Macular Vascular Complexity Analysis of Diabetes Mellitus by Swept-Source Optical Coherence Tomographic Angiography.

PURPOSE: This study was designed to evaluate the associations between retinal vascular complexity features, including fractal dimension (FD) and blood vessel tortuosity (BVT), and the severity of diabetic retinopathy (DR) by using optical coherence tomographic angiography (OCTA). METHODS: In this prospective cross-sectional study, 1,282 ocular-treatment-naive patients with type 2 diabetes mellitus (DM) (1,059 without DR and 223 with DR) registered in the community of Guangzhou, China, were enrolled. OCTA was used to measure FD and BVT in the superficial capillary plexus (SCP) and the deep capillary plexus (DCP). Univariate and multivariate linear regression analyses were performed to analyze the correlation of FD and BVT in different layers with DR severity. RESULTS: In this study, 1,282 patients with DM (1,282 eyes), with a mean age of 64.2 ± 7.8 years, were included. FD in the DCP decreased and BVT in the DCP increased in patients with DR compared with those in patients without DR, even after adjusting for confounding factors (p < 0.05). Trend analysis showed a significant decrease in the FD values as the DR progressed, whereas the BVT progressively increased with worsening DR severity (p < 0.01). The FD in DCP had a statistically significant positive correlation with FD in SCP and a negative correlation with BVT in SCP and BVT in DCP in all of the participants, including the non-DR group, moderate DR group, and severe DR group (p < 0.01). CONCLUSIONS: FD and BVT determined using OCTA might be useful parameters for objectively distinguishing DR from non-DR and indicating DR progression.

Genetic Variants, Circulating Level of MCP1 with Risk of Chronic Obstructive Pulmonary Disease: A Case-Control Study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) ranks one of the major causes of mortality worldwide. Inflammation is greatly involved in the pathogenesis of COPD. Monocyte chemoattractant protein-1 (MCP1) has been implicated to play an important role in the inflammatory response of various pathological processes. METHODS: In this study, we conducted a hospital-based case-control study in a Chinese population, aiming to evaluate the potential associations of genetic polymorphisms of the MCP1 gene (rs1024611, rs2857656, and rs4586) and circulating level of MCP1 with COPD risk. RESULTS: We found that rs1024611 (OR=1.37; 95% CI=1.11-1.69; P-value=0.004) and rs4586 (OR=1.33; 95% CI=1.09-1.63; P-value=0.006) were significantly associated with increased COPD risk. In the dominant model, both rs1024611 (OR=1.46; 95% CI=1.11-1.92; P-value=0.006) and rs4586 (OR=1.56; 95% CI=1.18-2.07; P-value=0.002) were significantly associated with increased COPD risk. Genotypes of rs1024611 and rs4586 with minor alleles had a significantly higher circulating level of MCP1 (P<0.001). Meanwhile, a circulating level of MCP1 was significantly associated with increased COPD risk (OR for per quartile increment=1.35, 95% CI=1.21-1.52, P<0.001). CONCLUSION: Our study indicated that genetic polymorphisms of the MCP1 gene and circulating level of MCP1 contributed to the COPD risk in the Chinese population. MCP1 contributed importantly to the pathophysiological process and occurrence of COPD.

Transplantation of Mesenchymal Stem Cells Attenuates Pulmonary Hypertension by Normalizing the Endothelial-to-Mesenchymal Transition.

For decades, stem cell therapies for pulmonary hypertension (PH) have progressed from laboratory hypothesis to clinical practice. Promising preclinical investigations have laid both a theoretical and practical foundation for clinical application of mesenchymal stem cells (MSCs) for PH therapy. However, the underlying mechanisms are still poorly understood. We sought to study the effects and mechanisms of MSCs on the treatment of PH. For in vivo experiments, the transplanted GFP+ MSCs were traced at different time points in the lung tissue of a chronic hypoxia-induced PH (CHPH) rat model. The effects of MSCs on PH pathogenesis were evaluated in both CHPH and sugen hypoxia-induced PH models. For in vitro experiments, primary pulmonary microvascular endothelial cells were cultured and treated with the MSC conditioned medium. The specific markers of endothelial-to-mesenchymal transition (EndMT) and cell migration properties were measured. MSCs decreased pulmonary arterial pressure and ameliorated the collagen deposition, and reduced the thickening and muscularization in both CHPH and sugen hypoxia-induced PH rat models. Then, MSCs significantly attenuated the hypoxia-induced EndMT in both the lungs of PH models and primary cultured rat pulmonary microvascular endothelial cells, as reflected by increased mesenchymal cell markers (fibronectin 1 and vimentin) and decreased endothelial cell markers (vascular endothelial cadherin and platelet endothelial cell adhesion molecule-1). Moreover, MSCs also markedly inhibited the protein expression and degradation of hypoxia-inducible factor-2α, which is known to trigger EndMT progression. Our data suggest that MSCs successfully prevent PH by ameliorating pulmonary vascular remodeling, inflammation, and EndMT. Transplantation of MSCs could potentially be a powerful therapeutic approach against PH.

