Impaired border zone formation and adverse remodeling after reperfused myocardial infarction in cannabinoid CB2 receptor deficient mice

Duerr, Georg Daniel; Heinemann, Jan C.; Gestrich, Christopher; Heuft, Tobias; Klaas, Timo; Keppel, Katharina; Roell, Wilhelm; Klein, Annette; Zimmer, Andreas; Velten, Markus; Kilić, Ana; Bîndilă, Laura; Lutz, Beat; Dewald, Oliver

doi:10.1016/j.lfs.2014.11.005

Cited by 27 publications

(30 citation statements)

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“…Further studies of remodeling processes in reperfused infarction in the CB2 −/− mice again confirmed the cardioprotective role of this receptor subtype [54]. In contrast to a rapid formation of granulation tissue and a compacted non-transmural scar in wild-type mice after 7 days of reperfusion, CB2 −/− mice showed a non-compacted transmural scar and a significantly worse cardiac function.…”

Section: Cb2 Receptor Knockout Mice (Cb2 −/− )mentioning

confidence: 60%

“…To begin with, circulating levels of endocannabinoids were elevated after cardiac injury, such as myocardial infarction in the rat [27] and ischemia/reperfusion in mice [28]. The CB2 receptors were upregulated in ischemic cardiomyocytes [28] and in cardiomyocytes following cultivation under hypoxia [29].…”

Section: Endocannabinoids and Cannabinoid Receptors In The Heartmentioning

confidence: 99%

“…In contrast to a rapid formation of granulation tissue and a compacted non-transmural scar in wild-type mice after 7 days of reperfusion, CB2 −/− mice showed a non-compacted transmural scar and a significantly worse cardiac function. Adverse myocardial remodeling in CB2 −/− mice has been associated with macrophage infiltration and low induction of tenascin C, collagen-Iα, or lysil oxidase [54].…”

Section: Cb2 Receptor Knockout Mice (Cb2 −/− )mentioning

confidence: 99%

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Cannabinoid CB1/CB2 Receptors in the Heart: Expression, Regulation, and Function

Kaschina¹

2016

Cannabinoids in Health and Disease

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Endocannabinoids exert their actions in the heart and vessels, at least in part, by stimulating the cannabinoid CB and the CB receptor subtypes which belong to a group of seven transmembrane-spanning receptors and are coupled to Gi/o-proteins. Activation of cardiovascular CB receptors leads to depressed cardiac contractility and hypotension. Conversely, in most studies, the CB receptor antagonists are cardioprotective against ischemia reperfusion injury, myocardial ischemia, heart failure, and cardiomyopathies. Evidence to date indicates that CB receptor activation is cardioprotective. CB receptor-mediated effects such as anti-inflammation and anti-fibrosis may be in part opposite to the actions of the CB receptor. The aim of this review is to up-date on recent experimental findings and controversies on the role of endocannabinoid system in the myocardial injury with emphasis on pathophysiological processes such as left ventricular remodeling, cardiac fibrosis, hypertrophy, and endothelial dysfunction. Recent experimental studies employing genetic deficiency of CB and CB receptors and endocannabinoid anandamide metabolizing enzymes are reviewed. Moreover, the protective mechanisms which are mediated by cannabinoid receptors during ischemic preconditioning as well as in the early and late phase after myocardial infarction are discussed in the context of possible therapeutic implications.Keywords: cannabinoid receptors, CB , CB , heart, myocardial infarction, heart remodeling . IntroductionEndocannabinoids, its degrading enzymes and the cannabinoid CB and CB receptors are present in rodent and human cardiovascular tissues. In addition to its role in the control of the central nervous system, the endocannabinoid system ECS may play a pivotal part in cardiovascular regulation by heart diseases reviewed in [ -] .In normal physiological conditions, ECS is not highly regulated. However, by cardiovascular pathologies, this system is activated and may reflect a protective response which limits cardiac injury. Activated ECS has been implicated in acute cardiovascular conditions such as hemorrhagic, septic, and cardiogenic shock as well as in chronic diseases such as coronary heart disease, heart failure, and cardiomyopathy.Endocannabinoids exert their actions in the heart and vessels, at least in part, by stimulating the cannabinoid CB and the CB receptor subtypes which belong to a group of seven transmembrane-spanning receptors and are coupled to Gi/o-proteins [ , ]. Signaling through the CB receptor elicits hypotension, bradycardia, and negative inotropy [ ]. Moreover, this receptor subtype is implicated in inflammation, apoptosis, oxidative stress [ ], and metabolic dysregulation [ ], thereby contributing to tissue injury. The CB receptors, on the contrary, may play a compensatory anti-inflammatory, anti-oxidative, and anti-atherogenic role [ , ] contributing to cardiovascular protection.Nevertheless, the role of cannabinoid receptors in the heart under several pathological conditions remains controversial. ...

