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ABSTRACT: PURPOSE: To describe and characterize a new approach to first-pass myocardial perfusion utilizing balanced steady-state free precession acquisition without the use of saturation recovery or other magnetization preparation. THEORY: The balanced steady-state free precession sequence is inherently sensitive to contrast agent enhancement of the myocardium. This sensitivity can be used to advantage in first-pass myocardial perfusion imaging by eliminating the need for magnetization preparation. METHODS: Bloch equation simulations, phantom experiments, and in vivo 2D imaging studies were run comparing the proposed technique with three other methods: saturation recovery spoiled gradient echo, saturation recovery steady-state free precession, and steady-state spoiled gradient echo without magnetization preparation. Additionally, an acquisition-reconstruction strategy for 3D perfusion imaging is proposed and initial experience with this approach is demonstrated in healthy subjects and one patient. RESULTS: Phantom experiments verified simulation results showing the sensitivity of the balanced steady-state free precession sequence to contrast agent enhancement in solid tissue is similar to that of magnetization-prepared acquisitions. Images acquired in normal volunteers showed the proposed technique provided superior signal and signal-to-noise ratio compared with all other sequences at baseline as well as postcontrast. CONCLUSIONS: A new approach to first-pass myocardial perfusion is presented that obviates the need for magnetization preparation and provides high signal-to-noise ratio. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.
Magnetic Resonance in Medicine 02/2013; · 2.96 Impact Factor
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Steve Oghumu,
Ran Dong,
Sanjay Varikuti,
Todd Shawler,
Thomas Kampfrath,
Cesar A Terrazas,
Claudio Lezama-Davila,
Brian M M Ahmer,
Caroline C Whitacre, Sanjay Rajagopalan,
Richard Locksley,
Arlene H Sharpe,
Abhay R Satoskar
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ABSTRACT: CXCR3, expressed mainly on activated T and NK cells, is implicated in a host of immunological conditions and can contribute either to disease resolution or pathology. We report the generation and characterization of a novel CXCR3 internal ribosome entry site bicistronic enhanced GFP reporter (CIBER) mouse in which enhanced GFP expression correlates with surface levels of CXCR3. Using CIBER mice, we identified two distinct populations of innate CD8(+) T cells based on constitutive expression of CXCR3. We demonstrate that CXCR3(+) innate CD8(+) T cells preferentially express higher levels of Ly6C and CD122, but lower levels of CCR9 compared with CXCR3(-) innate CD8(+) T cells. Furthermore, we show that CXCR3(+) innate CD8(+) T cells express higher transcript levels of antiapoptotic but lower levels of proapoptotic factors, respond more robustly to IL-2 and IL-15, and produce significantly more IFN-γ and granzyme B. Interestingly, CXCR3(+) innate CD8(+) T cells do not respond to IL-12 or IL-18 alone, but produce significant amounts of IFN-γ on stimulation with a combination of these cytokines. Taken together, these findings demonstrate that CXCR3(+) and CXCR3(-) innate CD8(+) T cells are phenotypically and functionally distinct. These newly generated CIBER mice provide a novel tool for studying the role of CXCR3 and CXCR3-expressing cells in vivo.
The Journal of Immunology 01/2013; · 5.79 Impact Factor
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ABSTRACT: Recent epidemiological studies have suggested a link between exposure to ambient air-pollution and susceptibility to metabolic disorders such as Type II diabetes mellitus. Previously, we provided evidence that both short- and long-term exposure to concentrated ambient particulate matter with aerodynamic diameter <2.5 μm (PM2.5) induces multiple abnormalities associated with the pathogenesis of Type II diabetes mellitus, including insulin resistance, visceral adipose inflammation, brown adipose mitochondrial adipose changes, and hepatic endoplasmic reticulum (ER) stress. In this report, we show that chronic inhalation exposure to PM2.5 (10 months exposure) induces macrophage infiltration and Unfolded Protein Response (UPR), an intracellular stress signaling that regulates cell metabolism and survival, in mouse white adipose tissue in vivo. Gene expression studies suggested that PM2.5 exposure induces two distinct UPR signaling pathways mediated through the UPR transducer inositol-requiring 1α (IRE1α): 1) ER-associated Degradation (ERAD) of unfolded or misfolded proteins, and 2) Regulated IRE1-dependent Decay (RIDD) of mRNAs. Along with the induction of the UPR pathways and macrophage infiltration, expression of genes involved in lipogenesis, adipocyte differentiation, and lipid droplet formation was increased in the adipose tissue of the mice exposed to PM2.5. In vitro study confirmed that PM2.5 can trigger phosphorylation of the UPR transducer IRE1α and activation of macrophages. These results provide novel insights into PM2.5-triggered cell stress response in adipose tissue and increase our understanding of pathophysiological effects of particulate air pollution on the development of metabolic disorders.
