Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of mouse model of cardiac failure - particulate matter effect on mouse model of cardiac failure: lung and heart left ventricle

ABSTRACT: Particulate Matter Triggers Carotid Body Dysfunction, Respiratory Dysynchrony and Cardiac Arrhythmias in Mice with Cardiac Failure; The mechanistic link between human exposure to airborne particulate matter (PM) pollution and the increased cardiovascular morbidity and mortality observed in people with congestive heart failure (CHF) is unknown. We now show that exposure of genetically-engineered mice with CHF (expressing a cardiac-specific CREB mutant transcription factor) to ambient PM (collected in Baltimore, mean aerodynamic diameter 1.9 um) unmasks severe autonomic morbidities manifested as significant reductions in heart rate variability, respiratory dysynchrony and increased frequency of serious ventricular arrhythmias, features not observed in PM-challenged wild type mice without CHF. PM exposure in CREB mice with CHF reflexly triggers autonomic dysfunction via heightened carotid body function as evidenced by pronounced afferent nerve responses to hypoxia and marked depression of breathing by hyperoxia challenge. Genomic analyses of lung and ventricular tissues revealed PM-induced molecular signatures of inflammation and oxidative stress. These findings in a murine model of cardiac failure provide the first direct assessment of autonomic function in response to PM challenge and are highly consistent with current epidemiologic findings on cardiovascular morbidity in susceptible PM-exposed human populations. We utilized a murine model of dilated cardiomyopathy to address potential mechanistic links between PM exposure and the development of life-threatening cardiac dysrhythmias. Experiment Overall Design: four group (n=3) of animals were treated by PBS or particulate matter (20mg/kg 1.9Âµm particulate matter) in Wild type or CD-1 dominate negative mice

ORGANISM(S): Mus musculus

SUBMITTER: Yong Huang

PROVIDER: E-GEOD-17478 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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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Transcription profiling of mouse model of cardiac failure - particulate matter effect on mouse model of cardiac failure: lung and heart left ventricle

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