Studying Adipose Endothelial Cell/Adipocyte Cross-Talk in Human Subcutaneous Adipose Tissue.

Microvascular endothelial cells (MVECs) have many critical roles, including control of vascular tone, regulation of thrombosis, and angiogenesis. Significant heterogeneity in endothelial cell (EC) genotype and phenotype depends on their vascular bed and host disease state. The ability to isolate MVECs from tissue-specific vascular beds and individual patient groups offers the opportunity to directly compare MVEC function in different disease states.

Inhibition of the voltage-gated potassium channel Kv1.5 by hydrogen sulfide attenuates remodeling through S-nitrosylation-mediated signaling.

The voltage-gated K channel plays a key role in atrial excitability, conducting the ultra-rapid rectifier K current (I) and contributing to the repolarization of the atrial action potential. In this study, we examine its regulation by hydrogen sulfide (HS) in HL-1 cardiomyocytes and in HEK293 cells expressing human Kv1.5.

Hydrogen sulfide regulates hippocampal neuron excitability via S-sulfhydration of Kv2.1.

Hydrogen sulfide (HS) is gaining interest as a mammalian signalling molecule with wide ranging effects. S-sulfhydration is one mechanism that is emerging as a key post translational modification through which HS acts. Ion channels and neuronal receptors are key target proteins for S-sulfhydration and this can influence a range of neuronal functions.

Kv1.3 voltage-gated potassium channels link cellular respiration to proliferation through a non-conducting mechanism.

Cellular energy metabolism is fundamental for all biological functions. Cellular proliferation requires extensive metabolic reprogramming and has a high energy demand. The Kv1.

Brown and beige adipose tissue regulate systemic metabolism through a metabolite interorgan signaling axis.

Brown and beige adipose tissue are emerging as distinct endocrine organs. These tissues are functionally associated with skeletal muscle, adipose tissue metabolism and systemic energy expenditure, suggesting an interorgan signaling network. Using metabolomics, we identify 3-methyl-2-oxovaleric acid, 5-oxoproline, and β-hydroxyisobutyric acid as small molecule metabokines synthesized in browning adipocytes and secreted via monocarboxylate transporters.

Unique Transcriptome Signature Distinguishes Patients With Heart Failure With Myopathy.

Background People with chronic heart failure (CHF) experience severe skeletal muscle dysfunction, characterized by mitochondrial abnormalities, which exacerbates the primary symptom of exercise intolerance. However, the molecular triggers and characteristics underlying mitochondrial abnormalities caused by CHF remain poorly understood. Methods and Results We recruited 28 patients with CHF caused by reduced ejection fraction and 9 controls.

Piezo1 channel activation mimics high glucose as a stimulator of insulin release.

Glucose and hypotonicity induced cell swelling stimulate insulin release from pancreatic β-cells but the mechanisms are poorly understood. Recently, Piezo1 was identified as a mechanically-activated nonselective Ca permeable cationic channel in a range of mammalian cells. As cell swelling induced insulin release could be through stimulation of Ca permeable stretch activated channels, we hypothesised a role for Piezo1 in cell swelling induced insulin release.

Multiple mechanisms mediating carbon monoxide inhibition of the voltage-gated K channel Kv1.5.

The voltage-gated K channel has key roles in the vasculature and in atrial excitability and contributes to apoptosis in various tissues. In this study, we have explored its regulation by carbon monoxide (CO), a product of the cytoprotective heme oxygenase enzymes, and a recognized toxin. CO inhibited recombinant Kv1.

A key role for peroxynitrite-mediated inhibition of cardiac ERG (Kv11.1) K channels in carbon monoxide-induced proarrhythmic early afterdepolarizations.

Exposure to CO causes early afterdepolarization arrhythmias. Previous studies in rats have indicated that arrhythmias arose as a result of augmentation of the late Na current. The purpose of the present study was to examine the basis for CO-induced arrhythmias in guinea pig myocytes in which action potentials (APs) more closely resemble those of human myocytes.