American Journal of Translational Research 01/2013; 5(2):224-34.
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ABSTRACT: To the Editor: Wells et al. (Sept. 6 issue)(1) report that when the computed tomography (CT)-derived diameter of the pulmonary artery is normalized to the aortic diameter (PA:A ratio), a PA:A ratio of more than 1 significantly and independently predicts severe exacerbations of chronic obstructive pulmonary disease (COPD). As compared with patients with a PA:A ratio of 1 or lower, patients with a PA:A ratio of more than 1 had a mean pulmonary-artery diameter that was 20% larger and a mean aortic diameter that was 6% smaller. This pattern of findings is consistent with the pathophysiological link between severity of . . .
New England Journal of Medicine 12/2012; 367(23):2253-2255. · 53.30 Impact Factor
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ABSTRACT: BACKGROUND: -The aim of this study was to test the accuracy of an automated 3-D PISA (in vitro and patients) and stroke volume technique (patients) to assess MR severity using real-time 3-D volume color flow Doppler transthoracic echocardiography (RT-VCFD). METHODS AND RESULTS: -Using an in vitro model of MR, the effective regurgitant orifice area (EROA) and volume (RVol) were measured by the PISA technique using 2-D and 3-D (automated "true" 3-D PISA) transthoracic echocardiography. The mean anatomical regurgitant orifice area (0.35±0.10cm(2)) was underestimated to a greater degree by the 2-D (0.12±0.05cm(2)) than the 3-D method (0.25±0.10cm(2)), p<0.001 for both. Compared to the flowmeter (40±14ml), the RVol by 2-D PISA (20±19ml) was underestimated (p<0.001), but the 3-D peak (43±16ml) and integrated PISA (38±14ml) based RVol were comparable (p>0.05 for both). In patients (n=30, functional MR), 3-D EROA correlated well with cardiac magnetic resonance (CMR) RVol r=0.84 and regurgitant fraction r=0.80. Compared to CMR Rvol (33±22ml), the integrated PISA RVol (34±26ml, p=0.42) was not significantly different, however, the peak PISA RVol was higher (48±27ml, p<0.001). In addition, RVol calculated as the difference in automated mitral and aortic stroke volumes by RT-VCFD was not significantly different from CMR (34±21ml vs. 33±22ml, p=0.33). CONCLUSIONS: -Automated RT-VCFD 3-D PISA is more accurate than 2-D PISA method to quantify MR. In patients with functional MR the 3-D RVol by integrated PISA is more accurate than a peak PISA technique. Automated 3-D stroke volume measurement can also be used as an adjunctive method to quantify MR severity.
Circulation Cardiovascular Imaging 12/2012; · 5.94 Impact Factor
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Diabetes 12/2012; 61(12):3037-45. · 8.29 Impact Factor
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ABSTRACT: There is a paucity of prospective cohort studies investigating the impact of environmental factors on the development of cardiometabolic (CM) disorders like type II diabetes (T2DM). The objective of the Air-Pollution and Cardiometabolic Diseases (AIRCMD) study is to investigate the impact of personal level air pollution measures [personal black carbon (BC)/sulfate measures] and ambient fine particulate matter [(PM(2.5))/NO(2)] levels on propensity to type II diabetes in Beijing, China. Subjects with metabolic syndrome will undergo four repeated study visits within each season over a one year period following an initial screening visit. At each study visit, subjects will be monitored for sub-acute exposure to personal and ambient measures of air-pollution exposure and will undergo a series of functional CM outcomes. The primary endpoints include independent associations between integrated 5-day mean exposure to PM(2.5) and BC and homeostasis model assessment of insulin resistance (HOMA-IR) measures, 24-hour mean diastolic and mean arterial pressure and endothelial-dependent vasodilatation. The secondary endpoints will explore the mechanistic explanation for a causal relationship between exposures and propensity for type II diabetes and will include additional functional outcomes such as arterial compliance, heart rate variability and plasma adipokines. The novel aspects of the study include the launch of infrastructure for future translational investigations in highly polluted urbanized environments and the creation of novel methodologies for linking personalized exposure measurements with functional CM outcomes. We believe that AIRCMD will allow for unprecedented new investigations into the association between environmental risk factors and CM disorders.
