Haiyan Tong

Publications of Haiyan Tong

• Omega-3 Fatty Acid Supplementation Appears to Attenuate Particulate Air Pollution Induced Cardiac Effects and Lipid Changes in Healthy Middle-Aged Adults.

  Authors: Haiyan Tong, Ana G Rappold, David Diaz-Sanchez, Susan E Steck, Jon Berntsen, Wayne E Cascio, Robert B Devlin, James M Samet

  Environmental health perspectives. 04/2012;

  Background: Air pollution exposure has been associated with adverse cardiovascular health effects. Findings of a recent epidemiologic study suggested that omega-3 fatty acid (fish oil)Background: Air pollution exposure has been associated with adverse cardiovascular health effects. Findings of a recent epidemiologic study suggested that omega-3 fatty acid (fish oil) supplementation blunted cardiac responses to air pollution exposure. Objectives: We conducted a randomized controlled exposure study to evaluate the efficacy of fish oil supplements in attenuating adverse cardiac effects of exposure to concentrated ambient fine and ultrafine particulate matter (CAP). Methods: Twenty-nine healthy middle-aged participants (mean age 58±1 yr) were supplemented in a randomized, double-blinded manner with 3g/day of either fish oil or olive oil for 4 weeks prior to sequential chamber exposure to filtered air and CAP (mean mass concentration 278±19 µg/m3) for 2 hrs. Cardiac responses were assessed by comparing time- and frequency-domain changes in heart rate variability (HRV) and electrocardiographic repolarization changes measured before, immediately after, and 20 hrs after exposure. Changes in plasma lipids were also evaluated at these time points. Results: Fish oil supplementation appeared to attenuate CAP-induced reductions in high-frequency/low-frequency ratio (HF/LF), as well as elevations in normalized LF (nLF) HRV, and prolongation of the QT interval corrected for heart rate (QTc). Very low-density lipoprotein and triglyceride concentrations increased significantly immediately after exposure to CAP in participants supplemented with olive oil, but not in those supplemented with fish oil. Conclusions: Exposure of healthy middle-aged adults to CAP for 2 hr induced acute cardiac and lipids changes following supplementation with olive oil, but not fish oil. Our findings suggest that omega-3 fatty acid supplements offer protection against the adverse cardiac and lipid effects associated with air pollution exposure.

• Differential cardiopulmonary effects of size-fractionated ambient particulate matter in mice.

  Authors: Haiyan Tong, Wan-Yun Cheng, James M Samet, M Ian Gilmour, Robert B Devlin

  Cardiovascular toxicology. 12/2010; 10(4):259-67.

  A growing body of evidence from epidemiological and toxicological studies provides a strong link between exposure to ambient particulate matter (PM) of varying size and increased cardiovascular andA growing body of evidence from epidemiological and toxicological studies provides a strong link between exposure to ambient particulate matter (PM) of varying size and increased cardiovascular and respiratory morbidity and mortality. This study was designed to evaluate the cardiopulmonary effects of ambient coarse, fine, and ultrafine particles collected in Chapel Hill, NC. Mice were exposed to each size fraction by oropharyngeal instillation. Twenty-four hours later, pulmonary inflammation was assessed by bronchoalveolar lavage and cardiac injury was measured using a Langendorff cardiac perfusion preparation. Recovery of post-ischemic left ventricular developed pressure and infarct size were measured as indeces of cardiac ischemia/reperfusion injury. Coronary flow rate was measured before, during, and after ischemia. We demonstrate that coarse PM caused the most significant pulmonary inflammatory responses. In contrast, hearts from ultrafine-exposed mice had significantly lower post-ischemic functional recovery and greater infarct size, while hearts from coarse and fine PM-exposed mice had no significant responses to ischemia/reperfusion. The coronary flow rate was significantly reduced in the ultrafine PM group. This study shows that exposure of mice to coarse PM results in significant pulmonary toxicity while ultrafine PM appears to enhance cardiac ischemia/reperfusion injury.

• Particle size-fraction analysis: gilmour et Al. Respond.

  Authors: M Ian Gilmour, Seung-Hyun Cho, Haiyan Tong, John K McGee, Q Todd Krantz, Richard W Baldauf

  Environmental health perspectives. 09/2010; 118(9):a380.

