Protection by selective mTORC2 inhibition of Zymosan-induced hypotension and systemic inflammation mediated via IKKα/IκB-α/NF-κB activation.

Non-septic shock is a serious condition leading to multiple organ dysfunction. Although targeting the mammalian target of the rapamycin complex 1 (mTORC1) signaling pathway exerts potent anti-inflammatory activity, little is known about mTORC2's contribution to non-septic shock. Thus, our research aims to investigate mTORC2's contribution and associated changes of IκB kinase (IKKα)/inhibitor κB (IκB-α)/nuclear factor-ĸB (NF-κB) pathway on Zymosan (ZYM)-induced non-septic rat model using the novel mTORC2 selective inhibitor JR-AB2-011.

Vasodilators activate the anion channel TMEM16A in endothelial cells to reduce blood pressure.

Systemic blood pressure is acutely controlled by total peripheral resistance as determined by the diameter of small arteries and arterioles, the contractility of which is regulated by endothelial cells lining the lumen of blood vessels. We investigated the physiological functions of the chloride (Cl) channel TMEM16A in endothelial cells. TMEM16A channels generated calcium (Ca)-activated Cl currents in endothelial cells from control () mice that were absent in those from mice with tamoxifen-inducible, endothelial cell-specific knockout of TMEM16A ( ecKO).

Vasodilators activate TMEM16A channels in endothelial cells to reduce blood pressure.

Unlabelled: Endothelial cells (ECs) regulate vascular contractility to control regional organ blood flow and systemic blood pressure. Several cation channels are expressed in ECs which regulate arterial contractility. In contrast, the molecular identity and physiological functions of anion channels in ECs is unclear.

Ovariectomy Via 12/15-lipoxygenase Augments Angiotensin II-Induced Hypertension and Its Pathogenesis in Female Mice.

Background: Ang II (angiotensin II) releases arachidonic acid from tissue phospholipids that is metabolized by 12/15-lipoxygenase (ALOX15), generating 12(S)- and 15(S)-hydroxyeicosatetraenoic acid (HETE), which have been implicated in cardiovascular and renal diseases. In this study, we tested the hypothesis that ovariectomy augments Ang II-induced hypertension and renal pathophysiological changes via ALOX15 activation in female mice.

Methods: Ang II (700 ng/kg/min) was infused subcutaneously by osmotic pumps for 2 weeks in intact and ovariectomized wild-type and knockout (ALOX15KO) female mice for evaluation of hypertension and associated pathogenesis.

White matter damage as a consequence of vascular dysfunction in a spontaneous mouse model of chronic mild chronic hypoperfusion with eNOS deficiency.

Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia after Alzheimer's disease (AD). Currently, the mechanistic insights into the evolution and progression of VCID remain elusive. White matter change represents an invariant feature.

Activation of GPR75 Signaling Pathway Contributes to the Effect of a 20-HETE Mimetic, 5,14-HEDGE, to Prevent Hypotensive and Tachycardic Responses to Lipopolysaccharide in a Rat Model of Septic Shock.

The orphan receptor, G protein-coupled receptor (GPR) 75, which has been shown to mediate various effects of 20-hydroxyeicosatetraenoic acid (20-HETE), is considered as a therapeutic target in the treatment of cardiovascular diseases in which changes in the production of 20-HETE play a key role in their pathogenesis. Our previous studies showed that 20-HETE mimetic, N -(20-hydroxyeicosa-5[Z],14[Z]-dienoyl)glycine (5,14-HEDGE), protects against vascular hyporeactivity, hypotension, tachycardia, and arterial inflammation induced by lipopolysaccharide (LPS) in rats. This study tested the hypothesis that the GPR75 signaling pathway mediates these effects of 5,14-HEDGE in response to systemic exposure to LPS.

A plasma membrane-localized polycystin-1/polycystin-2 complex in endothelial cells elicits vasodilation.

