Pathogenesis and Drug Development for Pulmonary Arterial Hypertension

Pathogenesis and Drug Development for Pulmonary Arterial Hypertensio

Chronic Thromboembolic Pulmonary Hypertension – from Diagnosis to Intervention

Chronic Thromboembolic Pulmonary Hypertension – from Diagnosis to Interventio

The BMPR2, ALK1 and ENG Genes Mutation in Congenital Heart DiseaseAssociated Pulmonary Artery Hypertension

The gene mutation is one of the background underlie the pathogenesis of pulmonary artery hypertension (PAH). Several genes have been recognized to be responsible for the development of PAH. The mutation in transforming growth factor-β (TGF-β) pathway is considered to be major genotype background in heritable PAH. The genetic mutation in bone morphogenetic protein receptor-2 (BMPR2), activin receptor-like kinase 1 (ALK-1) and endoglin (ENG) are known to cause heritable PAH. In congenital heart disease–associated PAH (CHDAPAH), their mutation are also presence

Diabetes-Related Ankyrin Repeat Protein (DARP/Ankrd23) Modifies Glucose Homeostasis by Modulating AMPK Activity in Skeletal Muscle.

Skeletal muscle is the major site for glucose disposal, the impairment of which closely associates with the glucose intolerance in diabetic patients. Diabetes-related ankyrin repeat protein (DARP/Ankrd23) is a member of muscle ankyrin repeat proteins, whose expression is enhanced in the skeletal muscle under diabetic conditions; however, its role in energy metabolism remains poorly understood. Here we report a novel role of DARP in the regulation of glucose homeostasis through modulating AMP-activated protein kinase (AMPK) activity. DARP is highly preferentially expressed in skeletal muscle, and its expression was substantially upregulated during myotube differentiation of C2C12 myoblasts. Interestingly, DARP-/- mice demonstrated better glucose tolerance despite similar body weight, while their insulin sensitivity did not differ from that in wildtype mice. We found that phosphorylation of AMPK, which mediates insulin-independent glucose uptake, in skeletal muscle was significantly enhanced in DARP-/- mice compared to that in wildtype mice. Gene silencing of DARP in C2C12 myotubes enhanced AMPK phosphorylation, whereas overexpression of DARP in C2C12 myoblasts reduced it. Moreover, DARP-silencing increased glucose uptake and oxidation in myotubes, which was abrogated by the treatment with AICAR, an AMPK activator. Of note, improved glucose tolerance in DARP-/- mice was abolished when mice were treated with AICAR. Mechanistically, gene silencing of DARP enhanced protein expression of LKB1 that is a major upstream kinase for AMPK in myotubes in vitro and the skeletal muscle in vivo. Together with the altered expression under diabetic conditions, our data strongly suggest that DARP plays an important role in the regulation of glucose homeostasis under physiological and pathological conditions, and thus DARP is a new therapeutic target for the treatment of diabetes mellitus

HEPARANASE EXPRESSION IN RENAL INTERSTITIAL MAY CONTRIBUTE TO EPITHELIAL AND ENDOTHELIAL CELLS INJURIES AFTER KIDNEY ISCHEMIC/ REPERFUSION EPISODE IN MICE

Kidney ischemia/reperfusion injury (I/R) is the most frequent cause of acute kidney injury (AKI). It had been reported that epithelial and endothelial injuries occurred during kidney I/R injury. Heparanase is an enzyme that degrades glycocalyx and contributes to I/R injury in the heart and liver. This study is to elucidate the association between heparanase expression and cell injuries in kidney I/R injury. We performed kidney I/R injury model in mice using renal pedicle clamping for 30 minutes and sacrificed the mice in day 1 (n=6) after operation. Sham-operation procedure (SO, n=5) was used as control. PAS staining was used to quantify tubular injury score. Serum creatinine was measured from orbital venous. Heparanase expression was quantified using western blot and real-time PCR. Heparanase localization and endothelial injury were shown by immunostaining of heparanase and double glycocalyx-von Willebrand factor. Kidney I/R induced an increase of serum creatinine level that was accompanied by elevation of tubular injury score and glycocalyx damage. Glycocalyx damage was identified using immunofluorescent staining that revealed a disruption of glycocalyx or lectin layer in the endothelial cells of intra-renal artery. This finding was associated with significant elevation of heparanase mRNA and protein level expression. We found that heparanase was expressed in the renal epithelial and interstitial cells. In conclusion, heparanase may induce endothelial and epithelial injury in the kidney I/R episode. Using heparanase expression as a early marker of AKI may possibly promising. Keywords: kidney I/R, epithelial injury, endothelial injury, heparanase, glycocalyx