• An integrated imaging approach to the study of oxidative stress generation by mitochondrial dysfunction in living cells.

  Authors: Wan-Yun Cheng, Haiyan Tong, Evan W Miller, Christopher J Chang, James Remington, Robert M Zucker, Philip A Bromberg, James M Samet, Thomas P J Hofer

  Environmental health perspectives. 04/2010; 118(7):902-8.

  The mechanisms of action of many environmental agents commonly involve oxidative stress resulting from mitochondrial dysfunction. Zinc is a common environmental metallic contaminant that has beenThe mechanisms of action of many environmental agents commonly involve oxidative stress resulting from mitochondrial dysfunction. Zinc is a common environmental metallic contaminant that has been implicated in a variety of oxidant-dependent toxicological responses. Unlike ions of other transition metals such as iron, copper, and vanadium, Zn(2+) does not generate reactive oxygen species (ROS) through redox cycling. To characterize the role of oxidative stress in zinc-induced toxicity. We used an integrated imaging approach that employs the hydrogen peroxide (H2O2)-specific fluorophore Peroxy Green 1 (PG1), the mitochondrial potential sensor 5,5 ,6,6 -tetrachloro-1,1 ,3,3 -tetraethylbenzimidazolylcarbocyanine iodide (JC-1), and the mitochondria-targeted form of the redox-sensitive genetically encoded fluorophore MTroGFP1 in living cells. Zinc treatment in the presence of the Zn(2+) ionophore pyrithione of A431 skin carcinoma cells preloaded with the H(2)O(2)-specific indicator PG1 resulted in a significant increase in H(2)O(2) production that could be significantly inhibited with the mitochondrial inhibitor carbonyl cyanide 3-chlorophenylhydrazone. Mitochondria were further implicated as the source of zinc-induced H(2)O(2) formation by the observation that exposure to zinc caused a loss of mitochondrial membrane potential. Using MTroGFP1, we showed that zinc exposure of A431 cells induces a rapid loss of reducing redox potential in mitochondria. We also demonstrated that zinc exposure results in rapid swelling of mitochondria isolated from mouse hearts. Taken together, these findings show a disruption of mitochondrial integrity, H(2)O(2) formation, and a shift toward positive redox potential in cells exposed to zinc. These data demonstrate the utility of real-time, live-cell imaging to study the role of oxidative stress in toxicological responses.

• Comparative toxicity of size-fractionated airborne particulate matter collected at different distances from an urban highway.

  Authors: Seung-Hyun Cho, Haiyan Tong, John K McGee, Richard W Baldauf, Q Todd Krantz, M Ian Gilmour

  Environmental health perspectives. 11/2009; 117(11):1682-9.

  Epidemiologic studies have reported an association between proximity to highway traffic and increased cardiopulmonary illnesses. We investigated the effect of size-fractionated particulate matterEpidemiologic studies have reported an association between proximity to highway traffic and increased cardiopulmonary illnesses. We investigated the effect of size-fractionated particulate matter (PM), obtained at different distances from a highway, on acute cardiopulmonary toxicity in mice. We collected PM for 2 weeks in July-August 2006 using a three-stage (ultrafine, < 0.1 microm; fine, 0.1-2.5 microm; coarse, 2.5-10 microm) high-volume impactor at distances of 20 m [near road (NR)] and 275 m [far road (FR)] from an interstate highway in Raleigh, North Carolina. Samples were extracted in methanol, dried, diluted in saline, and then analyzed for chemical constituents. Female CD-1 mice received either 25 or 100 microg of each size fraction via oropharyngeal aspiration. At 4 and 18 hr postexposure, mice were assessed for pulmonary responsiveness to inhaled methacholine, biomarkers of lung injury and inflammation; ex vivo cardiac pathophysiology was assessed at 18 hr only. Overall chemical composition between NR and FR PM was similar, although NR samples comprised larger amounts of PM, endotoxin, and certain metals than did the FR samples. Each PM size fraction showed differences in ratios of major chemical classes. Both NR and FR coarse PM produced significant pulmonary inflammation irrespective of distance, whereas both NR and FR ultrafine PM induced cardiac ischemia-reperfusion injury. On a comparative mass basis, the coarse and ultrafine PM affected the lung and heart, respectively. We observed no significant differences in the overall toxicity end points and chemical makeup between the NR and FR PM. The results suggest that PM of different size-specific chemistry might be associated with different toxicologic mechanisms in cardiac and pulmonary tissues.

