Gestational ozone inhalation elicits maternal cardiac dysfunction and transcriptional changes to placental pericytes and endothelial cells.

Ozone (O3) is a criteria air pollutant with the most frequent incidence of exceeding air quality standards. Inhalation of O3 is known to cause lung inflammation and consequent systemic health effects, including endothelial dysfunction. Epidemiologic data have shown that gestational exposure to air pollutants correlates with complications of pregnancy, including low birth weight, intrauterine growth deficiency, preeclampsia, and premature birth. Mechanisms underlying how air pollution may facilitate or exacerbate gestational complications remain poorly defined. The current study sought to uncover how gestational O3 exposure impacted maternal cardiovascular function, as well as the development of the placenta. Pregnant mice were exposed to 1PPM O3 or a sham filtered air (FA) exposure for 4 h on gestational day (GD) 10.5, and evaluated for cardiac function via echocardiography on GD18.5. Echocardiography revealed a significant reduction in maternal stroke volume and ejection fraction in maternally exposed dams. To examine the impact of maternal O3 exposure on the maternal-fetal interface, placentae were analyzed by single-cell RNA sequencing analysis. Mid-gestational O3 exposure led to significant differential expression of 4021 transcripts compared with controls, and pericytes displayed the greatest transcriptional modulation. Pathway analysis identified extracellular matrix organization to be significantly altered after the exposure, with the greatest modifications in trophoblasts, pericytes, and endothelial cells. This study provides insights into potential molecular processes during pregnancy that may be altered due to the inhalation of environmental toxicants.

Renin-angiotensin polymorphisms and QTc interval prolongation in end-stage renal disease.

BACKGROUND: Polymorphisms of renin-angiotensin system (RAS) genes in patients with end-stage renal disease (ESRD) on chronic hemodialysis may be associated with QTc interval prolongation, leading to fatal arrhythmias. The objective of this study was to determine (1) the prevalence of QTc prolongation in hemodialysis patients, and (2) the association of a prolonged QTc in these patients with RAS polymorphisms [angiotensin-converting enzyme-insertion/deletion (ACE-I/D), angiotensin type 1 receptor-A1166C (AT1R-A1166C), and angiotensinogen-M235T (AGT-M235T)]. METHODS: Twelve-lead electrocardiograms (ECGs), serum electrolytes (sodium, potassium, and calcium), and ACE and angiotensin II levels were obtained 10 to 12 hours after a hemodialysis session in 43 patients with ESRD on chronic hemodialysis [mean age (+/-SD), 55 +/- 14 years]. Using polymerase chain reaction (PCR), the presence of polymorphisms of the ACE-I/D, AT1R-A1166C, and AGT-M235T genes was determined from the buccal cells. A maximum QT interval in patients with sinus rhythm and normal QRS duration was corrected for heart rate using Hodges' formula. RESULTS: Fifty-eight percent of the patients had QTc interval prolongation (>440 msec). The ACE-DD genotype (P = 0.002) and the C allele of the AT1R-A1166C gene (P = 0.004), but not the AGT-M235T gene, contributed to QTc prolongation. CONCLUSION: Polymorphisms of ACE and AT1R genes additively contribute to QTc prolongation found in a great majority of ESRD patients. Therefore, ESRD patients with both or one of these polymorphisms may be at a higher risk for sudden cardiac death.

Tissue inhibitor of metalloproteinase-3 is associated with neuronal death in reperfusion injury.

Programmed cell death occurs in ischemia when cell surface death receptors (DRs) are stimulated by death-inducing ligands (DILs). Matrix metalloproteinases are extracellular matrix-degrading enzymes involved in the shedding of DRs and DILs from the cell surface. Tissue inhibitor of metalloproteinase-3 (TIMP-3), which is bound to the extracellular matrix, has been shown to promote apoptosis in cancer cell lines by inhibiting cell surface sheddases. Since apoptosis is an important mechanism of cell death in ischemia, the authors hypothesized that TIMP-3 would be expressed in ischemic neurons that are undergoing programmed cell death. Spontaneously hypertensive rats had a 90-minute middle cerebral artery occlusion with reperfusion. Transcription of TIMP-3 mRNA was measured by quantitative reverse transcription-polymerase chain reaction at 2, 6, 24 and 48 hours after reperfusion. Western blots were used to measure TIMP-3 protein expression. Spatial distribution and production of TIMP-3 was studied by immunohistochemistry at 3, 24, and 48 hours, 5 days, and 3 weeks. DNA fragmentation in cells dying by necrosis and apoptosis was identified with terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL). After 2 hours of reperfusion, TIMP-3 mRNA increased significantly in both ischemic and nonischemic hemispheres. Western blot analysis confirmed the identity of the TIMP-3, which appeared to be increased on the ischemic side. After 3 hours of reperfusion, TIMP-3 immunostaining was increased in neurons on the ischemic side, and by 24 hours the majority of the ischemic neurons were TIMP-3-positive. Dual-fluorescence staining for TUNEL and TIMP-3 showed that they were coexpressed in many neurons. The results suggest that ischemic neurons express TIMP-3, which may be inhibiting sheddases. The authors propose that TIMP-3 facilitates cell death in ischemic neurons. Further studies are needed to identify the sheddases inhibited by the TIMP-3, and on the effect of inhibition of matrix metalloproteinases on cell death mechanisms.