Divergent changes of p53 in pulmonary arterial endothelial and smooth muscle cells involved in the development of pulmonary hypertension.

The tumor-suppressive role of p53, a transcription factor that regulates the expression of many genes, has been linked to cell cycle arrest, apoptosis, and senescence. The noncanonical function or the pathogenic role of p53 has more recently been implicated in pulmonary vascular disease. We previously reported that rapid nuclear accumulation of hypoxia-inducible factor (HIF)-1α in pulmonary arterial smooth muscle cells (PASMCs) upregulates transient receptor potential channels and enhances Ca2+ entry to increase cytosolic Ca2+ concentration ([Ca2+]cyt). Also, we observed differences in HIF-1α/2α expression in PASMCs and pulmonary arterial endothelial cells (PAECs). Here we report that p53 is increased in PAECs, but decreased in PASMCs, isolated from mice with hypoxia-induced pulmonary hypertension (PH) and rats with monocrotaline (MCT)-induced PH (MCT-PH). The increased p53 in PAECs from rats with MCT-PH is associated with an increased ratio of Bax/Bcl-2, while the decreased p53 in PASMCs is associated with an increased HIF-1α. Furthermore, p53 is downregulated in PASMCs isolated from patients with idiopathic pulmonary arterial hypertension compared with PASMCs from normal subjects. Overexpression of p53 in normal PASMCs inhibits store-operated Ca2+ entry (SOCE) induced by passive depletion of intracellularly stored Ca2+ in the sarcoplasmic reticulum, while downregulation of p53 enhances SOCE. These data indicate that differentially regulated expression of p53 and HIF-1α/2α in PASMCs and PAECs and the cross talk between p53 and HIF-1α/2α in PASMCs and PAECs may play an important role in the development of PH via, at least in part, induction of PAEC apoptosis and PASMC proliferation.

Bortezomib alleviates experimental pulmonary hypertension by regulating intracellular calcium homeostasis in PASMCs.

The ubiquitin-proteasome system is considered to be the key regulator of protein degradation. Bortezomib (BTZ) is the first proteasome inhibitor approved by the US Food and Drug Administration for treatment of relapsed multiple myeloma and mantle cell lymphoma. Recently, BTZ treatment was reported to inhibit right ventricular hypertrophy and vascular remodeling in hypoxia-exposed and monocrotaline-injected rats. However, the underlying mechanisms remain poorly understood. We previously confirmed that hypoxia-elevated basal intracellular Ca(2+) concentration ([Ca(2+)]i) and store-operated Ca(2+) entry (SOCE) in pulmonary artery smooth muscle cells (PASMCs) are involved in pulmonary vascular remodeling. In this study we aim to determine whether BTZ attenuates the hypoxia-induced elevation of [Ca(2+)] in PASMCs and the signaling pathway involved in this mechanism. Our results showed that 1) in hypoxia- and monocrotaline-induced rat pulmonary hypertension (PH) models, BTZ markedly attenuated the development and progression of PH, 2) BTZ inhibited the hypoxia-induced increase in cell proliferation, basal [Ca(2+)]i, and SOCE in PASMCs, and 3) BTZ significantly normalized the hypoxia-upregulated expression of hypoxia-inducible factor-1α, bone morphogenetic protein 4, canonical transient receptor potential isoforms 1 and 6, and the hypoxia-downregulated expression of peroxisome proliferator-activated receptor-γ in rat distal pulmonary arteries and PASMCs. These results indicate that BTZ exerts its protective role in the development of PH potentially by inhibiting the canonical transient receptor potential-SOCE-[Ca(2+)]i signaling axis in PASMCs.

