Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension.

Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A-D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH; however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA-CREB-BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.

Phosphodiesterase 4D contributes to angiotensin II-induced abdominal aortic aneurysm through smooth muscle cell apoptosis.

Abdominal aortic aneurysm (AAA) is a permanent expansion of the abdominal aorta that has a high mortality but limited treatment options. Phosphodiesterase (PDE) 4 family members are cAMP-specific hydrolyzing enzymes and have four isoforms (PDE4A-PDE4D). Several pan-PDE4 inhibitors are used clinically. However, the regulation and function of PDE4 in AAA remain largely unknown. Herein, we showed that PDE4D expression is upregulated in human and angiotensin II-induced mouse AAA tissues using RT-PCR, western blotting, and immunohistochemical staining. Furthermore, smooth muscle cell (SMC)-specific Pde4d knockout mice showed significantly reduced vascular destabilization and AAA development in an experimental AAA model. The PDE4 inhibitor rolipram also suppressed vascular pathogenesis and AAA formation in mice. In addition, PDE4D deficiency inhibited caspase 3 cleavage and SMC apoptosis in vivo and in vitro, as shown by bulk RNA-seq, western blotting, flow cytometry and TUNEL staining. Mechanistic studies revealed that PDE4D promotes apoptosis by suppressing the activation of cAMP-activated protein kinase A (PKA) instead of the exchange protein directly activated by cAMP (Epac). Additionally, the phosphorylation of BCL2-antagonist of cell death (Bad) was reversed by PDE4D siRNA in vitro, which indicates that PDE4D regulates SMC apoptosis via the cAMP-PKA-pBad axis. Overall, these findings indicate that PDE4D upregulation in SMCs plays a causative role in AAA development and suggest that pharmacological inhibition of PDE4 may represent a potential therapeutic strategy.

Phosphodiesterase 4D promotes angiotensin II-induced hypertension in mice via smooth muscle cell contraction.

Hypertension is a common chronic disease, which leads to cardio-cerebrovascular diseases, and its prevalence is increasing. The cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway participates in multiple cardiovascular diseases. Phosphodiesterase (PDE) 4 has been shown to regulate PKA activity via cAMP specific hydrolysis. However, whether PDE4-cAMP-PKA pathway influences hypertension remains unknown. Herein, we reveal that PDE4D (one of PDE4 isoforms) expression is upregulated in the aortas of experimental hypertension induced by angiotensin II (Ang II). Furthermore, knockout of Pde4d in mouse smooth muscle cells (SMCs) attenuates Ang II-induced hypertension, arterial wall media thickening, vascular fibrosis and vasocontraction. Additionally, we find that PDE4D deficiency activates PKA-AMP-activated protein kinase (AMPK) signaling pathway to inhibit myosin phosphatase targeting subunit 1 (MYPT1)-myosin light chain (MLC) phosphorylation, relieving Ang II-induced SMC contraction in vitro and in vivo. Our results also indicate that rolipram, a PDE4 inhibitor, may be a potential drug for hypertension therapy.

The seasonal profile of proliferation and apoptosis in the prostate gland of the wild ground squirrel (Spermophilus dauricus).

The seasonal cycle of growth and regression in the prostate gland of wild ground squirrel provide a unique research model to understand the morphological changes of prostate glands. Our previous studies showed that the local production of dihydrotestosterone could affect the morphology and function of the prostate gland in either an autocrine or paracrine manner. In the present study, we attempted to gain more insight into this process by investigating the expression of key factors implicated in cell proliferation, apoptosis, and the cell cycle, including mechanistic target of rapamycin (mTOR), cyclin-D2, p21, p27 and retinoblastoma 1 (pRB). Morphological and histological observations confirmed that the prostate increased significantly in both size and weight during the breeding season. Positive immunostaining for proliferating cell nuclear antigen (PCNA) was mainly localized to the prostate epithelial cells during the breeding season, which is significantly higher in the prostate gland during the breeding season (2470 ± 81/mm2) than that in the nonbreeding season (324 ± 54/mm2). However, there was no significant difference in the prostate gland when compared between the breeding and nonbreeding seasons, with regards to TUNEL staining. Moreover, cell cycle regulators were mainly localized to the epithelial cells, including mTOR, cyclin-D2, p21, p27 and pRB. the immunostaining of mTOR and cyclin D2 were stronger during the breeding season, whereas the immunostaining of p27 and pRB were stronger during the nonbreeding season. The mRNA expression levels of mTOR, cyclin D2, and PCNA, were higher during the breeding season while those of p27 and p21 were higher during the nonbreeding season. Collectively, this study profiled the distinct expression pattern of key cell cycle regulators throughout the breeding and nonbreeding seasons. Collectively, these factors may play important roles in regulating the seasonal growth and regression of the prostatic epithelium in the wild ground squirrel.