Polycystin-1 (PC-1, PKD1), a receptor-like protein expressed by the gene, is present in a wide variety of cell types, but its cellular location, signaling mechanisms, and physiological functions are poorly understood. Here, by studying tamoxifen-inducible, endothelial cell (EC)-specific knockout ( ecKO) mice, we show that flow activates PC-1-mediated, Ca-dependent cation currents in ECs. EC-specific PC-1 knockout attenuates flow-mediated arterial hyperpolarization and vasodilation.

Pharmacological Inhibition of Mammalian Target of Rapamycin Attenuates Deoxycorticosterone Acetate Salt-Induced Hypertension and Related Pathophysiology: Regulation of Oxidative Stress, Inflammation, and Cardiovascular Hypertrophy in Male Rats.

The present study aimed to explore the contribution of mammalian target of rapamycin (mTOR) in deoxycorticosterone acetate (DOCA) salt-induced hypertension and related pathophysiological changes in cardiovascular and renal tissues. DOCA salt loading resulted in an increase in systolic blood pressure, diastolic blood pressure, and mean blood pressure along with the activity of ribosomal protein S6, the effector protein of mTOR. Treatment with rapamycin, the selective inhibitor of mTOR, initiated at the fourth week of DOCA- salt administration normalized the systolic blood pressure and attenuated ribosomal protein S6 activity in the heart, aorta, and kidney.

Renin-Angiotensin System Alterations in the Human Alzheimer's Disease Brain.

Background: Understanding Alzheimer's disease (AD) in terms of its various pathophysiological pathways is essential to unravel the complex nature of the disease process and identify potential therapeutic targets. The renin-angiotensin system (RAS) has been implicated in several brain diseases, including traumatic brain injury, ischemic stroke, and AD.

Objective: This study was designed to evaluate the protein expression levels of RAS components in postmortem cortical and hippocampal brain samples obtained from AD versus non-AD individuals.

2-Methoxyestradiol Ameliorates Angiotensin II-Induced Hypertension by Inhibiting Cytosolic Phospholipase Aα Activity in Female Mice.

[Figure: see text].

6β-Hydroxytestosterone Promotes Angiotensin II-Induced Hypertension via Enhanced Cytosolic Phospholipase Aα Activity.

[Figure: see text].

Testosterone Metabolite 6β-Hydroxytestosterone Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysms in Male Mice.

Background Sex is a prominent risk factor for abdominal aortic aneurysms (AAAs), and angiotensin II (Ang II) induces AAA formation to a greater degree in male than in female mice. We previously reported that cytochrome P450 1B1 contributes to the development of hypertension, as well as AAAs, in male mice. We also found that a cytochrome P450 1B1-generated metabolite of testosterone, 6β-hydroxytestosterone (6β-OHT), contributes to Ang II-induced hypertension and associated cardiovascular and renal pathogenesis in male mice.

mTOR inhibition as a possible pharmacological target in the management of systemic inflammatory response and associated neuroinflammation by lipopolysaccharide challenge in rats.

Neuroinflammation plays a critical role during sepsis triggered by microglial activation. Mammalian target of rapamycin (mTOR) has gained attraction in neuroinflammation, however, the mechanism remains unclear. Our goal was to assess the effects of mTOR inhibition by rapamycin on inflammation, microglial activation, oxidative stress, and apoptosis associated with the changes in the inhibitor-κB (IκB)-α/nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α) pathway activity following a systemic challenge with lipopolysaccharide (LPS).

Brain Testosterone-CYP1B1 (Cytochrome P450 1B1) Generated Metabolite 6β-Hydroxytestosterone Promotes Neurogenic Hypertension and Inflammation.

Previously, we showed that peripheral administration of 6β-hydroxytestosterone, a CYP1B1 (cytochrome P450 1B1)-generated metabolite of testosterone, promotes angiotensin II-induced hypertension in male mice. However, the site of action and the underlying mechanism by which 6β-hydroxytestosterone contributes to angiotensin II-induced hypertension is not known. Angiotensin II increases blood pressure by its central action, and CYP1B1 is expressed in the brain.