Science of The Total Environment 11/2012; · 3.29 Impact Factor
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Xiaohua Xu,
Xiaoquan Rao,
Tse-Yao Wang,
Silis Y Jiang,
Zhekang Ying,
Cuiqing Liu,
Aixia Wang,
Mianhua Zhong,
Jeffrey A Deiuliis,
Andrei Maiseyeu, Sanjay Rajagopalan,
Morton Lippmann,
Lung-Chi Chen,
Qinghua Sun
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ABSTRACT: BACKGROUND: It has been well recognized that toxicity of fine ambient air particulate matter (PM2.5) may depend on its chemical constituents, including components such as soluble metals that may theoretically exert distinctive effects. We have recently demonstrated an important effect of PM2.5 on metabolic function. Since transition metals, such as nickel (Ni), represent an important component of exposure in certain environments, and may significantly influence the toxicity of inhalational exposure, we investigated the effects of Ni as a variable component of ambient PM2.5 exposure. METHODS: Male ApoE knockout mice were exposed to filtered air (FA), fine-sized nickel sulfate particles alone (Ni) at 0.44 mug/m3, concentrated ambient air PM2.5 (CAPs) at a mean of 70 mug/m3, or CAPs+Ni in Tuxedo, NY, 6 hours/day, 5 days/week, for 3 months. RESULTS: Exposure to Ni, irrespective of co-exposure to CAPs, resulted in body weight gain, while exposure to CAPs+Ni significantly enhanced fasting glucose and worsened insulin resistance measures (HOMA-IR), when compared with exposure to CAPs alone. CAPs+Ni exposure induced a significant decrease in phosphorylation of AMP-activated protein kinase (AMPK) alpha. Exposure to Ni or CAPs+Ni significantly induced microcirculatory dysfunction and increased monocytic cell infiltration into lung and adipose, and decreased uncoupling protein 1 expression at gene and protein levels and several brown adipocyte-specific genes in adipose tissue. CONCLUSIONS: Ni exposure has effects on metabolic and inflammatory parameters that are comparable to that of CAPs. Additionally, Ni synergistically exacerbates CAPs-induced adverse effects on some of, but not all of, these parameters, that may be mediated via the AMPK signaling pathway. These findings have important implications for inhaled transition metal toxicity that may exert synergistic effects with other PM2.5 components.
Particle and Fibre Toxicology 11/2012; 9(1):40. · 7.25 Impact Factor
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ABSTRACT: There is increasing evidence suggesting links between exposure to environmental toxins and susceptibility to type 2 diabetes mellitus (DM). In this review, we summarize the experimental evidence to support this association that has been noted in many epidemiologic studies. Inflammation in response to particulate matter (PM(2.5)) exposure in air pollution represents a common mechanism that may interact with other pro-inflammatory influences in diet and life style to modulate susceptibility to cardiometabolic diseases. The role of innate immune cytokines released from macrophages in the lung is well known. In addition, chemokine triggers in response to air-pollution exposure may mediate a cellular response from the bone marrow/spleen through toll-like receptors (TLRs) and Nucleotide Oligomerization Domain receptors (NLRs) pathways to mediate inflammatory response in organs. Emerging data also seem to support a role for PM(2.5) exposure in endoplasmic reticulum stress-induced apoptosis and in brown adipose tissue dysfunction. Decreased expression of UCP1 in brown adipose tissue may account for reduced thermogenesis providing another link between PM(2.5) and insulin resistance. The implications of an experimental link between air-pollution exposure and type 2 DM are profound as air pollution is a pervasive risk factor throughout the world and even modest alleviation in exposure may provide substantial public health benefits.