Efficacy of prostaglandina E1 for the treatment of patients with thrombo-occlusive vasculitis: A protocol of systematic review and meta-analysis.

BACKGROUND: This study aims to explore the efficacy and safety of prostaglandina E1 (PE1) for the treatment of patients with thrombo-occlusive vasculitis (TOV). METHODS: Electronic databases (Cochrane Library, PUBMED, EMBASE, Web of Science, Scopus, the Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure) will be sought from onset to the March 1, 2020 without language and publication status restrictions. We will include any potential randomized controlled trials that examined the efficacy of PE1 for the treatment of patients with TOV. We will appraise study quality using Cochrane risk of bias tool, and will assess the evidence quality using Grading of Recommendations Assessment Development and Evaluation. We will use RevMan 5.3 Software for statistical analysis. RESULTS: A high-quality synthesis of present evidence of PE1 for the treatment of patients with TOV will be provided in this study. CONCLUSION: This study will provide evidence to judge whether PE1 is an effective intervention for TOV. SYSTEMATIC REVIEW REGISTRATION: INPLASY202040081.

Analyzing moisture-heat coupling in a wheat-soil system using data-driven vector autoregression model.

Soil temperature and moisture have a close relationship, the accurate controlling of which is important for crop growth. Mechanistic models built by previous studies need exhaustive parameters and seldom consider time stochasticity and lagging effect. To circumvent these problems, this study designed a data-driven stochastic model analyzing soil moisture-heat coupling. Firstly, three vector autoregression models are built using hourly data on soil moisture and temperature at the depth of 10, 30, and 90 cm. Secondly, from impulse response functions, the time lag and intensity of two variables' response to one unit of positive shock can be obtained, which describe the time length and strength at which temperature and moisture affect each other, indicating the degree of coupling. Thirdly, Granger causality tests unfold whether one variable's past value helps predict the other's future value. Analyzing data obtained from Shangqiu Experiment Station in Central China, we obtained three conclusions. Firstly, moisture's response time lag is 25, 50, and 120 h, while temperature's response time lag is 50, 120, and 120 h at 10, 30, and 90 cm. Secondly, temperature's response intensity is 0.2004, 0.0163, and 0.0035 °C for 1% variation in moisture, and moisture's response intensity is 0.0638%, 0.0163%, and 0.0050% for 1 °C variation in temperature at 10, 30, and 90 cm. Thirdly, the past value of soil moisture helps predict soil temperature at 10, 30, and 90 cm. Besides, the past value of soil temperature helps predict soil moisture at 10 and 30 cm, but not at 90 cm. We verified this model by using data from a different year and linking it to soil plant atmospheric continuum model.

The effect of response style on self-reported Conscientiousness across 20 countries.

Rankings of countries on mean levels of self-reported Conscientiousness continue to puzzle researchers. Based on the hypothesis that cross-cultural differences in the tendency to prefer extreme response categories of ordinal rating scales over moderate categories can influence the comparability of self-reports, this study investigated possible effects of response style on the mean levels of self-reported Conscientiousness in 22 samples from 20 countries. Extreme and neutral responding were estimated based on respondents' ratings of 30 hypothetical people described in short vignettes. In the vignette ratings, clear cross-sample differences in extreme and neutral responding emerged. These responding style differences were correlated with mean self-reported Conscientiousness scores. Correcting self-reports for extreme and neutral responding changed sample rankings of Conscientiousness, as well as the predictive validities of these rankings for external criteria. The findings suggest that the puzzling country rankings of self-reported Conscientiousness may to some extent result from differences in response styles.