposure-related programming of hypertension. We investigated whether in utero UFP exposure promotes placental stress by inflammation and oxidative stress, alterations in hydroxysteroid dehydrogenase 11b-type 2 (HSD11B2) and programming of RAS-related elements, and result in altered blood pressure in adult offspring. UFP were collected from ambient air using an aerosol concentrator and physicochemically characterized. Pregnant C57BL/6J pun/pun female mice were exposed to collected UFP (400 µg/kg accumulated dose) by intratracheal instillation and compared to control (nonexposed) and sterile H2O (vehicle) exposed mice. Embryo reabsorption and placental stress by measurement of the uterus, placental and fetal weights, dam serum and fetal cortisol, placental HSD11B2 DNA methylation and protein levels, were evaluated. Polycyclic aromatic hydrocarbon (PAH) biotransformation (CYP1A1 and NQO1 (NAD(P)H dehydrogenase (quinone)1)) enzymes, inflammation and oxidative stress in placentas and fetuses were measured. Postnatal day (PND) 50 in male offspring blood pressure was measured. Methylation and protein expression of (RAS)-related elements, angiotensin II receptor type 1 (AT1R) and angiotensin I-converting enzyme (ACE) in fetuses and lungs of PND 50 male offspring were also assessed. RESULTS: In utero UFP exposure induced placental stress as indicated by an increase in embryo reabsorption, decreases in the uterus, placental, and fetal weights, and HSD11B2 hypermethylation and protein downregulation. In utero UFP exposure induced increases in the PAH-biotransforming enzymes, intrauterine oxidative damage and inflammation and stimulated programming and activation of AT1R and ACE, which resulted in increased blood pressure in the PND 50 male offspring. CONCLUSIONS: In utero UFP exposure promotes placental stress through inflammation and oxidative stress, and programs RAS-related elements that result in altered blood pressure in the offspring. Exposure to UFP during fetal development could influence susceptibility to CVD in adulthood.