Central CYP1B1 (Cytochrome P450 1B1)-Estradiol Metabolite 2-Methoxyestradiol Protects From Hypertension and Neuroinflammation in Female Mice.

Previously, we showed that peripheral administration of 2-ME (2-methoxyestradiol), a CYP1B1 (cytochrome P450 1B1)-catechol--methyltransferase (COMT) generated metabolite of E2 (17β-Estradiol), protects against angiotensin II-induced hypertension in female mice. The demonstration that central E2 inhibits angiotensin II-induced hypertension, together with the expression of CYP1B1 in the brain, led us to hypothesize that E2-CYP1B1 generated metabolite 2-ME in the brain mediates its protective action against angiotensin II-induced hypertension in female mice. To test this hypothesis, we examined the effect of intracerebroventricularly (ICV) administered E2 in ovariectomized (OVX)-wild-type () and OVX- mice on the action of systemic angiotensin II.

6β-Hydroxytestosterone, a metabolite of testosterone generated by CYP1B1, contributes to vascular changes in angiotensin II-induced hypertension in male mice.

Background: Previously, we showed that 6β-hydroxytestosterone (6β-OHT), a cytochrome P450 1B1 (CYP1B1)-derived metabolite of testosterone, contributes to angiotensin II (Ang II)-induced hypertension in male mice. This study was conducted to test the hypothesis that 6β-OHT contributes to increased vascular reactivity, endothelial dysfunction, vascular hypertrophy, and reactive oxygen species production associated with Ang II-induced hypertension.

Methods: Eight- to 10-week-old intact or castrated C57BL/6 J (Cyp1b1 and Cyp1b1) mice were anesthetized for implantation of a micro-osmotic pump which delivered Ang II (700 ng/kg/day) or saline for 14 days.

Eicosanoids derived from cytochrome P450 pathway of arachidonic acid and inflammatory shock.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock, the most common form of vasodilatory shock, is a subset of sepsis in which circulatory and cellular/metabolic abnormalities are severe enough to increase mortality. Inflammatory shock constitutes the hallmark of sepsis, but also a final common pathway of any form of severe long-term tissue hypoperfusion.

Modulation of oxidative-nitrosative stress and inflammatory response by rapamycin in target and distant organs in rats exposed to hindlimb ischemia-reperfusion: the role of mammalian target of rapamycin.

Mammalian target of rapamycin (mTOR) has been recognized with potential immunomodulatory properties playing an important role in various physiopathological processes including ischemia-reperfusion (I/R) injury. I/R injury stimulate reactive oxygen and nitrogen species by activating nicotinamide adenine dinucleotide phosphate oxidase and inducible nitric oxide synthase, respectively. Controversial results have been obtained in different I/R models following localized I/R; however, the precise role of the mTOR signaling pathway remains undefined.

Cytochrome P450 1B1 Is Critical for Neointimal Growth in Wire-Injured Carotid Artery of Male Mice.

Background We have reported that cytochrome P450 1B1 ( CYP 1B1), expressed in cardiovascular tissues, contributes to angiotensin II -induced vascular smooth muscle cell ( VSMC ) migration and proliferation and development of hypertension in various experimental animal models via generation of reactive oxygen species. This study was conducted to determine the contribution of CYP 1B1 to platelet-derived growth factor-BB-induced VSMC migration and proliferation in vitro and to neointimal growth in vivo. Methods and Results VSMC s isolated from aortas of male Cyp1b1 and Cyp1b1 mice were used for in vitro experiments.

NF-κB activation mediates LPS-or zymosan-induced hypotension and inflammation reversed by BAY61-3606, a selective Syk inhibitor, in rat models of septic and non-septic shock.

