The process of vascular remodeling is associated with increased hypoxia. However, the contribution of hypoxia-inducible factor 1α (HIF1α), the key transcription factor mediating cellular hypoxic responses, to vascular remodeling is established, but not completely understood. In the angiotensin II (Ang II)-induced vascular remodeling model, HIF1α was increased and activated in vascular smooth muscle cells (VSMCs). Selective genetic disruption of Hif1a in VSMCs markedly ameliorated Ang II-induced vascular remodeling, as revealed by decreased blood pressure, aortic thickness, collagen deposition, inflammation, and aortic stiffness. VSMC Hif1a deficiency also specifically suppressed Ang II-induced infiltration of CD45 + CD11b + F4/80 + CD206 − M1 macrophages into the vessel. Mechanistically, HIF1α deficiency in VSMCs dramatically suppressed the expression of CCL7, a chemokine critical for macrophage recruitment. Bioinformatic analysis and chromatin immunoprecipitation assays revealed three functional hypoxia-response elements in the Ccl7 promoter, indicating that Ccl7 is a direct HIF1α target gene. Blocking CCL7 with antibody in vivo alleviated Ang II-induced hypertension and vascular remodeling, coincident with decreased macrophage infiltration. This study provides direct evidence that HIF1α activation in VSMCs exacerbates Ang II-induced macrophage infiltration and resultant vascular remodeling via its target gene Ccl7 , and thus may serve as a potential therapeutic target for remodeling-related vascular disease.

BackgroundHypothyroidism is an important risk factor for cardiovascular diseases, and autoimmune thyroiditis (AIT) is the leading cause of hypothyroidism. Recent studies showed that even AIT patients with euthyroidism still had an increased number of early atherosclerotic lesions. However, the precise mechanism is not yet known. This study aimed to investigate the association of thyroid function, thyroid autoimmunity, and cardiometabolic risk factors in non-obese AIT patients with euthyroidism.MethodsA total of 5,608 non-obese individuals including 1,402 AIT patient and 4,206 sex-, age-, and body mass index (BMI)-matched healthy controls were recruited.ResultsThe AIT patients had significantly lower free T3 and free T4 levels, and higher TSH, antithyroid peroxidase antibodies (TPOAb) and TgAb levels. The elevated levels of high sensitivity C reactive protein (hsCRP) and homeostasis model assessment of insulin resistance (HOMA-IR) were observed in the AIT patients than the controls [hsCRP: 0.65 (0.27–1.33) vs. 0.20 (0.03–0.74) mg/L; HOMA-IR: 2.78 ± 1.60 vs. 2.33 ± 1.49; all P < 0.05]. Thyroid function was not associated with metabolic parameters and inflammatory makers, while the TPOAb titer was positively associated with the HOMA-IR and hsCRP levels after adjustment for confounding factors (all P < 0.05). Multivariate regression analysis demonstrated that the TPOAb level was an independent influencing factor for the HOMA-IR and hsCRP levels (HOMA-IR: β = 0.058, P < 0.05; hsCRP: β = 0.108, P < 0.05).ConclusionThe TPOAb level is associated with HOMA-IR and hsCRP levels independently of thyroid function in non-obese individuals. Mild deviation of thyroid function within the normal range, chronic inflammation, and insulin resistance may be the links between AIT and atherosclerosis in the non-obese population.

Previously, a new procedure for measuring serum TSH receptor autoantibodies (TRAb) was reported in which the autoantibodies inhibit binding of a human monoclonal thyroid stimulating antibody M22 to TSHR-coated ELISA plate wells (TRAb ELISA). The aim of the present study was to evaluate the clinical performance of this assay in comparison to the second generation TRAb assay (TRAb LIA) based on the recombinant human TSH-receptor and chemiluminescence technology (TRAb LIA). Among the 158 patients, 84 patients suffered from Graves' disease (GD), 34 patients had Hashimoto's thyroiditis (HT), and 40 patients had euthyroid nodular thyroid disease (NTD) without signs of autoimmunity. TRAb measurements were performed according to the manufacturer's instructions. Out of 84 GD patients, 80 (95.2%) were TRAb positive as detected by the TRAb LIA. One GD patient had TRAb values within the grey zone (1.0-1.5 IU/l). All patients with HT and NTD were negative except in 6 (8.1%) cases whose TRAb values were within the grey zone. On the basis of the recommended cutoff value (TRAb 1.0 IU/l), the TRAb ELISA found 78 of 84 (92.9%) GD patients to be TRAb positive. None of the patients with HT, but two cases (5.0%) with NTD were TRAb positive. The diagnostic sensitivity of the TRAb LIA and TRAb ELISA assays was 95.2 and 92.9%, while the specificity was 100% and 97.3%, respectively. There was a close correlation (r=0.968, p<0.0001) between both assays in 84 patients with GD. Additionally, the between-run imprecision close to the cutoff limit was assessed. The calculated between-run coefficient of variation (CV) of the TRAb ELISA was 28.2% at the recommended cutoff value of 1.0 IU/l. Due to the evaluated imprecision data we propose a higher cutoff value correlating with a between-run CV of 20% (functional assay sensitivity). Our results indicate that due to a worse imprecision the TRAb ELISA has a slightly lower sensitivity and specificity compared to the TRAb LIA assay. These findings suggest that the M22 monoclonal antibody-based TRAb ELISA is not as reliable as other second generation TRAb assays in the diagnosis of Graves' diseases.

The complete nucleotide sequence of a Chinese isolate of tobacco bushy top virus (TBTV), designated TBTV-Ch, was determined from cDNA generated from double-stranded RNA extracted from diseased tobacco. The genome is 4152 nucleotides (nt) in size, contains four putative open reading frames (ORFs) and untranslated regions of 10 nt and 645 nt at the 5' and 3' ends, respectively. In genome organization and in the amino acid sequence of its potential products, the RNA of TBTV-Ch is similar to other umbraviruses sequenced to date. The results suggested that TBTV should be regarded as a definitive species of the genus Umbravirus.