Endothelin XIII.

Twenty-five years ago, a groundbreaking paper from Tsukuba University in Japan was published, identifying the sequence of the endothelin gene and peptide (Nature 332, 411-415, 1988). This work opened the way for the discovery of the endothelin receptors and the development of orally active endothelin receptor antagonists (ERAs). Today, ERAs are part of medical therapy of patients around the world for the treatment of pulmonary arterial hypertension.

Brefeldin A is an estrogenic, Erk1/2-activating component in the extract of Agaricus blazei mycelia.

We purified an Erk1/2-activating component in Agaricus blazei and identified it as brefeldin A (BFA). The extract of A. blazei mycelia (ABE) previously showed an estrogenic gene-expression profile and positive effects in patients with cardiovascular symptoms.

Endothelin XII.

Following the initial description of endothelium-dependent vasoconstriction in the early 1980s, it has been exactly 25 years since efforts to identify the sequence of the endothelin gene and peptide began in May 1987, work which resulted in a landmark paper submitted to Nature in December 1987 and published on March 31, 1988. The paper opened an entirely new field of research, followed by the inception of the International Conferences of Endothelin, the first of which was organized by Sir John Vane as Chair and held as the "First William Harvey Workshop on Endothelin" in London, UK, in December of 1988. Endothelin receptor antagonism has now been firmly established for more than a decade as a new, orally active drug treatment for patients with pulmonary arterial hypertension.

Estrogen-like activity and dual roles in cell signaling of an Agaricus blazei Murrill mycelia-dikaryon extract.

Agaricus blazei (A. blazei) Murrill mycelia-dikaryon has attracted the attention of scientists and clinicians worldwide owing to its potential for the treatment of cancer. However, little is known about its effect on other pathologies.

Lagerstroemia speciosa extract inhibit TNF-induced activation of nuclear factor-kappaB in rat cardiomyocyte H9c2 cells.

Aim Of The Study: Lagerstroemia speciosa has been used as a folk medicine among people with diabetes in the Philippines. It is known to exhibit antidiabetic, antiobesity, and glucose transport activities through mechanisms not well defined. Diabetes leads to cardiomyocyte hypertrophy in association with an upregulation of vasoactive factors and activation of nuclear factor (NF)-kappaB and activating protein-1.

Involvement of phospholipase C in endothelin 1-induced stimulation of Ca++ channels and basilar artery contraction in rabbits.

Endothelin 1 (ET-1) is a major cause of cerebral vasospasm after subarachnoid hemorrhage (SAH), and extracellular Cal++ influx plays an essential role in ET-1-induced vasospasm. The authors recently demonstrated that ET-1 activates two types of Ca"-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) and a store-operated Cal++ channel (SOCC) in vascular smooth-muscle cells located in the basilar arteries (BAs) of rabbits. In the present study, they investigate the effects of phospholipase C (PLC) on ET-1-induced activation of these Ca++ channels and BA contraction by using the PLC inhibitor U73122.

Endothelin and endothelial dysfunction.

Nitric oxide (NO) and endothelin (ET) produced in endothelial cells are leading molecules which regulate vascular function. Failure of the physiological balance between these two molecules is usually referred to as endothelial dysfunction. ET was initially identified as a potent vasoconstrictive peptide.

Molecular mechanisms for activation of voltage-independent Ca2+ channels by endothelin-1/endothelin-A receptors.

Endothelin-1 (ET-1) activates two types of Ca2+- permeable non-selective cation channels (designated NSCC-1 and NSCC-2) and a store-operated Ca2+ channel (SOCC) in Chinese hamster ovary cells expressing endothelin-A receptors (CHOETAR), which couple with Gq, Gs and G12. The purpose of this study was to identify the G proteins involved in the activation of these Ca channels, using mutated ETARs with coupling to either Gq or Gs/G12 (designated ETAR(Delta)385 and SerETAR, respectively) and a dominant negative mutant of G12 (G12G228A). ETAR(Delta)385 is truncated downstream of Cys385 in the C-terminal as palmitoylation sites, whereas SerET(A)R is unpalmitoylated because of substitution of all the cysteine residues to serine (CysCys --> SerSer).

Induction of endothelin-1 production in endothelial cells via co-operative action between CD40 and lectin-like oxidized LDL receptor (LOX-1).

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), originally identified as the major receptor for oxidized low-density lipoprotein in endothelial cells, mediates the interaction between activated platelets and endothelial cells. Stimulation of LOX-1 causes various functional changes in endothelial cells relevant to 'endothelial dysfunction'. This study investigated the cellular responses to platelet binding via LOX-1, comparing it with CD40, which also mediates platelet-binding in endothelial cells.

