Conventional cardiovascular imaging is invaluable for the assessment of late sequelae of atherosclerosis, such as diminished perfusion reserve and luminal stenosis. Molecular imaging provides complementary information about plaque composition and ongoing biologic processes in the vessel wall, allowing the early diagnosis and risk stratification of patients. Detection of enhanced glucose uptake, using 18F-FDG PET, has been proposed as a non-invasive approach to track macrophage activation as a critical event in the development and progression of atherosclerosis. In this study, we determined the impact of macrophage polarization on glucose metabolism and oxidative phosphorylation.
Methods
Murine peritoneal macrophages were incubated in the presence of interferon-γ (IFN-γ) plus tumor necrosis factor-α (TNF-α), lipopolysaccharide (LPS), or interleukin-4 (IL-4) to induce classic (M1 and MLPS) or alternative (M2) polarization, respectively. Glucose uptake was measured using 3H-deoxyglucose. Oxidative phosphorylation was evaluated using an extracellular flux analyzer. Mitochondrial DNA copy numbers were quantified by polymerase chain reaction. The expression of glucose transporter-1 (Glut-1), hexokinase-1 and -2 (Hk-1 and Hk-2, respectively), mitochondrial transcription factor-1 (Tfam), and cytochrome c oxidase subunit I (Cox-1) was determined by quantitative reverse transcription polymerase chain reaction.
Results
Stimulation of macrophages by LPS, but not polarization with either IFN-γ plus TNF-α (M1) or IL-4 (M2), resulted in a 2.5-fold increase in 3H-deoxyglucose uptake. Enhanced glucose uptake by MLPS macrophages paralleled the overexpression of rate-limiting proteins involved in transmembrane transport and intracellular trapping of glucose—that is, Glut-1, Hk-1, and Hk-2. Alternatively polarized M2 macrophages developed a markedly higher spare respiratory capacity than both nonpolarized and classically polarized M1 macrophages. M2 polarization was associated with a 4.6-fold increase in mitochondrial content of the cells, compared with nonpolarized macrophages. The expression of Tfam, a major regulator of mitochondrial biogenesis, and Cox-1, a critical component of respiratory chain, was significantly increased in M2 polarized macrophages.
Conclusion
Polarization of macrophages induces distinct metabolic profiles with respect to glycolysis versus oxidative phosphorylation, with alternatively polarized macrophages shifting to mitochondria as their main source of adenosine triphosphate. Only MLPS, but not M1 or M2 polarized macrophages, showed increased glucose uptake, suggesting that glucose metabolism is regulated independent of the polarization state and macrophage polarization may not be detectable by 18F-FDG PET.
Rupture and dissection are major causes of morbidity and mortality in arterial aneurysm and occur more frequently in rapidly expanding aneurysms. Current imaging modalities provide little information on aneurysm beyond size. Matrix metalloproteinase (MMP) activation plays a key role in the pathogenesis of aneurysm. We investigated whether imaging MMP activation in aneurysm helps predict its propensity to expansion. Methods: We used a model of carotid aneurysm in apolipoprotein E-deficient (apoE 2/2 ) mice. Radiotracers with specificity for activated MMPs were used to detect and quantify MMP activation by micro-SPECT/CT in vivo. Tracer uptake was confirmed by autoradiography and g-well counting, and specificity was demonstrated using an excess of unlabeled precursor and a specific MMP inhibitor. Results: We demonstrated that several MMPs are expressed with distinct temporal patterns in aneurysm. Significant focal uptake was observed in aneurysmal carotid arteries, peaking at 4 wk after aneurysm induction. In a group of animals imaged serially at 2 and 4 wk after aneurysm induction, MMP tracer uptake at 2 wk correlated well with the vessel area assessed by histology at 4 wk. Conclusion: Molecular imaging of MMP activation is a useful experimental, and potentially clinical, tool to noninvasively predict the propensity of an aneurysm to expansion in vivo.
Studies aimed at identifying the intracellular targets of ROS involved in redox signaling in macrophages and at elucidating the redox signaling mechanisms that control differentiation, activation, polarization, and death of monocytes and macrophages may ultimately lead to the development of novel preventive and therapeutic strategies for atherosclerosis.
Obstructive sleep apnea (OSA) is a common sleep disorder which can result in mood problems. The aim of this study was to evaluate the severity of depression and anxiety symptoms as the most prevalent psychological disturbances present in different severity of OSA. We performed a cross-sectional study of 685 recently diagnosed sleep-disordered patients, over the age of 18, referred to Noor Sleep Lab from August 2008 to November 2010. The participants filled the Beck depression inventory-II (BDI-II) and the Beck anxiety inventory (BAI) to assess the depression and anxiety symptoms. We collected other characteristics of subjects such as age, sex, body mass index (BMI) and Epworth sleepiness scale (ESS). Apnea hypopnea index (AHI) was determined by an overnight polysomnography. Mean age of the participants was 47.63 years (SD 11.73). More than half of patient had some degrees of depression and anxiety. AHI showed no significant correlation with BDI (p = 0.105, r = -0.070) or BAI (p = 0.712, r = -0.016). Obesity was not either correlated with depression or anxiety (p = 0.18, r = 0.05). Nonetheless, ESS was weakly correlated with depression (p = 0.001, r = 0.148) and anxiety scores (p = 0.006, r = 0.120). BMI and ESS means were significantly higher in patients with severe OSA (p = 0.000). In comparison with men, the severity of depressive and anxiety symptoms was significantly higher in women (p = 0.000). In this cross-sectional study of patients with sleep problems, OSA was not associated with severity of depression and anxiety symptoms.
Matrix metalloproteinases (MMPs) play a key role in the development of atherosclerosis and its complications. In vivo detection and quantification of MMP activation can help track the propensity to complications and response to therapy. We sought to establish an in vivo imaging approach for monitoring MMP activation in atherosclerotic mouse aorta and use it to assess the response to dietary modification.
Method and Results
Apo E−/− mice were fed normal chow or a high fat diet (HFD) for up to 3 months or HFD for 2 months followed by 1 month on normal chow. After three months of HFD, there was considerable atherosclerosis in the aorta. In vivo microSPECT/CT imaging using RP782 (an 111In-labeled tracer targeting activated MMPs) showed a heterogeneous pattern of tracer uptake along the aorta. Heterogeneity of RP782 uptake was confirmed by autoradiography, and specificity was demonstrated using excess unlabeled precursor. Tracer uptake quantified by microSPECT imaging significantly correlated with uptake quantified by autoradiography. Comparison of Oil Red O staining with autoradiography demonstrated areas of discordance between plaque presence and tracer uptake. HFD withdrawal led to significant reduction in RP782 uptake beyond the effect on plaque area. MMP expression and macrophage infiltration were similarly heterogeneous along the aorta and significantly reduced following withdrawal from the HFD. Finally, RP782 uptake significantly correlated with aortic macrophage content.
Conclusion
Molecular imaging of MMP activation reveals the heterogeneity of atherosclerotic plaques and is a useful tool for tracking plaque biology and response to therapy.
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