Vascular wall microenvironment: exosomes secreted by adventitial fibroblasts induced vascular calcification.

Vascular calcification often occurs in patients with chronic renal failure (CRF), which significantly increases the incidence of cardiovascular events in CRF patients. Our previous studies identified the crosstalk between the endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and the paracrine effect of VSMCs, which regulate the calcification of VSMCs. Herein, we aim to investigate the effects of exosomes secreted by high phosphorus (HPi) -induced adventitial fibroblasts (AFs) on the calcification of VSMCs and the underlying mechanism, which will further elucidate the important role of AFs in high phosphorus vascular wall microenvironment. The conditioned medium of HPi-induced AFs promotes the calcification of VSMCs, which is partially abrogated by GW4869, a blocker of exosomes biogenesis or release. Exosomes secreted by high phosphorus-induced AFs (AFsHPi-Exos) show similar effects on VSMCs. miR-21-5p is enriched in AFsHPi-Exos, and miR-21-5p enhances osteoblast-like differentiation of VSMCs by downregulating cysteine-rich motor neuron 1 (Crim1) expression. AFsHPi-Exos and exosomes secreted by AFs with overexpression of miR-21-5p (AFsmiR21M-Exos) significantly accelerate vascular calcification in CRF mice. In general, AFsHPi-Exos promote the calcification of VSMCs and vascular calcification by delivering miR-21-5p to VSMCs and subsequently inhibiting the expression of Crim1. Combined with our previous studies, the present experiment supports the theory of vascular wall microenvironment.

BMP-Id pathway targeted by cholesterol myristate suppresses the apoptosis of PC12 cells.

Identifying small molecules that suppress apoptosis is promising for the therapy of brain diseases. We recently showed that autocrine bone morphogenetic protein (BMP) signaling involves the effects of cholesterol myristate present in traditional Chinese medicine on mesenchymal stem cells. The present study evaluated the effects of cholesterol myristate on the apoptosis and BMP signaling of PC12 cells. PC12 cells transfected by the inhibitor of differentiation (Id1) promoter reporter construct target gene of BMP4 signaling; cholesterol myristate increases the activity of Id1 promoter. However, structurally related steroids such as cholesterol, ß-sitosterol and cholesten-3-one, lack of the myristate, did not affect the activity of Id1 promoter, suggesting that myristate is essential for the effect of cholesterol myristate. These effects depend on BMP signaling. Apoptosis analysis indicated that cholesterol myristate inhibited the apoptosis of PC12 cells induced in serum-free condition. Cholesterol myristate significantly increases the expression of BMP4, BMPRIA, p-Smad1/5/8, Id1 and its antiapoptotic target gene Bcl-xL in PC12 cells treated in serum-free condition. Moreover, BMP antagonist reduced the anti-apoptotic effect of cholesterol myristate. Thus, this study is to provide evidence that BMP-Id pathway targeted by cholesterol myristate suppresses the apoptosis of PC12 cells. Our findings are therefore of considerable therapeutic significance and provide the potential of newly exploiting cholesterol myristate and clinically in brain disease therapies.

The Yin and Yang of bone morphogenetic proteins in cancer.

Bone morphogenetic proteins (BMPs) were first studied as growth factors or morphogens of the transforming growth factor-beta superfamily. These growth molecules, originally associated with bone and cartilage development, are now known to play an important role in morphogenesis and homeostasis in many other tissues. More recently, significant contributions from BMPs, their receptors, and interacting molecules have been linked to carcinogenesis and tumor progression. On the other hand, BMPs can sometimes function as a tumor suppressor. Our report highlights these new roles in the pathogenesis of cancer that may suggest novel targets for therapeutic intervention.

Expression of bone morphogenetic protein2 (BMP2), BMP4 and BMP receptors in the bovine ovary but absence of effects of BMP2 and BMP4 during IVM on bovine oocyte nuclear maturation and subsequent embryo development.

Bone morphogenetic proteins (BMPs) have been implicated in the regulation of ovarian follicular development and are promising candidates to apply in IVM and IVF protocols. We investigated the expression of BMP2, BMP4 and BMP receptors in bovine ovaries and the effects of BMP2 and BMP4 during oocyte maturation on bovine IVM. Reverse transcription polymerase chain reaction studies with antral follicles showed the expression of BMPR-IA, BMPR-IB, ActR-IA, ActR-IIB, BMPR-II and BMP4 mRNA in all follicular compartments, while BMP2 mRNA was generally restricted to theca and cumulus tissue. Immunohistochemistry demonstrated the presence of BMPR-II in oocytes and granulosa cells of preantral follicles but only in oocytes of antral follicles. The immunostaining of BMP2 and BMP4 was limited to theca interna and approximately 25% of oocytes of antral follicles. Exogenously added BMP2 or BMP4 to IVM medium did not affect oocyte nuclear maturation, cumulus cell expansion, nor blastocyst formation following IVF. It is concluded that a BMP-signaling system, consisting of BMP2, BMP4, type II and I receptors, is present in bovine antral follicles and that this system plays a role in development and functioning of these follicles rather than in final oocyte maturation and cumulus expansion.

Changes in the Expression of Bone Morphogenetic Protein Receptor Type IA, IB and II in Human Prostate by the Suppression of Dihydrotestosterone / 대한비뇨기과학회지

PURPOSE: To investigate whether the expression of type IA, IB and II bone morphogenetic protein receptors (hBMPRs) are affected by the suppression of dihydrotestosterone (DHT) in the prostate tissues of patients with benign prostatic hyperplasia (BPH), we determined mRNA levels and protein expression patterns of the hBMPRs in human prostate tissues. MATERIALS AND METHODS: Frozen tissues were obtained during the transurethral resection of the prostate (TURP) in BPH patients who had taken the 5alpha-reductase inhibitor (finasteride), for 3 months prior to surgery, for the reduction of the prostate volume. Tissues from patients who had not taken finasteride prior to the TURP were used as controls. Patients over 50 years old, and with a prostate volume over 50ml, were included. Semiquantitative polymerase chain reaction (PCR) and immunoblotting were used to compare the expressions of the human bone morphogenetic protein receptors (hBMPRs) between the experimental group and the controls. RESULTS: All of the BMPRs proteins were expressed in the human benign prostate tissues, with various concentrations. The semiquantitative PCR analysis showed that the mRNA level of the hBMPRs tended to decrease following 5alpha-reductase inhibition, and the magnitude of this decrease was the greatest for the hBMPR-IB. CONCLUSIONS: In the human prostate, only the expression of hBMPR-IB was significantly reduced by the suppression of DHT. Further studies on the possible role of the hBMP-hBMPR-IB complex, in the abnormal proliferation of the prostate under physiological conditions, are warranted.