Functional and molecular effects of imidazoline receptor activation in heart failure

Stabile, Angelita Maria; Aceros, H.; Stockmeyer, Kim; Abdel‐Rahman, Abdel A.; Noiseux, Nicolas; Mukaddam‐Daher, Suhayla

doi:10.1016/j.lfs.2011.01.008

Cited by 12 publications

(7 citation statements)

References 46 publications

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“…3A). This finding, which extends similar findings in hypertension and heart failure (El-Ayoubi et al, 2002; Stabile et al, 2011), might reflect a compensatory response against oxidative stress for the following reasons. First, the enhanced p38 (Fig.…”

Section: Discussionsupporting

confidence: 88%

Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats

El-Sayed

Zakaria

Abdel-Ghany

et al. 2016

European Journal of Pharmacology

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Blunted cystathionine-γ lyase (CSE) activity (reduced endogenous H2S-level) is implicated in hypertension and myocardial dysfunction in diabetes. Here, we tested the hypothesis that CSE derived H2S mediates the cardiovascular protection conferred by the imidazoline I1 receptor agonist moxonidine in a diabetic rat model. We utilized streptozotocin (STZ; 55 mg/kg i.p) to induce diabetes in male Wistar rats. Four weeks later, STZ-treated rats received vehicle, moxonidine (2 or 6 mg/kg; gavage), CSE inhibitor DL-propargylglycine, (37.5 mg/kg i.p) or DL-propargylglycine with moxonidine (6 mg/kg) for 3 weeks. Moxonidine improved the glycemic state, and reversed myocardial hypertrophy, hypertension and baroreflex dysfunction in STZ-treated rats. Ex vivo studies revealed that STZ caused reductions in CSE expression/activity, H2S and nitric oxide (NO) levels and serum adiponectin and elevations in myocardial imidazoline I1 receptor expression, p38 and extracellular signal-regulated kinase, ERK1/2, phosphorylation and lipid peroxidation (expressed as malondialdehyde). Moxonidine reversed these biochemical responses, and suppressed the expression of death associated protein kinase-3. Finally, pharmacologic CSE inhibition (DL-propargylglycine) abrogated the favorable cardiovascular, glycemic and biochemical responses elicited by moxonidine. These findings present the first evidence for a mechanistic role for CSE derived H2S in the glycemic control and in the favorable cardiovascular effects conferred by imidazoline I1 receptor activation (moxonidine) in a diabetic rat model.

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Section: Discussionsupporting

confidence: 88%

Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats

El-Sayed

Zakaria

Abdel-Ghany

et al. 2016

European Journal of Pharmacology

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“…In this trial, the sympathetic activity was probably inhibited too much in patients who, at this advanced stage, require sympathetic activity (Cohn et al, 2003;Pocock et al, 2004). In the hamster model of cardiomyopathy, moxonidine improved cardiac performance by both central and direct cardiac sympathoinhibitory actions (Stabile et al, 2011). The same team showed that moxonidine prevents left ventricular hypertrophy and cardiac remodeling in hypertensive rats and in hamsters with cardiomyopathy (Mukaddam-Daher, 2012).…”

Section: Imidazoline Subtype 1 Receptors and In Vivo Effectsmentioning

confidence: 95%

Imidazoline Receptor System: The Past, the Present, and the Future

et al. 2019

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“…Baseline (pretreatment) and 2 week echocardiographic assessments of left ventricular (LV) anatomy and function were performed under 2% isoflurane anaesthesia as previously described (Aceros et al ., ; Stabile et al ., ) using a Sonos 5500 Imaging System (Philips, Philips Healthcare, Andover, MA, USA) with a 12 MHz transducer. An M‐mode tracing of the LV cavity allowed measurements of LV end‐diastolic and end‐systolic diameters (EDD and ESD respectively).…”

Section: Methodsmentioning

confidence: 99%

Celastrol protects ischaemic myocardium through a heat shock response with up‐regulation of haeme oxygenase‐1

Sarkissian

Cailhier

Borie

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSECelastrol, a triterpene from plants, has been used in traditional oriental medicine to treat various diseases. Here, we investigated the cardioprotective effects of celastrol against ischaemia. EXPERIMENTAL APPROACHProtective pathways induced by celastrol were investigated in hypoxic cultures of H9c2 rat cardiomyoblasts and in a rat model of myocardial infarction, assessed with echocardiographic and histological analysis. KEY RESULTSIn H9c2 cells, celastrol triggered reactive oxygen species (ROS) formation within minutes, induced nuclear translocation of the transcription factor heat shock factor 1 (HSF1) resulting in a heat shock response (HSR) leading to increased expression of heat shock proteins (HSPs). ROS scavenger N-acetylcysteine reduced expression of HSP70 and HSP32 (haeme oxygenase-1, HO-1). Celastrol improved H9c2 survival under hypoxic stress, and functional analysis revealed HSF1 and HO-1 as key effectors of the HSR, induced by celastrol, in promoting cytoprotection. In the rat ischaemic myocardium, celastrol treatment improved cardiac function and reduced adverse left ventricular remodelling at 14 days. Celastrol triggered expression of cardioprotective HO-1 and inhibited fibrosis and infarct size. In the peri-infarct area, celastrol reduced myofibroblast and macrophage infiltration, while attenuating up-regulation of TGF-β and collagen genes. CONCLUSIONS AND IMPLICATIONSCelastrol treatment induced an HSR through activation of HSF1 with up-regulation of HO-1 as the key effector, promoting cardiomyocyte survival, reduction of injury and adverse remodelling with preservation of cardiac function. Celastrol may represent a novel potent pharmacological cardioprotective agent mimicking ischaemic conditioning that could have a valuable impact in the treatment of myocardial infarction. AbbreviationsALT, alanine transaminase; AST, aspartate aminotransferase; EDD, end-diastolic diameter; EDV, end-diastolic volume; ESD, end-systolic diameter; ESV, end-systolic volume; GGT, γ-glutamyl transpeptidase; HO-1, haeme oxygenase-1; HPS, haematoxylin phloxine saffron; HSF1, heat shock factor 1; HSPs, heat shock proteins; HSR, heat shock response; LV, left ventricular; LVAW, left ventricular anterior wall; LVEF, left ventricular ejection fraction; LVFS, left ventricular fractional shortening; MI, myocardial infarction; NAC, N-acetylcysteine; ROS, reactive oxygen species; SV, stroke volume; TNT, troponin T; ZnPP-9, zinc protoporphyrin-9

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Functional and molecular effects of imidazoline receptor activation in heart failure

Cited by 12 publications

References 46 publications

Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats

Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats

Imidazoline Receptor System: The Past, the Present, and the Future

Celastrol protects ischaemic myocardium through a heat shock response with up‐regulation of haeme oxygenase‐1

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