Toxicologic Pathology 10/2012; · 1.91 Impact Factor
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Journal of the American College of Cardiology 10/2012; · 14.16 Impact Factor
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ABSTRACT: The introduction of dipeptidyl peptidase 4 (DPP4) inhibitors for the treatment of Type 2 diabetes acknowledges the fundamental importance of incretin hormones in the regulation of glycemia. Small molecule inhibitors of DPP4 exert their effects via inhibition of enzymatic degradation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). The widespread expression of DPP4 in tissues such as the vasculature and immune cells suggests that this protein may play a role in cardiovascular function. DPP4 is known to exert its effects via both enzymatic and non-enzymatic mechanisms. A soluble form of DPP4 lacking the cytoplasmic and transmembrane domain has also been recently recognized. Besides enzymatic inactivation of incretins, DPP4 also mediates degradation of many chemokines and neuropeptides. The non-enzymatic function of DPP4 plays a critical role in providing co-stimulatory signals to T cells via adenosine deaminase (ADA). DPP4 may also regulate inflammatory responses in innate immune cells such as monocytes and dendritic cells. The multiplicity of functions and targets suggests that DPP4 may play a distinct role aside from its effects on the incretin axis. Indeed recent studies in experimental models of atherosclerosis provide evidence for a robust effect for these drugs in attenuating inflammation and plaque development. Several prospective randomized controlled clinical trials in humans with established atherosclerosis are testing the effects of DPP4 inhibition on hard cardiovascular events.
Atherosclerosis 09/2012; · 3.79 Impact Factor
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ABSTRACT: Current understanding of the association between household air-pollution (HAP) and cardiovascular disease is primarily derived from outdoor air-pollution studies. The lack of accurate information on the contribution of HAP to cardiovascular events has prevented inclusion of such data in global burden of disease estimates with consequences in terms of health care allocation and national/international priorities. Understanding the health risks, exposure characterization, epidemiology and economics of the association between HAP and cardiovascular disease represents a pivotal unmet public health need. Interventions to reduce exposure to air-pollution in general, and HAP in particular are likely to yield large benefits and may represent a cost-effective and economically sustainable solution for many parts of the world. A multi-disciplinary effort that provides economically feasible technologic solutions in conjunction with experts that can assess the health, economic impact and sustainability are urgently required to tackle this problem.
Global heart. 09/2012; 7(3):207-213.
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ABSTRACT: Dipeptidyl peptidase-4 (DDP4) inhibitors target the enzymatic degradation of incretin peptides and represent a major advance in the treatment of type 2 diabetes. DPP4 has a number of nonenzymatic functions that involve its interaction with adenosine deaminase (ADA) and other extracellular matrix proteins. Here, we assessed the nonenzymatic role of DPP4 in regulating dendritic cell (DC)/macrophage-mediated adipose inflammation in obesity. Both obese humans and rodents demonstrated increased levels of DPP4 expression in DC/macrophage cell populations from visceral adipose tissue (VAT). The DPP4 expression increased during monocyte differentiation to DC/macrophages and with lipopolysaccharide (LPS)-induced activation of DC/macrophages. The DPP4 colocalized with membrane-bound ADA on human DCs and enhanced the ability of the latter to stimulate T-cell proliferation. The DPP4 interaction with ADA in human DC/macrophages was competitively inhibited by the addition of exogenous soluble DPP4. Knockdown of DPP4 in human DCs, but not pharmacologic inhibition of their enzymatic function, significantly attenuated the ability to activate T cells without influencing its capacity to secrete proinflammatory cytokines. The nonenzymatic function of DPP4 on DC may play a role in potentiation of inflammation in obesity by interacting with ADA. These findings suggest a novel role for the paracrine regulation of inflammation in adipose tissue by DPP4.
Diabetes 08/2012; · 8.29 Impact Factor
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Rumana Yasmeen,
Barbara Reichert,
Jeffrey Deiuliis,
Fangping Yang,
Alisha Lynch,
Joseph Meyers,
Molly Sharlach,
Sangsu Shin,
Katharina S Volz,
Kari B Green,
Kichoon Lee,
Hansjuerg Alder,
Gregg Duester,
Rudolf Zechner, Sanjay Rajagopalan,
Ouliana Ziouzenkova
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ABSTRACT: Mechanisms for sex- and depot-specific fat formation are unclear. We investigated the role of retinoic acid (RA) production by aldehyde dehydrogenase 1 (Aldh1a1, -a2, and -a3), the major RA-producing enzymes on sex-specific fat depot formation. Female Aldh1a1(-/-) mice, but not males, were resistant to high-fat (HF) diet-induced visceral adipose formation, whereas subcutaneous fat was reduced similarly in both groups. Sexual dimorphism in visceral fat (VF) was attributable to elevated adipose triglyceride lipase (Atgl) protein expression localized in clusters of multilocular Ucp1-positive cells in female Aldh1a1(-/-) compared with males. Estrogen decreased Aldh1a3 expression, limiting conversion of retinaldehyde (Rald) to RA. Rald effectively induced Atgl levels via nongenomic mechanisms, demonstrating indirect regulation by estrogen. Experiments in transgenic mice, expressing an RA receptor response element (RARE-lacZ) revealed HF diet-induced RARE activation in VF of females but not males. In humans, stromal cells isolated from VF of obese subjects also expressed higher levels of Aldh1 enzymes compared with lean subjects. Our data suggest that an HF diet mediates VF formation through a sex-specific autocrine Aldh1 switch, in which Rald-mediated lipolysis in Ucp1-positive visceral adipocytes is replaced by RA-mediated lipid accumulation. Our data suggest that Aldh1 is a potential target for sex-specific antiobesity therapy.