Heme oxygenase-1 derived carbon monoxide suppresses Aβ toxicity in astrocytes.

Neurodegeneration in Alzheimer's disease (AD) is extensively studied, and the involvement of astrocytes and other cell types in this process has been described. However, the responses of astrocytes themselves to amyloid β peptides ((Aβ; the widely accepted major toxic factor in AD) is less well understood. Here, we show that Aβ is toxic to primary cultures of astrocytes.

Redox-Dependent Modulation of T-Type Ca(2+) Channels in Sensory Neurons Contributes to Acute Anti-Nociceptive Effect of Substance P.

Aims: Neuropeptide substance P (SP) is produced and released by a subset of peripheral sensory neurons that respond to tissue damage (nociceptors). SP exerts excitatory effects in the central nervous system, but peripheral SP actions are still poorly understood; therefore, here, we aimed at investigating these peripheral mechanisms.

Results: SP acutely inhibited T-type voltage-gated Ca(2+) channels in nociceptors.

Regulation of the T-type Ca(2+) channel Cav3.2 by hydrogen sulfide: emerging controversies concerning the role of H2 S in nociception.

Ion channels represent a large and growing family of target proteins regulated by gasotransmitters such as nitric oxide, carbon monoxide and, as described more recently, hydrogen sulfide. Indeed, many of the biological actions of these gases can be accounted for by their ability to modulate ion channel activity. Here, we report recent evidence that H2 S is a modulator of low voltage-activated T-type Ca(2+) channels, and discriminates between the different subtypes of T-type Ca(2+) channel in that it selectively modulates Cav3.

Inhibition of T-type Ca2+ Channels by Hydrogen Sulfide.

T-type Ca(2+) channels are a distinct family of low voltage-activated Ca(2+) channels which serve many roles in different tissues. Several studies have implicated them, for example, in the adaptive responses to chronic hypoxia in the cardiovascular and endocrine systems. Hydrogen sulfide (H(2)S) was more recently discovered as an important signalling molecule involved in many functions, including O(2) sensing.

Heme Oxygenase-1 Influences Apoptosis via CO-mediated Inhibition of K+ Channels.

Hypoxic/ischemic episodes can trigger oxidative stress-mediated loss of central neurons via apoptosis, and low pO2 is also a feature of the tumor microenvironment, where cancer cells are particularly resistant to apoptosis. In the CNS, ischemic insult increases expression of the CO-generating enzyme heme oxygenase-1 (HO-1), which is commonly constitutively active in cancer cells. It has been proposed that apoptosis can be regulated by the trafficking and activity of K(+) channels, particularly Kv2.

T-Type Ca2+ Channel Regulation by CO: A Mechanism for Control of Cell Proliferation.

T-type Ca(2+) channels regulate proliferation in a number of tissue types, including vascular smooth muscle and various cancers. In such tissues, up-regulation of the inducible enzyme heme oxygenase-1 (HO-1) is often observed, and hypoxia is a key factor in its induction. HO-1 degrades heme to generate carbon monoxide (CO) along with Fe(2+) and biliverdin.

H2S does not regulate proliferation via T-type Ca2+ channels.

T-type Ca(2+) channels (Cav3.1, 3.2 and 3.

Oxygen-dependent hydroxylation by FIH regulates the TRPV3 ion channel.

Factor inhibiting HIF (FIH, also known as HIF1AN) is an oxygen-dependent asparaginyl hydroxylase that regulates the hypoxia-inducible factors (HIFs). Several proteins containing ankyrin repeat domains (ARDs) have been characterised as substrates of FIH, although there is little evidence for a functional consequence of hydroxylation on these substrates. This study demonstrates that the transient receptor potential vanilloid 3 (TRPV3) channel is hydroxylated by FIH on asparagine 242 within the cytoplasmic ARD.

Hydrogen sulfide inhibits Cav3.2 T-type Ca2+ channels.