• The role of beta-adrenergic receptor signaling in cardioprotection.

  Authors: Haiyan Tong, Daniel Bernstein, Elizabeth Murphy, Charles Steenbergen

  The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 07/2005; 19(8):983-5.

  This study examines the role of the beta2-adrenergic receptor (beta2-AR) in cardioprotection. The beta2-AR couples to Gs and Gi proteins. Gs activates PKA, which phosphorylates the receptor andThis study examines the role of the beta2-adrenergic receptor (beta2-AR) in cardioprotection. The beta2-AR couples to Gs and Gi proteins. Gs activates PKA, which phosphorylates the receptor and switches beta2-AR coupling from Gs to Gi. Prior to 20 min of global ischemia, mouse hearts were either perfused for 30 min without treatment (control), treated with 10 nmol/L of isoproterenol (ISO) for 5 min followed by 5 min washout, or preconditioned with 4 cycles of 5 min ischemia and 5 min reflow (PC). Recovery of left ventricular developed pressure (LVDP) and infarct size were measured. Intermittent ISO treatment improved post-ischemic recovery of LVDP (58.5+/-4.8% vs. 22.0+/-6.3% in control) and reduced infarct size (31.0+/-2.4% vs. 53.0+/-4.6% in control). The Gi inhibitor pertussis toxin blocked the ISO-induced improvement in postischemic LVDP and infarct size. To test the role of beta2-AR in PC, we studied mice lacking beta2-AR (beta2-AR-/-) and found that PC had no effect on postischemic LVDP or infarct size in beta2-AR-/-. To test whether PKA is required for the PC and ISO-induced protection, hearts were treated with the PKA inhibitors PKI and H-89. We found that PKI and H-89 blocked the PC- and ISO-induced improvement in postischemic LVDP and infarct size. These data show an important role for beta2-AR in cardioprotection and support the novel hypothesis that preconditioning involves switching of beta2-AR coupling from Gs to Gi.

• G protein-coupled receptor internalization signaling is required for cardioprotection in ischemic preconditioning.

  Authors: Haiyan Tong, Howard A Rockman, Walter J Koch, Charles Steenbergen, Elizabeth Murphy

  Circulation research. 05/2004; 94(8):1133-41.

  The present study is designed to explore the role of G protein-coupled receptors (GPCRs) in the protection afforded by ischemic preconditioning (PC). We used TG mice with cardiac-specificThe present study is designed to explore the role of G protein-coupled receptors (GPCRs) in the protection afforded by ischemic preconditioning (PC). We used TG mice with cardiac-specific overexpression of a Gbetagamma-sequestering peptide, betaARKct (TG betaARKct mice), to test whether the protection of PC is Gbetagamma-dependent. To test the role of G(i) protein, we used wild-type mice pretreated with the G(i) inhibitor pertussis toxin. Recovery of left ventricular developed pressure and infarct size were measured as indices of protection. PC induced protection in wild-type mice, but this protection was blocked by pertussis toxin treatment and was also blocked in TG betaARKct mice. To determine the mechanism of Gbetagamma-induced protection in PC, we investigated one of the downstream targets of Gbetagamma, the PI3K/p70S6K pathway. PC-induced phosphorylation of p70S6K was not blocked in TG betaARKct hearts; therefore, we investigated other targets of Gbetagamma. Recent studies suggest a role for Gbetagamma in GPCR internalization. We found that betaARKct, a specific PI3K inhibitor wortmannin, and bafilomycin A1, which all block receptor recycling, all blocked the protective effect of PC. To additionally test whether PI3K is involved in PC-activated receptor internalization and endosomal signaling, we used TG mice with cardiac-specific overexpression of a catalytically inactive mutant PI3Kgamma, which disrupts the recruitment of functional PI3K to agonist-activated GPCRs in vivo. We found that the catalytically inactive mutant of PI3Kgamma blocks the protection of PC. In summary, these data suggest the novel finding that the cardioprotective effect of PC requires receptor internalization.

