Abdominal aortic aneurysm (AAA) is a life-threatening chronic disease. Although low mural oxygen tension is present in the aneurysmal aorta, with increased hypoxia inducible factor (HIF)-1α expression, the role of HIF-1α in AAA pathogenesis remains uncertain. These experiments separately examined the influences of myeloid cell-specific HIF-1α deletion, as well as pharmacologic HIF-1α inhibition, on experimental AAA progression. Methods: AAAs were created via intra-aortic porcine pancreatic elastase (PPE) infusion in myeloid cell-specific HIF-1α conditional knockout (Lyz2 Cre+/HIF-1α Flox+/+) or control (HIF-1α Flox+/+) mice, as well as C57BL/6J mice treated with HIF-1α inhibitors or vehicle. AAA formation and progression was evaluated in vivo via ultrasonography, and histology at sacrifice. Results: HIF-1α mRNA expression was remarkably elevated in aneurysmal (PPE) as compared to non-aneurysmal (PBS), aortae. Flow cytometry detected nearly 65% of aortic CD11b+ myeloid cells expressed HIF-1α. Myeloid cell HIF-1α deletion reduced time-dependent aneurysmal enlargement noted following PPE infusion. Similar inhibition was observed in WT mice following daily treatment with acriflavine or doxorubicin (1 mg/kg), beginning 3 days prior to PPE infusion. Histologically, both myeloid cell HIF-1α deletion and pharmacologic HIF-1α inhibition attenuated medial elastin degradation and smooth muscle cell depletion, with reduced aortic mural macrophage and neovessel density compared to the corresponding controls. Conclusion: HIF-1α is an essential modulator of AAA pathogenesis, thus representing a novel pharmacologic target for medical disease management.
Abstract Background Aortic diameter is a critical parameter for the diagnosis of aortic dilated diseases. Aortic dilation has some common risk factors with cardiovascular diseases. This study aimed to investigate potential influence of traditional cardiovascular risk factors and the measures of subclinical atherosclerosis on aortic diameter of specific segments among adults. Methods Four hundred and eight patients with cardiovascular risk factors were prospectively recruited in the observational study. Comprehensive transthoracic M-mode, 2-dimensional Doppler echocardiographic studies were performed using commercial and clinical diagnostic ultrasonography techniques. The aortic dimensions were assessed at different levels: (1) the annulus, (2) the mid-point of the sinuses of Valsalva, (3) the sinotubular junction, (4) the ascending aorta at the level of its largest diameter, (5) the transverse arch (including proximal arch, mid arch, distal arch), (6) the descending aorta posterior to the left atrium, and (7) the abdominal aorta just distal to the origin of the renal arteries. Multivariable linear regression analysis was used for evaluating aortic diameter-related risk factors, including common cardiovascular risk factors, co-morbidities, subclinical atherosclerosis, lipid profile, and hematological parameters. Results Significant univariate relations were found between aortic diameter of different levels and most traditional cardiovascular risk factors. Carotid intima-media thickness was significantly correlated with diameter of descending and abdominal aorta. Multivariate linear regression showed potential effects of age, sex, body surface area and some other cardiovascular risk factors on aortic diameter enlargement. Among them, high-density lipoprotein cholesterol had a significantly positive effect on the diameter of ascending and abdominal aorta. Diastolic blood pressure was observed for the positive associations with diameters of five thoracic aortic segments, while systolic blood pressure was only independently related to mid arch diameter. Conclusion Aortic segmental diameters were associated with diastolic blood pressure, high-density lipoprotein cholesterol, atherosclerosis diseases and other traditional cardiovascular risk factors, and some determinants still need to be clarified for a better understanding of aortic dilation diseases.
Background Despite the importance of the renin-angiotensin (Ang) system in abdominal aortic aneurysm (AAA) pathogenesis, strategies targeting this system to prevent clinical aneurysm progression remain controversial and unproven. We compared the relative efficacy of two Ang II type 1 receptor blockers, telmisartan and irbesartan, in limiting experimental AAAs in distinct mouse models of aneurysm disease. Methodology/Principal Findings AAAs were induced using either 1) Ang II subcutaneous infusion (1000 ng/kg/min) for 28 days in male ApoE−/− mice, or 2) transient intra-aortic porcine pancreatic elastase infusion in male C57BL/6 mice. One week prior to AAA creation, mice started to daily receive irbesartan (50 mg/kg), telmisartan (10 mg/kg), fluvastatin (40 mg/kg), bosentan (100 mg/kg), doxycycline (100 mg/kg) or vehicle alone. Efficacy was determined via serial in vivo aortic diameter measurements, histopathology and gene expression analysis at sacrifice. Aortic aneurysms developed in 67% of Ang II-infused ApoE−/− mice fed with standard chow and water alone (n = 15), and 40% died of rupture. Strikingly, no telmisartan-treated mouse developed an AAA (n = 14). Both telmisartan and irbesartan limited aneurysm enlargement, medial elastolysis, smooth muscle attenuation, macrophage infiltration, adventitial neocapillary formation, and the expression of proteinases and proinflammatory mediators. Doxycycline, fluvastatin and bosentan did not influence aneurysm progression. Telmisartan was also highly effective in intra-aortic porcine pancreatic elastase infusion-induced AAAs, a second AAA model that did not require exogenous Ang II infusion. Conclusion/Significance Telmisartan suppresses experimental aneurysms in a model-independent manner and may prove valuable in limiting clinical disease progression.
Objective: Macrophages are functionally heterogenous. IL-4 and IL-13 promote an anti-inflammatory macrophage phenotype (alternatively activated or M2 macrophages). We explored the significance of M...
Astrocytes activate and crosstalk with neurons influencing inflammatory responses following ischemic stroke. The distribution, abundance, and activity of microRNAs in astrocytes-derived exosomes after ischemic stroke remains largely unknown. In this study, exosomes were extracted from primary cultured mouse astrocytes via ultracentrifugation, and exposed to oxygen glucose deprivation/re‑oxygenation injury to mimic experimental ischemic stroke. SmallRNAs from astrocyte-derived exosomes were sequenced, and differentially expressed microRNAs were randomly selected and verified by stem-loop real time quantitative polymerase chain reaction. We found that 176 microRNAs, including 148 known and 28 novel microRNAs, were differentially expressed in astrocyte-derived exosomes following oxygen glucose deprivation/re‑oxygenation injury. In gene ontology enrichment, Kyoto encyclopedia of genes and genomes pathway analyses, and microRNA target gene prediction analyses, these alteration in microRNAs were associated to a broad spectrum of physiological functions including signaling transduction, neuroprotection and stress responses. Our findings warrant further investigating of these differentially expressed microRNAs in human diseases particularly ischemic stroke.
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