Involvement of epidermal growth factor receptor-protein tyrosine kinase transactivation in endothelin-1-induced vascular contraction.

Object: Endothelin-1 (ET-1) is one of the major inducers of vasospasm following subarachnoid hemorrhage (SAH). It is generally accepted that extracellular signal-regulated kinase 1 and 2 (ERK1/2) are involved in ET-1-induced vascular contraction. In addition, ET-1 transactivates epidermal growth factor receptor (EGFR) protein tyrosine kinase (PTK), which leads to ERK1/2 stimulation.

Effects of phosphoinositide 3-kinase on endothelin-1-induced activation of voltage-independent Ca2+ channels and vasoconstriction.

We recently demonstrated that endothelin-1 (ET-1) activates two types of Ca(2+)-permeable nonselective cation channel (designated NSCC-1 and NSCC-2) and a store-operated Ca(2+) channel (SOCC) in rabbit basilar artery (BA) vascular smooth muscle cells (VSMCs). In this study, we investigated the effects of phosphoinositide 3-kinase (PI3K) on ET-1-induced activation of these channels and BA contraction by using PI3K inhibitors, wortmannin and LY 249002. To determine which Ca(2+) channels are activated via PI3K, monitoring of intracellular Ca(2+) concentration was performed.

Historical review: Endothelin.

Endothelin (ET) is a potent vasoconstrictive peptide that was isolated initially from the conditioned medium of cultured endothelial cells. In 1988, details of the isolation and identification, amino acid sequence, cDNA sequence and pharmacology of ET were published. Subsequently, ET isoforms, ET receptors and endothelin-converting enzyme (ECE) were cloned.

Characterization of G proteins involved in activation of nonselective cation channels and arachidonic acid release by norepinephrine/alpha1A-adrenergic receptors.

We demonstrated recently that norepinephrine activates Ca2+ -permeable nonselective cation channels (NSCCs) in Chinese hamster ovary cells stably expressing alpha1A-adrenergic receptors (CHO-alpha1A). Moreover, extracellular Ca2+ through NSCCs plays essential roles in norepinephrine-induced arachidonic acid release. The purpose of the present study was to identify the G proteins involved in the activation of NSCCs and arachidonic acid release by norepinephrine.

Involvement of extracellular Ca2+ influx and epidermal growth factor receptor tyrosine kinase transactivation in endothelin-1-induced arachidonic acid release.

1. Endothelin-1 (ET-1) activates two types of Ca(2+)-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) and a store-operated Ca(2+) channel (SOCC) in vascular smooth muscle cells (VSMCs). These channels can be distinguished by their sensitivity to Ca(2+)-channel blockers, SK&F 96365 and LOE 908.

Characterization of Ca2+ channels and G proteins involved in arachidonic acid release by endothelin-1/endothelinA receptor.

Endothelin-1 (ET-1) activates two types of Ca2+-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) and a store-operated Ca2+ channel (SOCC) in Chinese hamster ovary cells expressing endothelinA receptors (CHO-ETAR). These channels can be distinguished by their sensitivity to Ca2+ channel blockers 1-(beta-[3-(4-methoxyphenyl) propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride (SK&F 96365) and (R,S)-(3,4-dihydro-6,7-dimethoxy-isochinolin-1-yl)-2-phenyl-N,N-di[2-(2,3,4-trimethoxyphenyl)ethyl]acetamid mesylate (LOE 908). NSCC-1 is sensitive to LOE 908 and resistant to SK&F 96365; NSCC-2 is sensitive to both blockers, and SOCC is resistant to LOE 908 and sensitive to SK&F 96365.

Effects of nonselective cation channels and PI3K on endothelin-1-induced PYK2 tyrosine phosphorylation in C6 glioma cells.

We recently demonstrated that endothelin-1 (ET-1) activates two types of Ca2+-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) in C6 glioma cells. In the present study, we investigated the effects of NSCCs on the ET-1-induced proline-rich tyrosine kinase 2 (PYK2) phosphorylation in C6 glioma cells. In addition, we examined the effects of phosphoinositide 3-kinase (PI3K) on the ET-1-induced NSCCs activation and PYK2 phosphorylation.

Molecular mechanisms for the activation of Ca2+-permeable nonselective cation channels by endothelin-1 in C6 glioma cells.