Diabetes 08/2012; · 8.29 Impact Factor
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Ze Zheng,
Xiaohua Xu,
Xuebao Zhang,
Aixia Wang,
Chunbin Zhang,
Maik Hüttemann,
Lawrence I Grossman,
Lung Chi Chen, Sanjay Rajagopalan,
Qinghua Sun,
Kezhong Zhang
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ABSTRACT: BACKGROUND & AIMS: Air pollution is a global challenge to public health. Epidemiological studies have linked exposure to ambient particulate matter with aerodynamic diameters<2.5μm (PM(2.5)) to the development of metabolic diseases. In this study, we investigated the effect of PM(2.5) exposure on liver pathogenesis and the mechanism by which ambient PM(2.5) modulates hepatic pathways and glucose homeostasis. METHODS: Using "Ohio's Air Pollution Exposure System for the Interrogation of Systemic Effects (OASIS)-1", we performed whole-body exposure of mice to concentrated ambient PM(2.5) for 3 or 10weeks. Histological analyses, metabolic studies, as well as gene expression and molecular signal transduction analyses were performed to determine the effects and mechanisms by which PM(2.5) exposure promotes liver pathogenesis. RESULTS: Mice exposed to PM(2.5) for 10weeks developed a non-alcoholic steatohepatitis (NASH)-like phenotype, characterized by hepatic steatosis, inflammation, and fibrosis. After PM(2.5) exposure, mice displayed impaired hepatic glycogen storage, glucose intolerance, and insulin resistance. Further investigation revealed that exposure to PM(2.5) led to activation of inflammatory response pathways mediated through c-Jun N-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and Toll-like receptor 4 (TLR4), but suppression of the insulin receptor substrate 1 (IRS1)-mediated signaling. Moreover, PM(2.5) exposure repressed expression of the peroxisome proliferator-activated receptor (PPAR)γ and PPARα in the liver. CONCLUSIONS: Our study suggests that PM(2.5) exposure represents a significant "hit" that triggers a NASH-like phenotype and impairs hepatic glucose metabolism. The information from this work has important implications in our understanding of air pollution-associated metabolic disorders.
Journal of Hepatology 08/2012; · 9.26 Impact Factor
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ABSTRACT: Epidemiological studies suggest that fine particulate matter (PM(2.5)) may increase the risk for developing diabetes mellitus (DM). To evaluate possible mechanisms explaining these associations, we investigated if sub-acute ambient-level exposures can impair insulin sensitivity. Twenty-five healthy adults living in rural Michigan were transported to an urban location for 5 consecutive days (exposure-block) of daily 4- to 5-hour-long ambient air pollution exposures. Health outcomes, including the homeostasis model assessment of insulin resistance (HOMA-IR) the primary outcome of insulin sensitivity, were measured at 3 time points in relation to exposure-blocks: 7days prior to start; on the last exposure-day; and 7days after completion. PM(2.5) was monitored at the urban exposure site and at community monitors near subjects' residences. We calculated 3 "sub-acute" exposure periods (approximately 5-days-long) starting retrospective from the time of health outcome measurements (PM(2.5) ranges: 9.7±3.9 to 11.2±3.9μg·m(-3)). A 10μg·m(-3) increase in sub-acute PM(2.5) exposures was associated with increased HOMA-IR (+0.7, 95% confidence interval (CI) 0.1 to 1.3; p=0.023) and reduced heart rate variability (standard deviation of normal-to-normal intervals [-13.1ms, 95%CI -25.3 to -0.9; p=0.035]). No alterations in other outcomes (inflammatory markers, vascular function) occurred in relation to PM(2.5) exposures. Our findings suggest that ambient PM(2.5), even at low levels, may reduce metabolic insulin sensitivity supporting the plausibility that air pollution could potentiate the development of DM.
