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Metformin reduces air pollution-induced thrombosis

ABSTRACT: As our results suggested that metformin acts to limit mitochondrial ROS and calcium-mediated activation of IL-6, we reasoned it would likely affect other processes in alveolar macrophages triggered by exposure to particulate matter (PM). Therefore, we treated mice with metformin in the drinking water for 24 hours before we instilled PM intratracheally. We then flow-sorted alveolar macrophages from whole lung homogenates 24 hours later for transcriptomic analysis (RNA-Seq).

ORGANISM(S): Mus musculus

PROVIDER: GSE98731 | GEO | 2018/10/05

REPOSITORIES: GEO

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Project description:Zinc (Zn) is a major elemental component of respirable ambient particulate matter (PM) detected often at alarming levels in urban air. Exposure to PM has been widely associated with increased cardiovascular morbidity and mortality, however, it is not known what components or sources of PM are causative. We recently demonstrated that long-term episodic inhalation of combustion PM, having similar amount of Zn found in urban PM, caused myocardial lesions in rats. We further demonstrated that a single pulmonary exposure to Zn at high concentration is associated with disturbances in cardiac mitochondrial function, ion channel regulation, calcium homeostasis, and cell signaling. Therefore, in this study we investigated the role of PM-associated Zn in cardiac injury using multiple exposure scenarios. Male Wistar-Kyoto (WKY) rats of 12-14 wks age were intratracheally exposed (once per wk x 8 or16 wks) to either (1) saline (control); (2) PM having no soluble Zn; (3) combustion PM suspension containing 14.5 ug/mg water-soluble Zn at high and (4) low dose levels, (5) the aqueous fraction of this suspension devoid of solid insoluble particulate fraction (14.5 ug/mg soluble Zn), or (6) Zn sulfate. Zn concentrations were identical in groups 3, 5 and 6. Pulmonary toxicity was apparent in all exposure groups when compared to saline as determined by recovery of cells in bronchoalveolar lavage fluid. Long-term exposure to PM with or without soluble Zn, or Zn sulfate caused distinct myocardial lesions characterized by subepicardial and randomly distributed myocardial inflammation, degeneration, and fibrosis. The lesion severity was higher in those groups receiving Zn PM. Because cardiac mitochondria are likely the primary target of inhaled metal or other absorbed PM components, we analyzed mitochondrial DNA damage using QPCR and found that all exposure groups except those exposed to PM without Zn caused variable degree of damage. Aconitase activity, sensitive to inhibition by oxidative stress was inhibited slightly but significantly in rats receiving zinc sulfate. Although modest, microarray (Affymetrix) analysis revealed expression changes in the heart reflective of effects on cell signaling, inflammation/oxidative stress, mitochondrial fatty acid metabolisms and cell cycle regulation in rats exposed to zinc sulfate. However, these changes were minimal following exposure to PM devoid of soluble metals. We demonstrate that episodic subchronic pulmonary exposure to zinc sulfate causes cardiac injury and mitochondrial DNA damage. Thus, water-soluble PM-associated zinc may be one of the PM components responsible for cardiovascular morbidity. Keywords: Pulmonary exposure, Cardiac gene expression

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Metformin reduces air pollution-induced thrombosis

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