Sodium tanshinone IIA sulfonate inhibits hypoxia-induced enhancement of SOCE in pulmonary arterial smooth muscle cells via the PKG-PPAR-γ signaling axis.

Our laboratory previously showed that sodium tanshinone IIA sulfonate (STS) inhibited store-operated Ca(2+) entry (SOCE) through store-operated Ca(2+) channels (SOCC) via downregulating the expression of transient receptor potential canonical proteins (TRPC), which contribute to the formation of SOCC (Wang J, Jiang Q, Wan L, Yang K, Zhang Y, Chen Y, Wang E, Lai N, Zhao L, Jiang H, Sun Y, Zhong N, Ran P, Lu W. Am J Respir Cell Mol Biol 48: 125-134, 2013). The detailed molecular mechanisms by which STS inhibits SOCE and downregulates TRPC, however, remain largely unknown. We have previously shown that, under hypoxic conditions, inhibition of protein kinase G (PKG) and peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling axis results in the upregulation of TRPC (Wang J, Yang K, Xu L, Zhang Y, Lai N, Jiang H, Zhang Y, Zhong N, Ran P, Lu W. Am J Respir Cell Mol Biol 49: 231-240, 2013). This suggests that strategies targeting the restoration of this signaling pathway may be an effective treatment strategy for pulmonary hypertension. In this study, our results demonstrated that STS treatment can effectively prevent the hypoxia-mediated inhibition of the PKG-PPAR-γ signaling axis in rat distal pulmonary arterial smooth muscle cells (PASMCs) and distal pulmonary arteries. These effects of STS treatment were blocked by pharmacological inhibition or specific small interfering RNA knockdown of either PKG or PPAR-γ. Moreover, targeted PPAR-γ agonist markedly enhanced the beneficial effects of STS. These results comprehensively suggest that STS treatment can prevent hypoxia-mediated increases in intracellular calcium homeostasis and cell proliferation, by targeting and restoring the hypoxia-inhibited PKG-PPAR-γ signaling pathway in PASMCs.

Leydig cell tumor with lung metastasis diagnosed by lung biopsy.

Leydig cell tumors are very rare and account for only 3% of testicular tumors and are generally benign. Only less than 0.2% of all testicular cancers were evidenced by metastatic spread. We report a 34-year-old man visited hospital because of coughing sputum mixed with blood. His chest CT showed bilateral patch clouding opacity. He was suspected with allergic alveolitis and treated with methylprednisolone. However, his symptoms and general condition deteriorated, and he visited our hospital. He had no abnormal findings on physical examination. A chest radiograph showed pneumonia in whole lung and CT showed multiple nodules and diffused ground glass opacities in both lung fields. Lung biopsy confirmed a diagnosis of Leydig cell tumor with lung metastasis. The diagnosis is based on the histopathology and immunohistochemistry.

Mutual inhibitory mechanisms between PPARγ and Hif-1α: implication in pulmonary hypertension.

Transcription factor hypoxia-inducible factor 1α (Hif-1α) is known for its crucial role in promoting the pathogenesis of pulmonary hypertension (PH). Previous studies have indicated the in-depth mechanisms that Hif-1α increases the distal pulmonary arterial (PA) pressure and vascular remodeling by triggering the intracellular calcium homeostasis, especially the store-operated calcium entry (SOCE) process. In our recent research paper published in the Journal of Molecular Medicine, we found that the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) activation could attenuate the PH pathogenesis by suppressing the elevated distal PA pressure and vascular remodeling. Moreover, these effects are likely mediated through the inhibition of SOCE by suppressing Hif-1α. These results provided convincing evidence and novel mechanisms in supporting the protective roles of PPARγ on PH treatment. Then, by using comprehensive loss-of-function and gain-of-function strategies, we further identified the presence of a mutual inhibitory mechanism between PPARγ and Hif-1α. Basically, under chronic hypoxic stress, accumulated Hif-1α leads to abolished expression of PPARγ and progressive imbalance between PPARγ and Hif-1α, which promotes the PH progression; however, targeted PPARγ restoration approach reversely inhibits Hif-1α level and Hif-1α mediated signaling transduction, which subsequently attenuates the elevated pulmonary arterial pressure and vascular remodeling under PH pathogenesis.