We have previously demonstrated that the activation of the spleen tyrosine kinase (Syk)/inhibitory-κB (IκB)-α/nuclear factor-κB (NF-κB) p65 signalling pathway contributes to hypotension and inflammatory response in a rat models of zymosan (ZYM)-induced non-septic shock. The purpose of this study was to further examine the possible mechanism underlying the effect of inhibition of Syk by BAY61-3606 via NF-κB activity at the level of nuclear translocation regarding the production of vasodilator and proinflammatory mediators in lipopolysaccharide (LPS) (septic)- and ZYM (non-septic)-induced shock. Administration of LPS (10 mg/kg, ip) or ZYM (500 mg/kg, ip) to male Wistar rats decreased mean arterial pressure and increased heart rate that was associated with an increase in the activities of cyclooxygenase and nitric oxide synthase, tumour necrosis factor-α, and interleukin-8 levels, and NF-κB activation and nuclear translocation in sera and/or cardiovascular and renal tissues.

Deletion of DGCR8 in VSMCs of adult mice results in loss of vascular reactivity, reduced blood pressure and neointima formation.

DiGeorge syndrome chromosomal region 8 (DGCR8), a double-stranded-RNA-binding protein, participates in the miRNA biogenesis pathway and contributes to miRNA maturation by interacting with the RNAase III enzyme Drosha in cell nuclei. To investigate the role of DGCR8 in vascular smooth muscle cells (VSMCs) at the postnatal stages, we generated tamoxifen-inducible VSMC specific knockout (iKO) mice by crossing DGCR8 with VSMC specific tamoxifen-inducible Cre transgenic mice SMA-Cre-ER. DGCR8iKO mice display reduced body weight one month following tamoxifen treatment and died around 3 months.

Brain Cytosolic Phospholipase A2α Mediates Angiotensin II-Induced Hypertension and Reactive Oxygen Species Production in Male Mice.

Background: Recently, we reported that angiotensin II (Ang II)-induced hypertension is mediated by group IV cytosolic phospholipase A2α (cPLA2α) via production of prohypertensive eicosanoids. Since Ang II increases blood pressure (BP) via its action in the subfornical organ (SFO), it led us to investigate the expression and possible contribution of cPLA2α to oxidative stress and development of hypertension in this brain area.

Methods: Adenovirus (Ad)-green fluorescence protein (GFP) cPLA2α short hairpin (sh) RNA (Ad-cPLA2α shRNA) and its control Ad-scrambled shRNA (Ad-Scr shRNA) or Ad-enhanced cyan fluorescence protein cPLA2α DNA (Ad-cPLA2α DNA) and its control Ad-GFP DNA were transduced into SFO of cPLA2α+/+ and cPLA2α-/- male mice, respectively.

Protection by mTOR Inhibition on Zymosan-Induced Systemic Inflammatory Response and Oxidative/Nitrosative Stress: Contribution of mTOR/MEK1/ERK1/2/IKKβ/IκB-α/NF-κB Signalling Pathway.

Mammalian target of rapamycin (mTOR), a serine/threonine kinase regulate variety of cellular functions including cell growth, differentiation, cell survival, metabolism, and stress response, is now appreciated to be a central regulator of immune responses. Because mTOR inhibitors enhanced the anti-inflammatory activities of regulatory T cells and decreased the production of proinflammatory cytokines by macrophages, mTOR has been a pharmacological target for inflammatory diseases. In this study, we examined the role of mTOR in the production of proinflammatory and vasodilator mediators in zymosan-induced non-septic shock model in rats.

The role of Syk/IĸB-α/NF-ĸB pathway activation in the reversal effect of BAY 61-3606, a selective Syk inhibitor, on hypotension and inflammation in a rat model of zymosan-induced non-septic shock.

Spleen tyrosine kinase (Syk), a non-receptor tyrosine kinase, plays an important role in allergic diseases and inflammation. Syk triggers several intracellular signalling cascades including Toll-like receptor signalling to activate inflammatory responses following fungal infection but the role of this enzyme in zymosan (ZYM)-induced non-septic shock and its impacts on hypotension and inflammation in rats is not well understood. This study was conducted to determine the effects of Syk inhibition on ZYM-induced alterations in the expression and/or activities of Syk, inhibitor ĸB (IĸB)-α, and nuclear factor-ĸB (NF-ĸB) p65.