Abstract Mesp1 directs multipotential cardiovascular cell fates, even though it’s transiently induced prior to the appearance of cardiac progenitor program. Tracing Mesp1-expressing cells and their progeny allows isolation characterization earliest cells. Studying biology Mesp1-CPCs in culture ischemic disease models is an important initial step toward using them for heart treatment. Because Mesp1’s transitory nature, Mesp1-CPC lineages were traced by following EYFP expression murine Cre/+ ;...

Gravin, an A-kinase anchoring protein, targets protein kinase A (PKA), C (PKC), calcineurin and other signaling molecules to the beta2-adrenergic receptor (β2-AR). Gravin mediates desensitization/resensitization of by facilitating its phosphorylation PKA PKC. The role gravin in β-AR mediated regulation cardiac function is unclear. purpose this study was determine effect acute stimulation on contractility mice lacking functional gravin. Using echocardiographic analysis, we observed that...

Abstract Background The role of the immune system in stroke is well-recognised. Fingolimod, an immunomodulatory agent licensed for management relapsing-remitting multiple sclerosis, has been shown to provide benefit rodent models stroke. Its mechanism action, however, remains unclear. We hypothesised fingolimod increases number and/or function regulatory T cells (Treg), a lymphocyte population which promotes recovery. primary aim this study was rigorously investigate effect on Tregs mouse...

The role of dopamine D 1 -like receptors (DR) in the regulation renal Na + transporters, natriuresis, and blood pressure is well established. However, involvement angiotensin 1–7 (ANG 1−7)-Mas receptor balance not clear. present study aimed to investigate hypothesis that ANG can regulate homeostasis by modulating system. Sprague-Dawley rats were infused with saline alone (vehicle) or 1–7, antagonist A-779, DR agonist SKF38393, SCH23390. Infusion caused significant natriuresis diuresis...

Gravin, an A-kinase anchoring protein, is known to play a role in regulating key processes that lead inflammation and atherosclerosis development, namely, cell migration, proliferation, apoptosis. We investigated the of gravin development high-fat diet (HFD)-induced hyperlipidemia. Five-week-old male wild-type (WT) gravin-t/t mice were fed normal or HFD for 16 wk. Gravin-t/t showed significantly lower liver-to-body-weight ratio, cholesterol, triglyceride, very low-density lipoprotein levels...

Preclinical data indicate that fingolimod improves outcome post-ischaemia. This study used a rigorous design in normal male C57BL/6JOlaHsd mice and with common stroke comorbidities to further evaluate the translational potential of fingolimod. Stroke was induced via middle cerebral artery electrocoagulation 8-9-week old (young mice), 18 month (aged high-fat diet-fed 22-week ApoE-/- (hyperlipidaemic mice). Recovery evaluated using motor behavioural tests 3 7 days after stroke. Tissue damage...

Intracerebral haemorrhage (ICH) has no specific treatment, but accounts for up to 15% of all strokes and the highest mortality. Fingolimod (FTY720) is an immunomodulator approved management multiple sclerosis, with abundant evidence efficacy in experimental ischemic stroke, more limited ICH. The goal this study was confirm fingolimod ICH using rigorous statistically well-powered studies. induced C57BL/6JOlaHsd male female mice by intrastriatal bacterial collagenase injection. (0.5 mg/kg) or...

In this work, the sphingosine-1-phosphate receptor modulator fingolimod was assessed as a preclinical candidate for treatment of acute ischaemic stroke according to Stroke Therapy Academic Industry Roundtable (STAIR) recommendations. Young (15–17 weeks), aged (72–73 and ApoE−/- mice (20–21 weeks) fed high fat diet (all C57BL/6 mice) underwent permanent electrocoagulation left middle cerebral artery. Mice received either saline or (0.5 mg/kg 1 mg/kg) at 2-, 24-, 48-hours post-ischaemia via...

β‐adrenergic receptor (β‐AR) signaling is the primary mechanism to increase cardiac contractility. However, chronic β‐AR stimulation, which occurs in HF, results impairment of pathway, leading reduced contractility due part by desensitization these receptors. To induce contractility, β‐ARs signal through protein kinase A (PKA)‐dependent phosphorylation, affects calcium homeostasis. PKA binds A‐kinase anchoring proteins (AKAPs), localize and its substrates defined intracellular locations....

Abstract Multiple myeloma (MM) is a blood malignancy having its origin in differentiated B cells.1 The overall survival of MM patients has clearly improved with the use autologous stem cell transplantation and more recent introduction novel therapeutic strategies. However, for majority patients, disease will eventually relapse even after good initial response remains incurable. uncontrolled activation c-Myc due to translocation, mutation or alteration upstream signalling pathways common...

Atherosclerosis is a leading health problem and contributes to cardiovascular related mortality. Furthermore, hyperlipidemia major atherogenic factor.Understanding the cellular mechanisms atherosclerosis still lacking. Gravin (AKAP12), an A‐kinase anchoring protein (AKAP), scaffolds targets various signaling proteins specific intracellular locations has been implicated in mediating lipid metabolism. Thus, purpose of this study was determine whether absence gravin‐mediated would prevent...

Gravin, an A‐Kinase Anchoring Protein (AKAP) is a scaffolding protein in the heart involved modulation of cardiac contractility. Specifically, gravin scaffolds PKA, PKC, β‐arrestin and various other proteins to β 2 ‐adrenergic receptors (β ‐ARs) functions modulate contractility by mediating ‐ARs desensitization. We previously found that disruption scaffolding, using knockout (gravin‐t/t) mice, reduced hypertrophy induced chronic β‐AR stimulation with isoproterenol (ISO; 60mg/kg/day for 14...