We recently demonstrated that endothelin-1 (ET-1) activates two types of Ca(2+)-permeable nonselective cation channels (NSCC-1 and NSCC-2) in C6 glioma cells. It is possible to discriminate between these channels by using the Ca(2+) channel blockers SK&F 96365 (1-[beta-(3-[4-methoxyphenyl]propoxy)-4-methoxyphenethyl]-1H-imidazole hydrochloride) and LOE 908 [(R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di-[2-(2,3,4-trimethoxyphenyl)ethyl]-acetamide]. LOE 908 is a blocker for NSCC-1 and NSCC-2, whereas SK&F 96365 is an inhibitor for NSCC-2.

Effects of the Ca++-permeable nonselective cation channel blocker LOE 908 on subarachnoid hemorrhage-induced vasospasm in the basilar artery in rabbits.

Object: The Ca++ influx into vascular smooth-muscle cells (VSMCs) plays a fundamental role in the development and chronic effects of vasospasm after subarachnoid hemorrhage (SAH). The Ca++-permeable nonselective cation channels (NSCCs) are activated by several endothelium-derived constricting factors such as endothelin 1 (ET-1) and thromboxane A2. Moreover, the receptor-operated Ca++ channel blocker LOE 908 inhibits ET-1-induced extracellular Ca++ influx via NSCCs in the VSMCs of the basilar artery (BA) and the NSCC-dependent part of ET-1-induced vasoconstriction of BA rings.

Oxidized LDL receptor gene (OLR1) is associated with the risk of myocardial infarction.

Lectin-like oxidized low-density lipoprotein receptor (LOX-1/OLR1) has been suggested to play a role in the progression of atherogenesis. We analyzed the OLR1 gene and found a single nucleotide polymorphism (SNP), G501C, in patients with ischemic heart disease from a single family, which resulted in the missense mutation of K167N in LOX-1 protein. We compared the group of patients with myocardial infarction (MI) (n=102) with a group of clinically healthy subjects (n=102), and found that the MI group had a significantly high frequency of 501G/C+501C/C (38.

Involvements of voltage-independent Ca2+ channels and phosphoinositide 3-kinase in endothelin-1-induced PYK2 tyrosine phosphorylation.

We demonstrated recently that endothelin-1 (ET-1) activates two types of Ca(2+)-permeable nonselective cation channels [designated nonselective cation channel (NSCC)-1 and NSCC-2] and a store-operated Ca(2+) channel (SOCC) in rabbit internal carotid artery vascular smooth muscle cells (ICA VSMCs). These channels can be distinguished by their sensitivity to Ca(2+) channel blockers 1-(beta-[3-(4-methoxyphenyl) propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride (SK&F 96365) and (R,S)-(3,4-dihydro-6,7-dimethoxy-isochinolin-1-yl)-2-phenyl-N,N-di[2-(2,3,4-trimethoxyphenyl)ethyl]acetamid mesylate (LOE 908). NSCC-1 is sensitive to LOE 908 and resistant to SK&F 96365, NSCC-2 is sensitive to both LOE 908 and SK&F 96365, and SOCC is resistant to LOE 908 and sensitive to SK&F 96365.

Lectin-like oxidized LDL receptor-1 is a cell-adhesion molecule involved in endotoxin-induced inflammation.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a major endothelial receptor for oxidized low-density lipoprotein, and is assumed to play a proatherogenic role in atherosclerosis. LOX-1 expression is induced by inflammatory cytokines as well as by proatherogenic stimuli. LOX-1 protein binds agedapoptotic cells, activated platelets, and bacteria, suggesting that it may have diverse activities in vivo.

Role of phosphoinositide 3-kinase in the nonselective cation channel activation by endothelin-1/endothelinB receptor.

We recently demonstrated that endothelin-1 (ET-1) activates two types of Ca(2+)-permeable nonselective cation channel (designated NSCC-1 and NSCC-2) in Chinese hamster ovarian cells expressing endothelin(B) receptor (CHO-ET(B)R). These channels can be discriminated using the Ca(2+) channel blockers, LOE 908 and SK&F 96365. LOE 908 is a blocker of NSCC-1 and NSCC-2, whereas SK&F 96365 is a blocker of NSCC-2.

LOX-1 expressed in cultured rat chondrocytes mediates oxidized LDL-induced cell death-possible role of dephosphorylation of Akt.

The oxidative changes of lipids in cartilage proceed with ageing and with the grade of osteoarthritis. To clarify the role of oxidatively modified lipids in articular cartilage in osteoarthritis, here, we investigated lectin-like oxidized LDL receptor (LOX-1) in rat cultured articular chondrocytes. LOX-1 expression was detectable in basal culture condition and enhanced by the treatment of oxidized LDL and interleukin-1beta.