Science of The Total Environment 08/2012; · 3.29 Impact Factor
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ABSTRACT: High-fat diet (HFD) is associated with adipose inflammation, which contributes to key components of metabolic abnormalities. The expanded adipose tissue mass associated with obesity is the result of hyperplasia and hypertrophy of adipocytes. In this study, we investigated the effects of long-term HFD on adipocyte progenitor cell (APC) population and adipose-specific gene profiles in both white and brown adipose, and the role of perivascular adipose in the alteration of vascular function in response to HFD.
Male C57BL/6 mice were fed a standard normal diet (ND) or HFD for about 8 months. Glucose metabolism was assessed by an intraperitoneal glucose tolerance test. APC population and adipose-related gene profile were evaluated, and vascular function was measured in the presence or absence of perivascular adipose. Adiponectin and AMPK activity were also investigated.
HFD induced insulin resistance and glucose intolerance, and resulted in a decrease in APC population in brown, but not in white adipose tissue, when compared with animals fed a ND, with differential alterations of white and brown adipocyte-specific gene expression in brown and white adipose. Additionally, HFD led to altered vascular function in arteries in the presence of perivascular adipose tissue, which is associated with increased superoxide production. Adiponectin and AMPK activity were significantly decreased in response to long-term HFD.
These findings suggest that long-term high-fat intake differentially alters adipocyte progenitor population and adipose-related gene expression in adipose tissue, and adiponectin-AMPK signaling might be involved. In addition, HFD induces changes in perivascular adipose-mediated vascular function.
Life sciences 06/2012; 90(25-26):1001-9. · 2.56 Impact Factor
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Loren E Wold,
Zhekang Ying,
Kirk R Hutchinson,
Markus Velten,
Matthew W Gorr,
Christina Velten,
Dane J Youtz,
Aixia Wang,
Pamela A Lucchesi,
Qinghua Sun, Sanjay Rajagopalan
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ABSTRACT: Air pollution is a pervasive environmental health hazard that occurs over a lifetime of exposure in individuals from many industrialized societies. However, studies have focused primarily on exposure durations that correspond to only a portion of the lifespan. We therefore tested the hypothesis that exposure over a considerable portion of the lifespan would induce maladaptive cardiovascular responses.
C57BL/6 male mice were exposed to concentrated ambient particles <2.5 µm (particulate matter, PM or PM(2.5)) or filtered air (FA), 6 h/d, 5 d/wk, for 9 months. Assessment of cardiac contractile function, coronary arterial flow reserve, isolated cardiomyocyte function, expression of hypertrophic markers, calcium handling proteins, and cardiac fibrosis were then performed. Mean daily concentrations of PM(2.5) in the exposure chamber versus ambient daily PM(2.5) concentration at the study site were 85.3 versus 10.6 µg/m(3) (7.8-fold concentration), respectively. PM(2.5) exposure resulted in increased hypertrophic markers leading to adverse ventricular remodeling characterized by myosin heavy chain (MHC) isoform switch and fibrosis, decreased fractional shortening (39.8 ± 1.4 FA versus 27.9 ± 1.3 PM, FS%), and mitral inflow patterns consistent with diastolic dysfunction (1.95 ± 0.05 FA versus 1.52 ± 0.07 PM, E/A ratio). Contractile reserve to dobutamine was depressed (62.3 ± 0.9 FA versus 49.2 ± 1.5 PM, FS%) in response to PM(2.5) without significant alterations in maximal vasodilator flow reserve. In vitro cardiomyocyte function revealed depressed peak shortening (8.7 ± 0.6 FA versus 7.0 ± 0.4 PM, %PS) and increased time-to-90% shortening (72.5 ± 3.2 FA versus 82.8 ± 3.2 PM, ms) and re-lengthening (253.1 ± 7.9 FA versus 282.8 ± 9.3 PM, ms), which were associated with upregulation of profibrotic markers and decreased total antioxidant capacity. Whole-heart SERCA2a levels and the ratio of α/β-MHC were both significantly decreased (P<0.05) in PM(2.5)-exposed animals, suggesting a switch to fetal programming.