Vascular smooth muscle cells (VSMCs), plays a crucial role in the progression of atherosclerosis response to angiotensin II (Ang II). Gravin, one A‐kinase anchoring proteins, targets protein kinase A (PKA), C (PKC), and other molecular different cellular compartments coordinates signal transduction. The purpose this study is investigate gravin mediating Ang signaling pathway VSMCs during using truncated (gravin‐t/t) mice. Our data showed that ‐induced migration proliferation was decreased...

Gravin, an A kinase anchoring protein is involved in the desensitization cycle of β2‐adrenergic receptors (β2‐ARs) upon agonist stimulation via localized scaffolding important β2‐AR pathway signaling components. Gravin scaffolds key proteins including (PKA), C and other molecules to β2‐AR. The goal this study was evaluate whether disruption PKA/gravin interaction restricts cardiac hypertrophy induced by chronic β‐AR with isoproterenol (ISO) (60mg/kg/day for 14 days) gravin knockout (t/t)...

Evidence to date suggests that a positive interaction between natriuretic factors promotes sodium excretion maintain homeostasis and blood pressure. Although the involvement of renal dopamine D1 receptor (D1R) in promoting is well established; role Angiotensin (Ang) 1-7 Mas (MasR) not clear. Here we provide evidence for functional these two G protein-coupled receptors which response Ang via MasR dependent on D1R activation. Male Sprague Dawley rats comparable weight age were infused with...

The role of angiotensin in etiology cardiovascular diseases especially hypertension is well established. Renin-angiotensin-aldosterone contributes to the development and maintenance directly by increases vascular tone renal sodium reabsorption or indirectly increasing oxidative stress inflammation. Contrary this pathological arm, (Ang) 1-7 via Mas receptors has been reported protect function although exact mechanism not yet clear. We have previously shown that leads dopamine D1 receptor...

Beta-adrenergic receptor (β-AR) desensitization culminating in impaired β-AR signaling triggers the vicious cascade of HF. Gravin; an A-kinase anchoring protein (AKAP) is crucial for β-ARs upon agonist stimulation. Our previous studies have shown that disruption gravin’s scaffolding imparts protection against isoproterenol induced HF mice. The goal this study was to further compare protective effects absence gravin standard β blocker therapy such as Carvedilol and Bisoprolol. After inducing...

Gravin (AKAP12), one of the A-Kinase-Binding-Proteins (AKAPs), serves as a scaffold protein linking β 2 -adrenergic receptor (β -AR), phosphatase 2B and several kinases including Protein Kinase A (PKA) C (PKC). The presence gravin facilitates signal transduction -AR thus affects cardiac excitation-contraction coupling. We previously showed decreased hypertrophy, increased contractility arrhythmias in gravin-KO mice, following chronic β-AR stimulation. This response was associated with...

Atherosclerosis is an inflammatory response principally in the walls of arteries contributing to cardiovascular related mortality, which can be induced by diets rich fats. Gravin (AKAP12), A‐kinase anchoring protein (AKAP), targeted specific intracellular locations with kinase A (PKA) as well other signaling molecules. It has been shown that gravin regulate cholesterol efflux and LDL receptor expression via SREBPS activation. The purpose this study was determine whether absence mediated...

Gravin, an A kinase anchoring protein (AKAP), scaffolds (PKA) and other signaling molecules to the β2-adrenergic receptor (AR). Gravin plays a vital role in desensitization of β2-AR upon agonist stimulation. The objective this study was evaluate whether disruption PKA/gravin interaction prevents cardiac hypertrophy induced by chronic β-AR stimulation correlate ventricular hemodynamics hypertrophy. Chronic wild-type (WT) gravin truncated (t/t) mutant mice with isoproterenol (ISO) (60mg/kg/day...

Gravin, an A kinase anchoring protein expressed in the myocardium, localizes (PKA), C and other signaling molecules to β2-adrenergic receptor (β2-AR). PKA modulates cardiac function by phosphorylating key substrates of excitation-contraction coupling mechanism such as troponin I, phospholamban, L-type Ca2+ channels ryanodine receptor. is activated upon agonist stimulation β-ARs, thus, purpose this study was determine whether disruption PKA/Gravin interaction would alter β-AR stimulation. WT...

Cardiac contractility is physiologically modulated primarily through beta‐adrenergic (β‐AR) receptor signaling. Beta‐adrenergic stimulation signals phosphorylation of downstream proteins such as protein kinase A (PKA). PKA substrate facilitated its co‐localization with signaling partner by A‐kinase anchoring (AKAPs). In particular, mAKAP (muscle‐selective AKAP) localizes and target substrates phosphodiesterase‐4D3 (PDE4D3). From different genomic databases, we have recently identified...

The purpose of this study was to investigate the effect knockout gravin, an A kinase anchoring protein, on regulation cardiac function by protein (PKA) and C (PKC). We measured PKA activity, PKC activity substrate phosphorylation in wild‐type (WT) gravin (KO) mice stimulated with isoproterenol (ISO; 30 mg/kg/day x 14 days). Basal significantly increased both WT KO treated ISO (WT Vehicle: 0.023±0.0041; ISO: 0.098±0.021; 0.020±0.0021; 0.069±0.0090; A.U.; p=0.0023). However, had a decreased...