Sex-mediated effects of transglutaminase 2 inhibition on endothelial function in human resistance arteries from diabetic and non-diabetic patients.

Transglutaminase 2 (TG2) is an enzyme with multiple conformations. In its open conformation, TG2 exhibits transamidase activity linked to fibrosis, arterial remodeling, and endothelial dysfunction, a process enhanced by high glucose in endothelial cells. However, the closed conformation of TG2 contributes to transmembrane signaling and nitric oxide (NO)-dependent vasorelaxation.

Pharmacological modulation of transglutaminase 2 in the unilateral ureteral obstruction mouse model.

Background: Transglutaminase 2 (TG2) is a multifunctional enzyme involved in fibrosis by promoting transforming-growth-factor-β1 and crosslinking of extracellular matrix proteins. These functions are dependent on the open conformation, while the closed state of TG2 can induce vasodilation. We explored the putative protective role of TG2 in its closed state on development of renal fibrosis and blood pressure (BP) regulation.

The Melatonin Derivative ITH13001 Prevents Hypertension and Cardiovascular Alterations in Angiotensin II-Infused Mice.

Inflammatory mechanisms and oxidative stress seem to contribute to the pathogenesis of hypertension. ITH13001 is a melatonin-phenyl-acrylate hybrid that moderately induces the antioxidant transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) and has a potent oxidant scavenging effect compared with other derivatives of its family. Here we investigated the effect of ITH13001 on hypertension and the associated cardiovascular alterations.

Combined effects of methadone and quetiapine on respiratory rate, haemodynamic variables, and temperature in conscious rats.

Fatal poisonings where both methadone and quetiapine are detected post-mortem occurs frequently in legal autopsy cases. It is unclear whether quetiapine increases the risk of fatal methadone poisoning or if it is merely detected due to widespread use. We hypothesized that methadone and quetiapine would have additive toxic effects on respiratory rate, blood pressure, and the QTc-interval.

Sex-Dependent Impairment of Endothelium-Dependent Relaxation in Aorta of Mice with Overexpression of Hyaluronan in Tunica Media.

Diabetic macroangiopathy is characterized by increased extracellular matrix deposition, including excessive hyaluronan accumulation, vessel thickening and stiffness, and endothelial dysfunction in large arteries. We hypothesized that the overexpression of hyaluronan in the tunica media also led to endothelial cell (EC) dysfunction. To address this hypothesis, we investigated the following in the aortas of mice with excessive hyaluronan accumulation in the tunica media (HAS-2) and wild-type mice: EC dysfunction via myograph studies, nitric oxide (NO) bioavailability via diaminofluorescence, superoxide formation via dihydroethidium fluorescence, and the distances between ECs via stereological methods.

Erectile Dysfunction and Altered Contribution of KCa1.1 and KCa2.3 Channels in the Penile Tissue of Type-2 Diabetic db/db Mice.

Background: Activation of endothelial small conductance calcium-activated K+ channels (KCa2.3) and intermediate conductance calcium-activated K+ channels (KCa3.1) leads to vascular relaxation.

Combined effects of quetiapine and opioids: A study of autopsy cases, drug users and sedation in rats.

Fatal opioid poisonings often involve methadone or morphine. This study aimed to elucidate if quetiapine, a widely used sedative antipsychotic medication, may increase the risk of fatal opioid poisoning by additive inhibitory effects on the central nervous system. We used data from 323 cases of fatal methadone or/and morphine poisonings autopsied from 2013 to 2020, a survey of 34 drug users, and performed blinded placebo-controlled studies in 75 Flinders Resistant Line rats receiving three cumulative intraperitoneal doses of vehicle, methadone (2.

Erectile Dysfunction and Altered Contribution of KCa1.1 and KCa2.3 Channels in the Penile Tissue of Type-2 Diabetic db/db Mice.

Background: Activation of endothelial small conductance calcium-activated K channels (KCa2.3) and intermediate conductance calcium-activated K channels (KCa3.1) leads to vascular relaxation.

Differential contribution of renal cytochrome P450 enzymes to kidney endothelial dysfunction and vascular oxidative stress in obesity.

Arachidonic acid (AA)-derived cytochrome P450 (CYP) derivatives, epoxyeicosatrienoic acids (EETs) and 20-hidroxyeicosatetranoic acid (20-HETE), play a key role in kidney tubular and vascular functions and blood pressure. Altered metabolism of CYP epoxygenases and CYP hydroxylases has differentially been involved in the pathogenesis of metabolic disease-associated vascular complications, although the mechanisms responsible for the vascular injury are unclear. The present study aimed to assess whether obesity-induced changes in CYP enzymes may contribute to oxidative stress and endothelial dysfunction in kidney preglomerular arteries.

Cystamine Treatment Fails to Prevent the Development of Pulmonary Hypertension in Chronic Hypoxic Rats.