• Preconditioning: is the Akt-ion in the PI3K pathway?

  Authors: Elizabeth Murphy, Haiyan Tong, Charles Steenbergen

  Journal of molecular and cellular cardiology. 10/2003; 35(9):1021-5.

• Phosphorylation of glycogen synthase kinase-3beta during preconditioning through a phosphatidylinositol-3-kinase--dependent pathway is cardioprotective.

  Authors: Haiyan Tong, Kenichi Imahashi, Charles Steenbergen, Elizabeth Murphy

  Circulation research. 04/2002; 90(4):377-9.

  We previously reported that activation of phosphatidylinositol-3-kinase (PI3-kinase) is involved in ischemic preconditioning (PC). Our goal was to determine downstream targets of PI3-kinase. InWe previously reported that activation of phosphatidylinositol-3-kinase (PI3-kinase) is involved in ischemic preconditioning (PC). Our goal was to determine downstream targets of PI3-kinase. In perfused rat hearts, PC (4 cycles of 5 minutes of ischemia and 5 minutes of reflow) increased phosphorylation of glycogen synthase kinase-3beta (GSK-3beta), a downstream target of PI3-kinase and protein kinase B (PKB), an effect that was blocked by wortmannin. Because phosphorylation inactivates GSK-3beta, we examined whether PC-induced phosphorylation and inhibition of GSK-3beta is important in PC by using two inhibitors of GSK-3beta, lithium and SB 216763. Pretreatment of perfused rat hearts with lithium or SB 216763, before ischemia, mimicked the protective effects of PC; hearts treated with either lithium or SB 216763 had improved postischemic function and reduced infarct size. These findings indicate that inhibition of GSK-3beta is protective and that this PI3-kinase--dependent signaling pathway may play an important role in ischemic preconditioning.

• Influence of acid functionalization on the cardiopulmonary toxicity of carbon nanotubes and carbon black particles in mice

  Authors: Haiyan Tong, John K. McGee, Rajiv K. Saxena, Urmila P. Kodavanti, Robert B. Devlin, M. Ian Gilmour

  Toxicology and Applied Pharmacology.

  Engineered carbon nanotubes are being developed for a wide range of industrial and medical applications. Because of their unique properties, nanotubes can impose potentially toxic effects,Engineered carbon nanotubes are being developed for a wide range of industrial and medical applications. Because of their unique properties, nanotubes can impose potentially toxic effects, particularly if they have been modified to express functionally reactive chemical groups on their surface. The present study was designed to evaluate whether acid functionalization (AF) enhanced the cardiopulmonary toxicity of single-walled carbon nanotubes (SWCNT) as well as control carbon black particles. Mice were exposed by oropharyngeal aspiration to 10 or 40 μg of saline-suspended single-walled carbon nanotubes (SWCNTs), acid-functionalized SWCNTs (AF-SWCNTs), ultrafine carbon black (UFCB), AF-UFCB, or 2 μg LPS. 24 hours later, pulmonary inflammatory responses and cardiac effects were assessed by bronchoalveolar lavage and isolated cardiac perfusion respectively, and compared to saline or LPS-instilled animals. Additional mice were assessed for histological changes in lung and heart. Instillation of 40 μg of AF-SWCNTs, UFCB and AF-UFCB increased percentage of pulmonary neutrophils. No significant effects were observed at the lower particle concentration. Sporadic clumps of particles from each treatment group were observed in the small airways and interstitial areas of the lungs according to particle dose. Patches of cellular infiltration and edema in both the small airways and in the interstitium were also observed in the high dose group. Isolated perfused hearts from mice exposed to 40 μg of AF-SWCNTs had significantly lower cardiac functional recovery, greater infarct size, and higher coronary flow rate than other particle-exposed animals and controls, and also exhibited signs of focal cardiac myofiber degeneration. No particles were detected in heart tissue under light microscopy. This study indicates that while acid functionalization increases the pulmonary toxicity of both UFCB and SWCNTs, this treatment caused cardiac effects only with the AF-carbon nanotubes. Further experiments are needed to understand the physico-chemical processes involved in this phenomenon.