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Section: Cb2 Receptor Knockout Mice (Cb2 −/− )mentioning

confidence: 60%

Section: Endocannabinoids and Cannabinoid Receptors In The Heartmentioning

confidence: 99%

Section: Cb2 Receptor Knockout Mice (Cb2 −/− )mentioning

confidence: 99%

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Cannabinoid CB1/CB2 Receptors in the Heart: Expression, Regulation, and Function

Kaschina¹

2016

Cannabinoids in Health and Disease

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“…The MIinduced changes in the expression of endocannabinoid 2-AG synthesizing and metabolizing enzymes were comparable in both WT and CB2-/-mice. Given that global CB2 deficiency per se has multiple effects on cardiac healing responses, [6][7][8][9] we subsequently focused only on WT mice to study the consequences of pharmacological MAGL inhibition on acute post-MI inflammation and healing.…”

Section: Discussionmentioning

confidence: 99%

“…5 CB2 deficiency in mice (CB2-/-) leads to exaggerated myocardial ischemia-reperfusion injury and unfavorable post-myocardial infarction (MI) healing. [6][7][8][9] The beneficial effects of CB2 signaling in this setting involve cardioprotective mechanisms as well as anti-fibrotic and anti-inflammatory effects. 6,7,10 CB2 is most abundantly expressed on immune cells, including myeloid cells.…”

Section: Introductionmentioning

confidence: 99%

2-Arachidonoylglycerol mobilizes myeloid cells and worsens heart function after acute myocardial infarction

Schloss¹,

Horckmans

Guillamat-Prats³

et al. 2018

Cardiovascular Research

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Aims Myocardial infarction (MI) leads to an enhanced release of endocannabinoids and a massive accumulation of neutrophils and monocytes within the ischaemic myocardium. These myeloid cells originate from haematopoietic precursors in the bone marrow and are rapidly mobilized in response to MI. We aimed to determine whether endocannabinoid signalling is involved in myeloid cell mobilization and cardiac recruitment after ischaemia onset. Methods and results Intravenous administration of endocannabinoid 2-arachidonoylglycerol (2-AG) into wild type (WT) C57BL6 mice induced a rapid increase of blood neutrophil and monocyte counts as measured by flow cytometry. This effect was blunted when using cannabinoid receptor 2 knockout mice. In response to MI induced in WT mice, the lipidomic analysis revealed significantly elevated plasma and cardiac levels of the endocannabinoid 2-AG 24 h after infarction, but no changes in anandamide, palmitoylethanolamide, and oleoylethanolamide. This was a consequence of an increased expression of 2-AG synthesizing enzyme diacylglycerol lipase and a decrease of metabolizing enzyme monoacylglycerol lipase (MAGL) in infarcted hearts, as determined by quantitative RT–PCR analysis. The opposite mRNA expression pattern was observed in bone marrow. Pharmacological blockade of MAGL with JZL184 and thus increased systemic 2-AG levels in WT mice subjected to MI resulted in elevated cardiac CXCL1, CXCL2, and MMP9 protein levels as well as higher cardiac neutrophil and monocyte counts 24 h after infarction compared with vehicle-treated mice. Increased post-MI inflammation in these mice led to an increased infarct size, an impaired ventricular scar formation assessed by histology and a worsened cardiac function in echocardiography evaluations up to 21 days. Likewise, JZL184-administration in a myocardial ischaemia-reperfusion model increased cardiac myeloid cell recruitment and resulted in a larger fibrotic scar size. Conclusion These findings suggest that changes in endocannabinoid gradients due to altered tissue levels contribute to myeloid cell recruitment from the bone marrow to the infarcted heart, with crucial consequences on cardiac healing and function.

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Genetic Manipulation of the Endocannabinoid System

Zimmer

2015

Handbook of Experimental Pharmacology

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The physiological and pathophysiological functions of the endocannabinoid system have been studied extensively using transgenic and targeted knockout mouse models. The first gene deletions of the cannabinoid CB(1) receptor were described in the late 1990s, soon followed by CB(2) and FAAH mutations in early 2000. These mouse models helped to elucidate the fundamental role of endocannabinoids as retrograde transmitters in the CNS and in the discovery of many unexpected endocannabinoid functions, for example, in the skin, bone and liver. We now have knockout mouse models for almost every receptor and enzyme of the endocannabinoid system. Conditional mutant mice were mostly developed for the CB(1) receptor, which is widely expressed on many different neurons, astrocytes and microglia, as well as on many cells outside the CNS. These mouse strains include "floxed" CB(1) alleles and mice with a conditional re-expression of CB(1). The availability of these mice made it possible to decipher the function of CB(1) in specific neuronal circuits and cell populations or to discriminate between central and peripheral effects. Many of the genetic mouse models were also used in combination with viral expression systems. The purpose of this review is to provide a comprehensive overview of the existing genetic models and to summarize some of the most important discoveries that were made with these animals.

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Impaired border zone formation and adverse remodeling after reperfused myocardial infarction in cannabinoid CB2 receptor deficient mice

Cited by 27 publications

References 28 publications

Cannabinoid CB1/CB2 Receptors in the Heart: Expression, Regulation, and Function

Cannabinoid CB1/CB2 Receptors in the Heart: Expression, Regulation, and Function

2-Arachidonoylglycerol mobilizes myeloid cells and worsens heart function after acute myocardial infarction

Genetic Manipulation of the Endocannabinoid System

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