Long-term exposure to environmentally relevant concentrations of PM(2.5) resulted in a cardiac phenotype consistent with incipient heart failure.
Circulation Heart Failure 06/2012; 5(4):452-61. · 6.29 Impact Factor
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Xiaohua Xu,
Furong Deng,
Xinbiao Guo,
Peng Lv,
Mianhua Zhong,
Cuiqing Liu,
Aixia Wang,
Kevin Tzan,
Silis Y Jiang,
Morton Lippmann, Sanjay Rajagopalan,
Qingshan Qu,
Lung-Chi Chen,
Qinghua Sun
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ABSTRACT: Many studies have linked ambient fine particulate matter (aerodynamic diameters less than 2.5 μm, PM₂.₅) air pollution to increased morbidity and mortality of cardiovascular diseases in the general population, but the biologic mechanisms of these associations are yet to be elucidated. In this study, we aimed to evaluate the relationship between daily variations in exposure to PM₂.₅ and inflammatory responses in mice during and for 2 months after the Beijing Olympic Games. Male C57BL/6 mice were exposed to Beijing PM₂.₅ or filtered air (FA) in 2008 during the 2 months of Beijing Olympic and Paralympic Games, and for 2 months after the end of the Games. During the Games, circulating monocyte chemoattractant protein 1 and interleukin 6 were increased significantly in the PM₂.₅ exposure group, when compared with the FA control group, although there were no significant inter-group differences in tumor necrosis factor-α or interferon-γ, or in macrophages, neutrophils or lymphocytes in the spleen or thymus between these 2 groups. However, macrophages were significantly increased in the lung and visceral fat with increasing PM₂.₅. After the Olympic Games, there were no significant PM₂.₅-associated differences for macrophages, neutrophils or lymphocytes in the thymus, but macrophages were significantly elevated in the lung, spleen, subcutaneous and visceral fat with increasing PM₂.₅, and the numbers of macrophages were even higher after than those during the Games. Moreover, the number of neutrophils was markedly higher in the spleen for the PM₂.₅-exposed- than the FA-group. These data suggest that short-term increases in exposure to ambient PM₂.₅ leads to increased systemic inflammatory responses, primarily macrophages and neutrophils in the lung, spleen, and visceral adipose tissue. Short-term air quality improvements were significantly associated with reduced overall inflammatory responses.
Toxicology Letters 05/2012; 212(2):147-56. · 3.23 Impact Factor
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Fangping Yang,
Xulang Zhang,
Andrei Maiseyeu,
Georgeta Mihai,
Rumana Yasmeen,
David DiSilvestro,
Santosh K Maurya,
Muthu Periasamy,
K Valerie Bergdall,
Gregg Duester,
Chandan K Sen,
Sashwati Roy,
L James Lee, Sanjay Rajagopalan,
Ouliana Ziouzenkova
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ABSTRACT: Although alginate-poly-L-lysine (AP(L)) encapsulation of cells producing bioactive peptides has been widely tested, it is unknown whether AP(L) supports lasting catabolic functions of encapsulated cells in adipose tissue, which are required for obesity reduction. We tested functions of AP(L)-encapsulated fibroblasts isolated from wild-type (WT) and aldehyde dehydrogenase 1a1 knockout mice (KO), which resist obesity on a high-fat (HF) diet, have a higher metabolic rate, and express increased levels of thermogenic uncoupling protein-1 (Ucp1) in their deleterious visceral fat depots compared to WT mice. To enable in vivo detection and quantification, fibroblasts were stably transfected with green-fluorescent protein. WT- or KO-containing microcapsules were injected into two visceral depots of WT mice fed an HF diet. Eighty days after transplantation, microcapsules were located in vivo using magnetic resonance imaging. KO microcapsules prevented weight gain in obese WT mice compared to a mock- and WT capsule-injected groups on an HF diet. The weight loss in KO-treated mice corresponded to lipid reduction and induction of thermogenesis in the injected visceral fat. The non-treated subcutaneous fat was not altered. Our data suggest that the AP(L) polymer supports long-term catabolic functions of genetically-modified fibroblasts, which can be potentially used for depot-specific obesity treatment.
Biomaterials 05/2012; 33(22):5638-49. · 7.40 Impact Factor