A case of reversible cerebral vasoconstriction syndrome associated with anti-phospholipid antibody syndrome and systemic lupus erythematosus

The pathomechanisms and treatment strategy for rare presentations of reversible cerebral vasoconstriction syndrome (RCVS) with anti-phospholipid syndrome (APS) remain to be determined. We report a 67-year-old woman with APS who presented with ischemic stroke due to RCVS. She was treated with low-dose cilostazol and lomerizine hydrochloride, which resulted in functional improvement and recovery of vasoconstriction within 12 weeks. Her plasma endothelin-1 level was decreased after relief of vasoconstriction, compared with the pre-treatment condition. Increased plasma endothelin-1 may be related to the underlying pathomechanism of RCVS with APS, against which cilostazol and lomerizine hydrochloride could be effective

25 years of endothelin research: the next generation

In the past three decades, endothelin and endothelin receptor antagonists have received great scientific and clinical interest, leading to the publication of more than 27,000 scientific articles since its discovery. The Thirteenth International Conference on Endothelin (ET-13) was held on September 8–11, 2013, at Tokyo Campus of the University of Tsukuba in Japan. Close to 300 scientists from 25 countries from around the world came to Tokyo to celebrate the anniversary of the discovery of the endothelin peptide discovered 25 years ago at the University of Tsukuba. This article summarizes some of the highlights of the conference, the anniversary celebration ceremony, and particularly the participation of next generation of endothelin researchers in endothelin science and the anniversary celebration. As a particular highlight, next generation endothelin researchers wrote a haiku (a traditional form of Japanese poetry originating from consisting of no more than three short verses and 27 on, or Japanese phonetic units) to describe the magic of endothelin science which they presented to the conference audience at the anniversary ceremony. The text of each haiku – both in its original language together with the English translation – is part of this article providing in an exemplary fashion how poetry can be bridged with science. Finally, we give an outlook towards the next 25 years of endothelin research

In vivo induction of activin A-producing alveolar macrophages supports the progression of lung cell carcinoma

Alveolar macrophages (AMs) are crucial for maintaining normal lung function. They are abundant in lung cancer tissues, but their pathophysiological significance remains unknown. Here we show, using an orthotopic murine lung cancer model and human carcinoma samples, that AMs support cancer cell proliferation and thus contribute to unfavourable outcome. Inhibin beta A (INHBA) expression is upregulated in AMs under tumor-bearing conditions, leading to the secretion of activin A, a homodimer of INHBA. Accordingly, follistatin, an antagonist of activin A is able to inhibit lung cancer cell proliferation. Single-cell RNA sequence analysis identifies a characteristic subset of AMs specifically induced in the tumor environment that are abundant in INHBA, and distinct from INHBA-expressing AMs in normal lungs. Moreover, postnatal deletion of INHBA/activin A could limit tumor growth in experimental models. Collectively, our findings demonstrate the critical pathological role of activin A-producing AMs in tumorigenesis, and provides means to clearly distinguish them from their healthy counterparts.Taniguchi S., Matsui T., Kimura K., et al. In vivo induction of activin A-producing alveolar macrophages supports the progression of lung cell carcinoma. Nature Communications 14, 143 (2023); https://doi.org/10.1038/s41467-022-35701-8

Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction

Cholesteatoma, which potentially results from tympanic membrane retraction, is characterized by intractable local bone erosion and subsequent hearing loss and brain abscess formation. However, the pathophysiological mechanisms underlying bone destruction remain elusive. Here, we performed a single-cell RNA sequencing analysis on human cholesteatoma samples and identify a pathogenic fibroblast subset characterized by abundant expression of inhibin βA. We demonstrate that activin A, a homodimer of inhibin βA, promotes osteoclast differentiation. Furthermore, the deletion of inhibin βA /activin A in these fibroblasts results in decreased osteoclast differentiation in a murine model of cholesteatoma. Moreover, follistatin, an antagonist of activin A, reduces osteoclastogenesis and resultant bone erosion in cholesteatoma. Collectively, these findings indicate that unique activin A-producing fibroblasts present in human cholesteatoma tissues are accountable for bone destruction via the induction of local osteoclastogenesis, suggesting a potential therapeutic target.Shimizu K., Kikuta J., Ohta Y., et al. Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction. Nature Communications 14, 4417 (2023); https://doi.org/10.1038/s41467-023-40094-3