Introduction: Pulmonary hypertension is characterized by vasoconstriction and remodeling of pulmonary arteries, leading to right ventricular hypertrophy and failure. We have previously found upregulation of transglutaminase 2 (TG2) in the right ventricle of chronic hypoxic rats. The hypothesis of the present study was that treatment with the transglutaminase inhibitor, cystamine, would inhibit the development of pulmonary arterial remodeling, pulmonary hypertension, and right ventricular hypertrophy.

Pirfenidone Is a Vasodilator: Involvement of K7 Channels in the Effect on Endothelium-Dependent Vasodilatation in Type-2 Diabetic Mice.

Endothelial cell dysfunction and fibrosis are associated with worsening of the prognosis in patients with cardiovascular disease. Pirfenidone has a direct antifibrotic effect, but vasodilatation may also contribute to the effects of pirfenidone. Therefore, in a first study we investigated the mechanisms involved in the relaxant effect of pirfenidone in rat intrapulmonary arteries and coronary arteries from normal mice.

Endothelial K 1.1 and K 3.1 channels mediate rat intrarenal artery endothelium-derived hyperpolarization response.

Aim: Endothelium-derived hyperpolarization (EDH)-mediated response plays an essential role in the control of kidney preglomerular circulation, but the identity of the K channels involved in this response is still controversial. We hypothesized that large- (K 1.1), intermediate- (K 3.

Transglutaminase 2 as a novel target in chronic kidney disease - Methods, mechanisms and pharmacological inhibition.

Chronic kidney disease (CKD) is a global health problem with a prevalence of 10-15%. Progressive fibrosis of the renal tissue is a main feature of CKD, but current treatment strategies are relatively unspecific and delay, but do not prevent, CKD. Exploration of novel pharmacological targets to inhibit fibrosis development are therefore important.

Transglutaminase 2 Inhibitor LDN 27219 Age-Dependently Lowers Blood Pressure and Improves Endothelium-Dependent Vasodilation in Resistance Arteries.

Transglutaminase 2 (TG2) is an enzyme which in the open conformation exerts transamidase activity, leading to protein cross-linking and fibrosis. In the closed conformation, TG2 participates in transmembrane signaling as a G protein. The unspecific transglutaminase inhibitor cystamine causes vasorelaxation in rat resistance arteries.

Endothelial Dysfunction and Passive Changes in the Aorta and Coronary Arteries of Diabetic db/db Mice.

Endothelial cell dysfunction and vessel stiffening are associated with a worsened prognosis in diabetic patients with cardiovascular diseases. The present study hypothesized that sex impacts endothelial dysfunction and structural changes in arteries from diabetic mice. In diabetic (db/db) and normoglycaemic (db/db+) mice, the mechanical properties were investigated in pressurized isolated left anterior descending coronary arteries and aorta segments that were subjected to tensile testing.

Novel selective PDE type 1 inhibitors cause vasodilatation and lower blood pressure in rats.

Background And Purpose: The PDE enzymes (PDE1-11) hydrolyse and thus inactivate cyclic nucleotides and are important in the regulation of the cardiovascular system. Here,we have investigated the effects on the cardiovascular system, of two novel selective PDE1 inhibitors, Lu AF41228 and Lu AF58027.

Experimental Approach: We used rat mesenteric small arteries (internal diameters of 200-300 μm), RT-PCR and measured isometric wall tension.

CYP epoxygenase-derived HO is involved in the endothelium-derived hyperpolarization (EDH) and relaxation of intrarenal arteries.

Reactive oxygen species (ROS) like hydrogen peroxide (HO) are involved in the in endothelium-derived hyperpolarization (EDH)-type relaxant responses of coronary and mesenteric arterioles. The role of ROS in kidney vascular function has mainly been investigated in the context of harmful ROS generation associated to kidney disease. The present study was sought to investigate whether HO is involved in the endothelium-dependent relaxations of intrarenal arteries as well the possible endothelial sources of ROS generation involved in these responses.

Vascular Reactivity Profile of Novel KCa 3.1-Selective Positive-Gating Modulators in the Coronary Vascular Bed.

Opening of intermediate-conductance calcium-activated potassium channels (KC a 3.1) produces membrane hyperpolarization in the vascular endothelium. Here, we studied the ability of two new KC a 3.

Involvement of transglutaminase 2 and voltage-gated potassium channels in cystamine vasodilatation in rat mesenteric small arteries.

Background And Purpose: Vasodilatation may contribute to the neuroprotective and vascular anti-remodelling effect of the tissue transglutaminase 2 (TG2) inhibitor cystamine. Here, we hypothesized that inhibition of TG2 followed by blockade of smooth muscle calcium entry and/or inhibition of Rho kinase underlies cystamine vasodilatation.

Experimental Approach: We used rat mesenteric small arteries and RT-PCR, immunoblotting, and measurements of isometric wall tension, intracellular Ca(2+) ([Ca(2+)]i ), K(+) currents (patch clamp), and phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and myosin regulatory light chain, in our experiments.