The importance of H2S as a physiological signaling molecule continues to develop, and ion channels are emerging as a major family of target proteins through which H2S exerts many actions. The purpose of the present study was to investigate its effects on T-type Ca(2+) channels. Using patch-clamp electrophysiology, we demonstrate that the H2S donor, NaHS (10 μM-1 mM) selectively inhibits Cav3.

Heme oxygenase-1 regulates cell proliferation via carbon monoxide-mediated inhibition of T-type Ca2+ channels.

Induction of the antioxidant enzyme heme oxygenase-1 (HO-1) affords cellular protection and suppresses proliferation of vascular smooth muscle cells (VSMCs) associated with a variety of pathological cardiovascular conditions including myocardial infarction and vascular injury. However, the underlying mechanisms are not fully understood. Over-expression of Cav3.

Inhibition of the cardiac Na⁺ channel Nav1.5 by carbon monoxide.

Sublethal carbon monoxide (CO) exposure is frequently associated with myocardial arrhythmias, and our recent studies have demonstrated that these may be attributable to modulation of cardiac Na(+) channels, causing an increase in the late current and an inhibition of the peak current. Using a recombinant expression system, we demonstrate that CO inhibits peak human Nav1.5 current amplitude without activation of the late Na(+) current observed in native tissue.

Carbon monoxide inhibition of Cav3.2 T-type Ca2+ channels reveals tonic modulation by thioredoxin.

T-type Ca(2+) channels play diverse roles in tissues such as sensory neurons, vascular smooth muscle, and cancers, where increased expression of the cytoprotective enzyme, heme oxygenase-1 (HO-1) is often found. Here, we report regulation of T-type Ca(2+) channels by carbon monoxide (CO) a HO-1 by-product. CO (applied as CORM-2) caused a concentration-dependent, poorly reversible inhibition of all T-type channel isoforms (Cav3.

Carbon monoxide induces cardiac arrhythmia via induction of the late Na+ current.

Rationale: Clinical reports describe life-threatening cardiac arrhythmias after environmental exposure to carbon monoxide (CO) or accidental CO poisoning. Numerous case studies describe disruption of repolarization and prolongation of the QT interval, yet the mechanisms underlying CO-induced arrhythmias are unknown.

Objectives: To understand the cellular basis of CO-induced arrhythmias and to identify an effective therapeutic approach.

Carbon monoxide mediates the anti-apoptotic effects of heme oxygenase-1 in medulloblastoma DAOY cells via K+ channel inhibition.

Tumor cell survival and proliferation is attributable in part to suppression of apoptotic pathways, yet the mechanisms by which cancer cells resist apoptosis are not fully understood. Many cancer cells constitutively express heme oxygenase-1 (HO-1), which catabolizes heme to generate biliverdin, Fe(2+), and carbon monoxide (CO). These breakdown products may play a role in the ability of cancer cells to suppress apoptotic signals.

Cellular consequences of the expression of Alzheimer's disease-causing presenilin 1 mutations in human neuroblastoma (SH-SY5Y) cells.

Mutations in the presenilin 1 (PS1) gene lead to early-onset Alzheimer's disease with the S170F mutation causing the earliest reported age of onset. Expression of this, and other PS1 mutations, in SH-SY5Y cells resulted in significant loss of cellular viability compared to control cells. Basal Ca2+ concentrations in PS1 mutants were never lower than controls and prolonged incubation in Ca2+ -free solutions did not deplete Ca2+ stores, demonstrating there was no difference in Ca2+ leak from endoplasmic reticulum (ER) stores in PS1 mutants.

Modulation of ion channels by hydrogen sulfide.

Significance: Evidence of the ability of the gasotransmitter hydrogen sulfide (H(2)S) to serve as a regulator of many physiological functions, including control of blood pressure, regulation of cardiac function, protection of neurons, and cardiomyocytes against apoptosis, and in pain sensation is accumulating. However, the mechanisms accounting for its many actions are not yet well understood.

Recent Advances: Following the pioneering studies of the regulation of N-methyl-d-aspartate receptors and ATP-sensitive K(+) channels by H(2)S, data continue to emerge indicating that H(2)S modulates other ion channel types.